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Journal articles on the topic 'Protein amyloid fibril'
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1
Dean, Dexter N., and Jennifer C. Lee. "Modulating functional amyloid formation via alternative splicing of the premelanosomal protein PMEL17." Journal of Biological Chemistry 295, no. 21 (April 10, 2020): 7544–53. http://dx.doi.org/10.1074/jbc.ra120.013012.
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The premelanosomal protein (PMEL17) forms functional amyloid fibrils involved in melanin biosynthesis. Multiple PMEL17 isoforms are produced, two of which arise from excision of a cryptic intron within the amyloid-forming repeat (RPT) domain, leading to long (lRPT) and short (sRPT) isoforms with 10 and 7 imperfect repeats, respectively. Both lRPT and sRPT isoforms undergo similar pH-dependent mechanisms of amyloid formation and fibril dissolution. Here, using human PMEL17, we tested the hypothesis that the minor, but more aggregation-prone, sRPT facilitates amyloid formation of lRPT. We observed that cross-seeding by sRPT fibrils accelerates the rate of lRPT aggregation, resulting in propagation of an sRPT-like twisted fibril morphology, unlike the rodlike structure that lRPT normally adopts. This templating was specific, as the reversed reaction inhibited sRPT fibril formation. Despite displaying ultrastructural differences, self- and cross-seeded lRPT fibrils had a similar β-sheet structured core, revealed by Raman spectroscopy, limited-proteolysis, and fibril disaggregation experiments, suggesting the fibril twist is modulated by N-terminal residues outside the amyloid core. Interestingly, bioinformatics analysis of PMEL17 homologs from other mammals uncovered that long and short RPT isoforms are conserved among members of this phylogenetic group. Collectively, our results indicate that the short isoform of RPT serves as a “nucleator” of PMEL17 functional amyloid formation, mirroring how bacterial functional amyloids assemble during biofilm formation. Whereas bacteria regulate amyloid assembly by using individual genes within the same operon, we propose that the modulation of functional amyloid formation in higher organisms can be accomplished through alternative splicing.
2
Šneideris, Tomas, Lina Baranauskienė, Jonathan G. Cannon, Rasa Rutkienė, Rolandas Meškys, and Vytautas Smirnovas. "Looking for a generic inhibitor of amyloid-like fibril formation among flavone derivatives." PeerJ 3 (September 24, 2015): e1271. http://dx.doi.org/10.7717/peerj.1271.
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A range of diseases is associated with amyloid fibril formation. Despite different proteins being responsible for each disease, all of them share similar features including beta-sheet-rich secondary structure and fibril-like protein aggregates. A number of proteins can form amyloid-like fibrilsin vitro, resembling structural features of disease-related amyloids. Given these generic structural properties of amyloid and amyloid-like fibrils, generic inhibitors of fibril formation would be of interest for treatment of amyloid diseases. Recently, we identified five outstanding inhibitors of insulin amyloid-like fibril formation among the pool of 265 commercially available flavone derivatives. Here we report testing of these five compounds and of epi-gallocatechine-3-gallate (EGCG) on aggregation of alpha-synuclein and beta-amyloid. We used a Thioflavin T (ThT) fluorescence assay, relying on halftimes of aggregation as the measure of inhibition. This method avoids large numbers of false positive results. Our data indicate that four of the five flavones and EGCG inhibit alpha-synuclein aggregation in a concentration-dependent manner. However none of these derivatives were able to increase halftimes of aggregation of beta-amyloid.
3
Buell, Alexander K. "The growth of amyloid fibrils: rates and mechanisms." Biochemical Journal 476, no. 19 (October 11, 2019): 2677–703. http://dx.doi.org/10.1042/bcj20160868.
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Abstract Amyloid fibrils are β-sheet-rich linear protein polymers that can be formed by a large variety of different proteins. These assemblies have received much interest in recent decades, due to their role in a range of human disorders. However, amyloid fibrils are also found in a functional context, whereby their structural, mechanical and thermodynamic properties are exploited by biological systems. Amyloid fibrils form through a nucleated polymerisation mechanism with secondary processes acting in many cases to amplify the number of fibrils. The filamentous nature of amyloid fibrils implies that the fibril growth rate is, by several orders of magnitude, the fastest step of the overall aggregation reaction. This article focusses specifically on in vitro experimental studies of the process of amyloid fibril growth, or elongation, and summarises the state of knowledge of its kinetics and mechanisms. This work attempts to provide the most comprehensive summary, to date, of the available experimental data on amyloid fibril elongation rate constants and the temperature and concentration dependence of amyloid fibril elongation rates. These data are compared with those from other types of protein polymers. This comparison with data from other polymerising proteins is interesting and relevant because many of the basic ideas and concepts discussed here were first introduced for non-amyloid protein polymers, most notably by the Japanese school of Oosawa and co-workers for cytoskeletal filaments.
4
Waterhouse, Sarah H., and Juliet A. Gerrard. "Amyloid Fibrils in Bionanotechnology." Australian Journal of Chemistry 57, no. 6 (2004): 519. http://dx.doi.org/10.1071/ch04070.
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An amyloid fibril is a highly ordered, insoluble form of protein that results when a normally soluble protein aggregates via a self-association process to form a structured nanotube. Such fibrils can now be routinely generated from purified proteins in the laboratory, and have attracted burgeoning interest due to their role in a variety of disease states. This article focusses on a new alternative direction in amyloid research, exploring the potential application of the amyloid fibril as a form of nanotubular scaffolding in bionanotechnology.
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Stepanenko, Olga V., Maksim I. Sulatsky, Ekaterina V. Mikhailova, Olesya V. Stepanenko, Irina M. Kuznetsova, Konstantin K. Turoverov, and Anna I. Sulatskaya. "Trypsin Induced Degradation of Amyloid Fibrils." International Journal of Molecular Sciences 22, no. 9 (May 2, 2021): 4828. http://dx.doi.org/10.3390/ijms22094828.
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Proteolytic enzymes are known to be involved in the formation and degradation of various monomeric proteins, but the effect of proteases on the ordered protein aggregates, amyloid fibrils, which are considered to be extremely stable, remains poorly understood. In this work we study resistance to proteolytic degradation of lysozyme amyloid fibrils with two different types of morphology and beta-2-microglobulun amyloids. We showed that the proteolytic enzyme of the pancreas, trypsin, induced degradation of amyloid fibrils, and the mechanism of this process was qualitatively the same for all investigated amyloids. At the same time, we found a dependence of efficiency and rate of fibril degradation on the structure of the amyloid-forming protein as well as on the morphology and clustering of amyloid fibrils. It was assumed that the discovered relationship between fibrils structure and the efficiency of their degradation by trypsin can become the basis of a new express method for the analysis of amyloids polymorphism. Unexpectedly lower resistance of both types of lysozyme amyloids to trypsin exposure compared to the native monomeric protein (which is not susceptible to hydrolysis) was attributed to the higher availability of cleavage sites in studied fibrils. Another intriguing result of the work is that the cytotoxicity of amyloids treated with trypsin was not only failing to decline, but even increasing in the case of beta-2-microglobulin fibrils.
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Lempart, Justine, Eric Tse, James A. Lauer, Magdalena I. Ivanova, Alexandra Sutter, Nicholas Yoo, Philipp Huettemann, Daniel Southworth, and Ursula Jakob. "Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity." Life Science Alliance 2, no. 5 (September 18, 2019): e201900486. http://dx.doi.org/10.26508/lsa.201900486.
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The universally abundant polyphosphate (polyP) accelerates fibril formation of disease-related amyloids and protects against amyloid cytotoxicity. To gain insights into the mechanism(s) by which polyP exerts these effects, we focused on α-synuclein, a well-studied amyloid protein, which constitutes the major component of Lewy bodies found in Parkinson’s disease. Here, we demonstrate that polyP is unable to accelerate the rate-limiting step of α-synuclein fibril formation but effectively nucleates fibril assembly once α-synuclein oligomers are formed. Binding of polyP to α-synuclein either during fibril formation or upon fibril maturation substantially alters fibril morphology and effectively reduces the ability of α-synuclein fibrils to interact with cell membranes. The effect of polyP appears to be α-synuclein fibril specific and successfully prevents the uptake of fibrils into neuronal cells. These results suggest that altering the polyP levels in the extracellular space might be a potential therapeutic strategy to prevent the spreading of the disease.
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Bondarev, Stanislav, Kirill Antonets, Andrey Kajava, Anton Nizhnikov, and Galina Zhouravleva. "Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification." International Journal of Molecular Sciences 19, no. 8 (August 4, 2018): 2292. http://dx.doi.org/10.3390/ijms19082292.
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Amyloids are unbranched protein fibrils with a characteristic spatial structure. Although the amyloids were first described as protein deposits that are associated with the diseases, today it is becoming clear that these protein fibrils play multiple biological roles that are essential for different organisms, from archaea and bacteria to humans. The appearance of amyloid, first of all, causes changes in the intracellular quantity of the corresponding soluble protein(s), and at the same time the aggregate can include other proteins due to different molecular mechanisms. The co-aggregation may have different consequences even though usually this process leads to the depletion of a functional protein that may be associated with different diseases. The protein co-aggregation that is related to functional amyloids may mediate important biological processes and change of protein functions. In this review, we survey the known examples of the amyloid-related co-aggregation of proteins, discuss their pathogenic and functional roles, and analyze methods of their studies from bacteria and yeast to mammals. Such analysis allow for us to propose the following co-aggregation classes: (i) titration: deposition of soluble proteins on the amyloids formed by their functional partners, with such interactions mediated by a specific binding site; (ii) sequestration: interaction of amyloids with certain proteins lacking a specific binding site; (iii) axial co-aggregation of different proteins within the same amyloid fibril; and, (iv) lateral co-aggregation of amyloid fibrils, each formed by different proteins.
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Xu, Sherry C. S., Josephine G. LoRicco, Anthony C. Bishop, Nathan A. James, Welby H. Huynh, Scott A. McCallum, Nadia R. Roan, and George I. Makhatadze. "Sequence-independent recognition of the amyloid structural motif by GFP protein family." Proceedings of the National Academy of Sciences 117, no. 36 (August 24, 2020): 22122–27. http://dx.doi.org/10.1073/pnas.2001457117.
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Cnidarian fluorescent protein (FP) derivatives such as GFP, mCherry, and mEOS2 have been widely used to monitor gene expression and protein localization through biological imaging because they are considered functionally inert. We demonstrate that FPs specifically bind amyloid fibrils formed from many natural peptides and proteins. FPs do not bind other nonamyloid fibrillar structures such as microtubules or actin filaments and do not bind to amorphous aggregates. FPs can also bind small aggregates formed during the lag phase and early elongation phase of fibril formation and can inhibit amyloid fibril formation in a dose-dependent manner. These findings suggest caution should be taken in interpreting FP-fusion protein localization data when amyloid structures may be present. Given the pathological significance of amyloid-related species in some diseases, detection and inhibition of amyloid fibril formation using FPs can provide insights on developing diagnostic tools.
9
Pepys, M. B. "Pathogenesis, diagnosis and treatment of systemic amyloidosis." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1406 (February 28, 2001): 203–11. http://dx.doi.org/10.1098/rstb.2000.0766.
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Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that disrupt tissue structure and cause disease. Although about 20 different unrelated proteins can form amyloid fibrils in vivo , all such fibrils share a common cross–β core structure. Some natural wild–type proteins are inherently amyloidogenic, form fibrils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino–acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the fibrils, amyloid deposits always contain the non–fibrillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes specific calcium–dependent binding to amyloid fibrils. SAP contributes to amyloidogenesis, probably by stabilizing amyloid fibrils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, specific, non–invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid fibril precursor proteins leads to regression of amyloid deposits with clinical benefit. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end–stage organ failure by dialysis or transplantation, and vigorous efforts to control underlying conditions responsible for production of fibril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of fibrillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid fibril clearance in vivo .
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Trusova, Valeriya, Olga Zhytniakivska, Uliana Tarabara, Kateryna Vus, and Galyna Gorbenko. "Interactions of Fibrillar Insulin with Proteins: A Molecular Docking Study." 2, no. 2 (June 2, 2022): 133–40. http://dx.doi.org/10.26565/2312-4334-2022-2-17.
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During the last decades growing attention has been paid to ascertaining the factors responsible for the toxic potential of particular protein aggregates, amyloid fibrils, whose formation is associated with a range of human pathologies, including the neurodegenerative diseases, systemic amyloidosis, type II diabetes, etc. Despite significant progress in elucidating the mechanisms of cytotoxic action of amyloid fibrils, the role of fibril-protein interactions in determining the amyloid toxicity remains poorly understood. In view of this, in the present study the molecular docking techniques has been employed to investigate the interactions between the insulin amyloid fibrils (InsF) and three biologically important multifunctional proteins, viz. serum albumin, lysozyme and insulin in their native globular state. Using the ClusPro, HDOCK, PatchDock and COCOMAPS web servers, along with BIOVIA Discovery Studio software, the structural characteristics of fibril-protein complexes such as the number of interacting amino acid residues, the amount of residues at fibril and protein interfaces, the contributions of various kinds of interactions, buried area upon the complex formation, etc. It was found that i) hydrophilic-hydrophilic and hydrophilic-hydrophobic interactions play dominating role in the formation of fibril-protein complexes; ii) there is no significant differences between the investigated proteins in the number of fibrillar interacting residues; iii) the dominating hydrogen bond forming residues are represented by glutamine and asparagine in fibrillar insulin, lysine in serum albumin and arginine in lysozyme; iv) polar buried area exceeds the nonpolar one upon the protein complexation with the insulin fibrils. The molecular docking evidence for the localization of phosphonium fluorescent dye TDV at the fibril-protein interface was obtained.
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Raman, Bakthisaran, Tadato Ban, Miyo Sakai, Saloni Y. Pasta, Tangirala Ramakrishna, Hironobu Naiki, Yuji Goto, and Ch Mohan Rao. "αB-crystallin, a small heat-shock protein, prevents the amyloid fibril growth of an amyloid β-peptide and β2-microglobulin." Biochemical Journal 392, no. 3 (December 6, 2005): 573–81. http://dx.doi.org/10.1042/bj20050339.
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αB-crystallin, a small heat-shock protein, exhibits molecular chaperone activity. We have studied the effect of αB-crystallin on the fibril growth of the Aβ (amyloid β)-peptides Aβ-(1–40) and Aβ-(1–42). αB-crystallin, but not BSA or hen egg-white lysozyme, prevented the fibril growth of Aβ-(1–40), as revealed by thioflavin T binding, total internal reflection fluorescence microscopy and CD spectroscopy. Comparison of the activity of some mutants and chimaeric α-crystallins in preventing Aβ-(1–40) fibril growth with their previously reported chaperone ability in preventing dithiothreitol-induced aggregation of insulin suggests that there might be both common and distinct sites of interaction on α-crystallin involved in the prevention of amorphous aggregation of insulin and fibril growth of Aβ-(1–40). αB-crystallin also prevents the spontaneous fibril formation (without externally added seeds) of Aβ-(1–42), as well as the fibril growth of Aβ-(1–40) when seeded with the Aβ-(1–42) fibril seed. Sedimentation velocity measurements show that αB-crystallin does not form a stable complex with Aβ-(1–40). The mechanism by which it prevents the fibril growth differs from the known mechanism by which it prevents the amorphous aggregation of proteins. αB-crystallin binds to the amyloid fibrils of Aβ-(1–40), indicating that the preferential interaction of the chaperone with the fibril nucleus, which inhibits nucleation-dependent polymerization of amyloid fibrils, is the mechanism that is predominantly involved. We found that αB-crystallin prevents the fibril growth of β2-microglobulin under acidic conditions. It also retards the depolymerization of β2-microglobulin fibrils, indicating that it can interact with the fibrils. Our study sheds light on the role of small heat-shock proteins in protein conformational diseases, particularly in Alzheimer's disease.
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Karunarathne, Kanchana, Nabila Bushra, Olivia Williams, Imad Raza, Laura Tirado, Diane Fakhre, Fadia Fakhre, and Martin Muschol. "Self-Assembly of Amyloid Fibrils Into 3D Gel Clusters Versus 2D Sheets." Biomolecules 13, no. 2 (January 24, 2023): 230. http://dx.doi.org/10.3390/biom13020230.
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The deposition of dense fibril plaques represents the pathological hallmark for a multitude of human disorders, including many neurodegenerative diseases. Fibril plaques are predominately composed of amyloid fibrils, characterized by their underlying cross beta-sheet architecture. Research into the mechanisms of amyloid formation has mostly focused on characterizing and modeling the growth of individual fibrils and associated oligomers from their monomeric precursors. Much less is known about the mechanisms causing individual fibrils to assemble into ordered fibrillar suprastructures. Elucidating the mechanisms regulating this “secondary” self-assembly into distinct suprastructures is important for understanding how individual protein fibrils form the prominent macroscopic plaques observed in disease. Whether and how amyloid fibrils assemble into either 2D or 3D supramolecular structures also relates to ongoing efforts on using amyloid fibrils as substrates or scaffolds for self-assembling functional biomaterials. Here, we investigated the conditions under which preformed amyloid fibrils of a lysozyme assemble into larger superstructures as a function of charge screening or pH. Fibrils either assembled into three-dimensional gel clusters or two-dimensional fibril sheets. The latter displayed optical birefringence, diagnostic of amyloid plaques. We presume that pH and salt modulate fibril charge repulsion, which allows anisotropic fibril–fibril attraction to emerge and drive the transition from 3D to 2D fibril self-assembly.
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Watanabe-Nakayama, Takahiro, Kenjiro Ono, Masahiro Itami, Ryoichi Takahashi, David B. Teplow, and Masahito Yamada. "High-speed atomic force microscopy reveals structural dynamics of amyloid β1–42 aggregates." Proceedings of the National Academy of Sciences 113, no. 21 (May 9, 2016): 5835–40. http://dx.doi.org/10.1073/pnas.1524807113.
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Aggregation of amyloidogenic proteins into insoluble amyloid fibrils is implicated in various neurodegenerative diseases. This process involves protein assembly into oligomeric intermediates and fibrils with highly polymorphic molecular structures. These structural differences may be responsible for different disease presentations. For this reason, elucidation of the structural features and assembly kinetics of amyloidogenic proteins has been an area of intense study. We report here the results of high-speed atomic force microscopy (HS-AFM) studies of fibril formation and elongation by the 42-residue form of the amyloid β-protein (Aβ1–42), a key pathogenetic agent of Alzheimer's disease. Our data demonstrate two different growth modes of Aβ1–42, one producing straight fibrils and the other producing spiral fibrils. Each mode depends on initial fibril nucleus structure, but switching from one growth mode to another was occasionally observed, suggesting that fibril end structure fluctuated between the two growth modes. This switching phenomenon was affected by buffer salt composition. Our findings indicate that polymorphism in fibril structure can occur after fibril nucleation and is affected by relatively modest changes in environmental conditions.
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Ferreira, Elisabete, Zaida L. Almeida, Pedro F. Cruz, Marta Silva e Sousa, Paula Veríssimo, and Rui M. M. Brito. "Searching for the Best Transthyretin Aggregation Protocol to Study Amyloid Fibril Disruption." International Journal of Molecular Sciences 23, no. 1 (December 30, 2021): 391. http://dx.doi.org/10.3390/ijms23010391.
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Several degenerative amyloid diseases, with no fully effective treatment, affect millions of people worldwide. These pathologies—amyloidoses—are known to be associated with the formation of ordered protein aggregates and highly stable and insoluble amyloid fibrils, which are deposited in multiple tissues and organs. The disruption of preformed amyloid aggregates and fibrils is one possible therapeutic strategy against amyloidosis; however, only a few compounds have been identified as possible fibril disruptors in vivo to date. To properly identify chemical compounds as potential fibril disruptors, a reliable, fast, and economic screening protocol must be developed. For this purpose, three amyloid fibril formation protocols using transthyretin (TTR), a plasma protein involved in several amyloidoses, were studied using thioflavin-T fluorescence assays, circular dichroism (CD), turbidity, dynamic light scattering (DLS), and transmission electron microscopy (TEM), in order to characterize and select the most appropriate fibril formation protocol. Saturation transfer difference nuclear magnetic resonance spectroscopy (STD NMR) was successfully used to study the interaction of doxycycline, a known amyloid fibril disruptor, with preformed wild-type TTR (TTRwt) aggregates and fibrils. DLS and TEM were also used to characterize the effect of doxycycline on TTRwt amyloid species disaggregation. A comparison of the TTR amyloid morphology formed in different experimental conditions is also presented.
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Hasanbašić, Samra, Alma Jahić, Selma Berbić, Magda Tušek Žnidarič, and Eva Žerovnik. "Inhibition of Protein Aggregation by Several Antioxidants." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/8613209.
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Amyloid fibril formation is a shared property of all proteins; therefore, model proteins can be used to study this process. We measured protein aggregation of the model amyloid-forming protein stefin B in the presence and absence of several antioxidants. Amyloid fibril formation by stefin B was routinely induced at pH 5 and 10% TFE, at room temperature. The effects of antioxidants NAC, vitamin C, vitamin E, and the three polyphenols resveratrol, quercetin, and curcumin on the kinetics of fibril formation were followed using ThT fluorescence. Concomitantly, the morphology and amount of the aggregates and fibrils were checked by transmission electron microscopy (TEM). The concentration of the antioxidants was varied, and it was observed that different modes of action apply at low or high concentrations relative to the binding constant. In order to obtain more insight into the possible mode of binding, docking of NAC, vitamin C, and all three polyphenols was done to the monomeric form of stefin B.
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Ziaunys, Mantas, Tomas Sneideris, and Vytautas Smirnovas. "Exploring the potential of deep-blue autofluorescence for monitoring amyloid fibril formation and dissociation." PeerJ 7 (August 16, 2019): e7554. http://dx.doi.org/10.7717/peerj.7554.
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Protein aggregation into amyloid fibrils has been linked to multiple neurodegenerative disorders. Determining the kinetics of fibril formation, as well as their structural stability are important for the mechanistic understanding of amyloid aggregation. Tracking both fibril association and dissociation is usually performed by measuring light scattering of the solution or fluorescence of amyloid specific dyes, such as thioflavin-T. A possible addition to these methods is the recently discovered deep-blue autofluorescence (dbAF), which is linked to amyloid formation. In this work we explore the potential of this phenomenon to monitor amyloid fibril formation and dissociation, as well as show its possible relation to fibril size rather than amyloid structure.
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Belashova, Tatyana A., Anna A. Valina, Evgeniy I. Sysoev, Maria E. Velizhanina, Andrew A. Zelinsky, and Alexey P. Galkin. "Search and Identification of Amyloid Proteins." Methods and Protocols 6, no. 1 (February 4, 2023): 16. http://dx.doi.org/10.3390/mps6010016.
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Amyloids are fibrillar proteins with a cross-β structure. Pathological amyloids are associated with the development of a number of incurable diseases, while functional amyloids regulate vital processes. The detection of unknown amyloids in living objects is a difficult task, and therefore the question of the prevalence and biological significance of amyloids remains open. We present a description of two methods, the combination of which makes it possible to find and identify amyloid proteins in the proteome of various organisms. The method of proteomic screening for amyloids allows the detection of the proteins that form SDS-resistant aggregates. SDS resistance is a general feature of amyloid fibrils. Protein aggregates resistant to SDS treatment can be collected by ultracentrifugation and further identified by mass spectrometry. However, in addition to amyloids, SDS-resistant aggregates contain some non-amyloid proteins. To test the amyloid properties of proteins identified by proteomic screening, we developed the method of fibril immunoprecipitation followed by Congo red staining and birefringence analysis. The methods of proteomic screening and immunoprecipitation of fibrillar proteins have been successfully tested and applied for the identification of amyloid proteins in yeast and vertebrates.
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Hamidi Asl, Kamran, Juris J. Liepnieks, Masaaki Nakamura, and Merrill D. Benson. "Organ-Specific (Localized) Synthesis of Ig Light Chain Amyloid." Journal of Immunology 162, no. 9 (May 1, 1999): 5556–60. http://dx.doi.org/10.4049/jimmunol.162.9.5556.
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Abstract Ig amyloidosis is usually a systemic disease with multisystem involvement. However, in a significant number of cases amyloid deposition is limited to one specific organ. It has not been determined if the Ig light chain (LC) amyloid precursor protein in localized amyloidosis is synthesized by circulating plasma cells with targeting of the amyloid fibril-forming process to one specific organ, or whether the synthesis of Ig LC and fibril formation occurs entirely as a localized process. In the present study local synthesis of an amyloid fibril precursor LC was investigated. Amyloid fibrils were isolated from a ureter that was obstructed by extensive infiltration of the wall with amyloid. Amino acid sequence analysis of the isolated fibril subunit protein proved it to be derived from a λII Ig LC. Plasma cells within the lesion stained positively with labeled anti-λ Ab and by in situ hybridization using an oligonucleotide probe specific for λ-LC mRNA. RT-PCR of mRNA extracted from the tumor and direct DNA sequencing gave the nucleotide sequence coding specifically for the λII amyloid subunit protein, thus confirming local synthesis of the LC protein.
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Selig, Emily E., Courtney O. Zlatic, Dezerae Cox, Yee-Foong Mok, Paul R. Gooley, Heath Ecroyd, and Michael D. W. Griffin. "N- and C-terminal regions of αB-crystallin and Hsp27 mediate inhibition of amyloid nucleation, fibril binding, and fibril disaggregation." Journal of Biological Chemistry 295, no. 29 (May 16, 2020): 9838–54. http://dx.doi.org/10.1074/jbc.ra120.012748.
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Small heat-shock proteins (sHSPs) are ubiquitously expressed molecular chaperones that inhibit amyloid fibril formation; however, their mechanisms of action remain poorly understood. sHSPs comprise a conserved α-crystallin domain flanked by variable N- and C-terminal regions. To investigate the functional contributions of these three regions, we compared the chaperone activities of various constructs of human αB-crystallin (HSPB5) and heat-shock 27-kDa protein (Hsp27, HSPB1) during amyloid formation by α-synuclein and apolipoprotein C-II. Using an array of approaches, including thioflavin T fluorescence assays and sedimentation analysis, we found that the N-terminal region of Hsp27 and the terminal regions of αB-crystallin are important for delaying amyloid fibril nucleation and for disaggregating mature apolipoprotein C-II fibrils. We further show that the terminal regions are required for stable fibril binding by both sHSPs and for mediating lateral fibril–fibril association, which sequesters preformed fibrils into large aggregates and is believed to have a cytoprotective function. We conclude that although the isolated α-crystallin domain retains some chaperone activity against amyloid formation, the flanking domains contribute additional and important chaperone activities, both in delaying amyloid formation and in mediating interactions of sHSPs with amyloid aggregates. Both these chaperone activities have significant implications for the pathogenesis and progression of diseases associated with amyloid deposition, such as Parkinson's and Alzheimer's diseases.
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Almeida, Zaida L., and Rui M. M. Brito. "Amyloid Disassembly: What Can We Learn from Chaperones?" Biomedicines 10, no. 12 (December 17, 2022): 3276. http://dx.doi.org/10.3390/biomedicines10123276.
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Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple tissues. In this cascade of events, soluble oligomeric species are formed, which are among the most cytotoxic molecular entities along the amyloid cascade. The direct or indirect action of these amyloid soluble oligomers and amyloid protofibrils and fibrils in several tissues and organs lead to cell death in some cases and organ disfunction in general. There are dozens of different proteins and peptides causing multiple amyloid pathologies, chief among them Alzheimer’s, Parkinson’s, Huntington’s, and several other neurodegenerative diseases. Amyloid fibril disassembly is among the disease-modifying therapeutic strategies being pursued to overcome amyloid pathologies. The clearance of preformed amyloids and consequently the arresting of the progression of organ deterioration may increase patient survival and quality of life. In this review, we compiled from the literature many examples of chemical and biochemical agents able to disaggregate preformed amyloids, which have been classified as molecular chaperones, chemical chaperones, and pharmacological chaperones. We focused on their mode of action, chemical structure, interactions with the fibrillar structures, morphology and toxicity of the disaggregation products, and the potential use of disaggregation agents as a treatment option in amyloidosis.
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Sneideris, Tomas, Mantas Ziaunys, Brett K. Y. Chu, Rita P. Y. Chen, and Vytautas Smirnovas. "Self-Replication of Prion Protein Fragment 89-230 Amyloid Fibrils Accelerated by Prion Protein Fragment 107-143 Aggregates." International Journal of Molecular Sciences 21, no. 19 (October 8, 2020): 7410. http://dx.doi.org/10.3390/ijms21197410.
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Prion protein amyloid aggregates are associated with infectious neurodegenerative diseases, known as transmissible spongiform encephalopathies. Self-replication of amyloid structures by refolding of native protein molecules is the probable mechanism of disease transmission. Amyloid fibril formation and self-replication can be affected by many different factors, including other amyloid proteins and peptides. Mouse prion protein fragments 107-143 (PrP(107-143)) and 89-230 (PrP(89-230)) can form amyloid fibrils. β-sheet core in PrP(89-230) amyloid fibrils is limited to residues ∼160–220 with unstructured N-terminus. We employed chemical kinetics tools, atomic force microscopy and Fourier-transform infrared spectroscopy, to investigate the effects of mouse prion protein fragment 107-143 fibrils on the aggregation of PrP(89-230). The data suggest that amyloid aggregates of a short prion-derived peptide are not able to seed PrP(89-230) aggregation; however, they accelerate the self-replication of PrP(89-230) amyloid fibrils. We conclude that PrP(107-143) fibrils could facilitate the self-replication of PrP(89-230) amyloid fibrils in several possible ways, and that this process deserves more attention as it may play an important role in amyloid propagation.
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Kelly, Jeffery W., and William E. Balch. "Amyloid as a natural product." Journal of Cell Biology 161, no. 3 (May 12, 2003): 461–62. http://dx.doi.org/10.1083/jcb.200304074.
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Amyloid fibrils, such as those found in Alzheimer's and the gelsolin amyloid diseases, result from the misassembly of peptides produced by either normal or aberrant intracellular proteolytic processing. A paper in this issue by Marks and colleagues (Berson et al., 2003) demonstrates that intra-melanosome fibrils are formed through normal biological proteolytic processing of an integral membrane protein. The resulting peptide fragment assembles into fibrils promoting the formation of melanin pigment granules. These results, along with the observation that amyloid fibril formation by bacteria is highly orchestrated, suggest that fibril formation is an evolutionary conserved biological pathway used to generate natural product nanostructures.
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Sakalauskas, Andrius, Mantas Ziaunys, and Vytautas Smirnovas. "Concentration-dependent polymorphism of insulin amyloid fibrils." PeerJ 7 (December 10, 2019): e8208. http://dx.doi.org/10.7717/peerj.8208.
Full textAbstract:
Protein aggregation into highly structured fibrils has long been associated with several neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease. Polymorphism of amyloid fibrils increases the complexity of disease mechanisms and may be one of the reasons for the slow progress in drug research. Here we report protein concentration as another factor leading to polymorphism of insulin amyloid fibrils. Moreover, our data suggests that insulin amyloid conformation can self-replicate only via elongation, while seed-induced nucleation will lead to environment-defined conformation of fibrils. As similar observations were already described for a couple of other amyloid proteins, we suggest it to be a generic mechanism for self-replication of different amyloid fibril conformations.
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Kumar, Jatish, Hasier Eraña, Elena López-Martínez, Nathalie Claes, Víctor F. Martín, Diego M. Solís, Sara Bals, Aitziber L. Cortajarena, Joaquín Castilla, and Luis M. Liz-Marzán. "Detection of amyloid fibrils in Parkinson’s disease using plasmonic chirality." Proceedings of the National Academy of Sciences 115, no. 13 (March 12, 2018): 3225–30. http://dx.doi.org/10.1073/pnas.1721690115.
Full textAbstract:
Amyloid fibrils, which are closely associated with various neurodegenerative diseases, are the final products in many protein aggregation pathways. The identification of fibrils at low concentration is, therefore, pivotal in disease diagnosis and development of therapeutic strategies. We report a methodology for the specific identification of amyloid fibrils using chiroptical effects in plasmonic nanoparticles. The formation of amyloid fibrils based on α-synuclein was probed using gold nanorods, which showed no apparent interaction with monomeric proteins but effective adsorption onto fibril structures via noncovalent interactions. The amyloid structure drives a helical nanorod arrangement, resulting in intense optical activity at the surface plasmon resonance wavelengths. This sensing technique was successfully applied to human brain homogenates of patients affected by Parkinson’s disease, wherein protein fibrils related to the disease were identified through chiral signals from Au nanorods in the visible and near IR, whereas healthy brain samples did not exhibit any meaningful optical activity. The technique was additionally extended to the specific detection of infectious amyloids formed by prion proteins, thereby confirming the wide potential of the technique. The intense chiral response driven by strong dipolar coupling in helical Au nanorod arrangements allowed us to detect amyloid fibrils down to nanomolar concentrations.
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Pradhan, Tejaswini, Karthikeyan Annamalai, Riddhiman Sarkar, Stefanie Huhn, Ute Hegenbart, Stefan Schönland, Marcus Fändrich, and Bernd Reif. "Seeded fibrils of the germline variant of human λ-III immunoglobulin light chain FOR005 have a similar core as patient fibrils with reduced stability." Journal of Biological Chemistry 295, no. 52 (October 22, 2020): 18474–84. http://dx.doi.org/10.1074/jbc.ra120.016006.
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Systemic antibody light chains (AL) amyloidosis is characterized by deposition of amyloid fibrils derived from a particular antibody light chain. Cardiac involvement is a major risk factor for mortality. Using MAS solid-state NMR, we studied the fibril structure of a recombinant light chain fragment corresponding to the fibril protein from patient FOR005, together with fibrils formed by protein sequence variants that are derived from the closest germline (GL) sequence. Both analyzed fibril structures were seeded with ex-vivo amyloid fibrils purified from the explanted heart of this patient. We find that residues 11-42 and 69-102 adopt β-sheet conformation in patient protein fibrils. We identify arginine-49 as a key residue that forms a salt bridge to aspartate-25 in the patient protein fibril structure. In the germline sequence, this residue is replaced by a glycine. Fibrils from the GL protein and from the patient protein harboring the single point mutation R49G can be both heterologously seeded using patient ex-vivo fibrils. Seeded R49G fibrils show an increased heterogeneity in the C-terminal residues 80-102, which is reflected by the disappearance of all resonances of these residues. By contrast, residues 11-42 and 69-77, which are visible in the MAS solid-state NMR spectra, show 13Cα chemical shifts that are highly like patient fibrils. The mutation R49G thus induces a conformational heterogeneity at the C terminus in the fibril state, whereas the overall fibril topology is retained. These findings imply that patient mutations in FOR005 can stabilize the fibril structure.
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Galzitskaya, Oxana. "New Mechanism of Amyloid Fibril Formation." Current Protein & Peptide Science 20, no. 6 (May 20, 2019): 630–40. http://dx.doi.org/10.2174/1389203720666190125160937.
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Polymorphism is a specific feature of the amyloid structures. We have studied the amyloid structures and the process of their formation using the synthetic and recombinant preparations of Aβ peptides and their three fragments. The fibrils of different morphology were obtained for these peptides. We suppose that fibril formation by Aβ peptides and their fragments proceeds according to the simplified scheme: destabilized monomer → ring-like oligomer → mature fibril that consists of ringlike oligomers. We are the first who did 2D reconstruction of amyloid fibrils provided that just a ringlike oligomer is the main building block in fibril of any morphology, like a cell in an organism. Taking this into account it is easy to explain the polymorphism of fibrils as well as the splitting of mature fibrils under different external actions, the branching and inhomogeneity of fibril diameters. Identification of regions in the protein chains that form the backbone of amyloid fibril is a direction in the investigation of amyloid formation. It has been demonstrated for Aβ(1-42) peptide and its fragments that their complete structure is inaccessible for the action of proteases, which is an evidence of different ways of association of ring-like oligomers with the formation of fibrils. Based on the electron microscopy and mass spectrometry data, we have proposed a molecular model of the fibril formed by both Aβ peptide and its fragments. In connection with this, the unified way of formation of fibrils by oligomers, which we have discovered, could facilitate the development of relevant fields of medicine of common action.
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Ramshini, Hassan, Reza Tayebee, Alessandra Bigi, Francesco Bemporad, Cristina Cecchi, and Fabrizio Chiti. "Identification of Novel 1,3,5-Triphenylbenzene Derivative Compounds as Inhibitors of Hen Lysozyme Amyloid Fibril Formation." International Journal of Molecular Sciences 20, no. 22 (November 7, 2019): 5558. http://dx.doi.org/10.3390/ijms20225558.
Full textAbstract:
Deposition of soluble proteins as insoluble amyloid fibrils is associated with a number of pathological states. There is a growing interest in the identification of small molecules that can prevent proteins from undergoing amyloid fibril formation. In the present study, a series of small aromatic compounds with different substitutions of 1,3,5-triphenylbenzene have been synthesized and their possible effects on amyloid fibril formation by hen egg white lysozyme (HEWL), a model protein for amyloid formation, and of their resulting toxicity were examined. The inhibitory effect of the compounds against HEWL amyloid formation was analyzed using thioflavin T and Congo red binding assays, atomic force microscopy, Fourier-transform infrared spectroscopy, and cytotoxicity assays, such as the 3-(4,5-Dimethylthiazol)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay and caspase-3 activity measurements. We found that all compounds in our screen were efficient inhibitors of HEWL fibril formation and their associated toxicity. We showed that electron-withdrawing substituents such as –F and –NO2 potentiated the inhibitory potential of 1,3,5-triphenylbenzene, whereas electron-donating groups such as –OH, –OCH3, and –CH3 lowered it. These results may ultimately find applications in the development of potential inhibitors against amyloid fibril formation and its biologically adverse effects.
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Saelices, Lorena, Kevin Chung, Ji H. Lee, Whitaker Cohn, Julian P. Whitelegge, Merrill D. Benson, and David S. Eisenberg. "Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition." Proceedings of the National Academy of Sciences 115, no. 29 (June 28, 2018): E6741—E6750. http://dx.doi.org/10.1073/pnas.1805131115.
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Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutantTTRgene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.
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HIGUCHI, Keiichi, Kumiko KOGISHI, Jing WANG, Chen XIA, Takuya CHIBA, Takatoshi MATSUSHITA, and Masanori HOSOKAWA. "Accumulation of pro-apolipoprotein A-II in mouse senile amyloid fibrils." Biochemical Journal 325, no. 3 (August 1, 1997): 653–59. http://dx.doi.org/10.1042/bj3250653.
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Apolipoprotein A-II (apoA-II), the major apoprotein of serum high-density lipoprotein, is deposited as amyloid fibrils (AApoAII) in murine senile amyloidosis. We have identified and purified a more basic amyloid protein from old-mouse liver. N-terminal sequencing of the protein revealed that the pro-segment of five amino acid residues (Ala-Leu-Val-Lys-Arg) extended from the N-terminal glutamine residue of mature apoA-II protein. MS analysis revealed the deposit of intact pro-apoA-II protein (molecular mass 9319 Da). Antiserum was prepared for staining of the AApoAII amyloid deposition. The relative abundance of pro-apoA-II to mature apoA-II in the amyloid-fibril fraction isolated from livers of mice with severe amyloidosis was 14.1%. The similar abundance of pro-apoA-II in the amyloid fibril fraction from the spleen (16.3%) suggested that deposited pro-apoA-II originated from the blood. The concentration of pro-apoA-II was much lower in the serum (1.5% of mature apoA-II) than in the amyloid-fibril fraction. There was no difference in the content of pro-apoA-II between the amyloidogenetic R1.P1-Apoa2c and amyloid-resistant SAMR1 strains at the age of 3 months. The abundance of pro-apoA-II in the amyloid-fibril fraction compared with the serum suggested that it plays a key role in the initialization of mouse senile amyloidosis.
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Noi, Kentaro, Kichitaro Nakajima, Keiichi Yamaguchi, Masatomo So, Kensuke Ikenaka, Hideki Mochizuki, Yuji Goto, and Hirotsugu Ogi. "Acceleration of amyloid fibril formation by multichannel sonochemical reactor." Japanese Journal of Applied Physics 61, SG (March 10, 2022): SG1002. http://dx.doi.org/10.35848/1347-4065/ac4142.
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Abstract The formation of amyloid fibrils of various amyloidogenic proteins is dramatically enhanced by ultrasound irradiation. To apply this phenomenon to the study of protein aggregation science and diagnosis of neurodegenerative diseases, a multichannel ultrasound irradiation system with individually adjustable ultrasound irradiation conditions is necessary. Here, we develop a sonochemical reaction system, where an ultrasonic transducer is placed in each well of a 96-well microplate to perform ultrasonic irradiation of sample solutions under various conditions with high reproducibility, and applied it to study the amyloid fibril formation of amyloid β, α-synuclein, β2-microglobulin, and lysozyme. The results clearly show that our instrument is superior to the conventional shaking method in terms of the degree of acceleration and reproducibility of fibril formation reaction. The acceleration degree is controllable by controlling the driving voltage applied to each transducer. We have thus succeeded in developing a useful tool for the study of amyloid fibril formation in various proteins.
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Yagi-Utsumi, Maho, and Koichi Kato. "Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates." Molecules 27, no. 15 (July 26, 2022): 4787. http://dx.doi.org/10.3390/molecules27154787.
Full textAbstract:
Protein folding is the most fundamental and universal example of biomolecular self-organization and is characterized as an intramolecular process. In contrast, amyloidogenic proteins can interact with one another, leading to protein aggregation. The energy landscape of amyloid fibril formation is characterized by many minima for different competing low-energy structures and, therefore, is much more enigmatic than that of multiple folding pathways. Thus, to understand the entire energy landscape of protein aggregation, it is important to elucidate the full picture of conformational changes and polymorphisms of amyloidogenic proteins. This review provides an overview of the conformational diversity of amyloid-β (Aβ) characterized from experimental and theoretical approaches. Aβ exhibits a high degree of conformational variability upon transiently interacting with various binding molecules in an unstructured conformation in a solution, forming an α-helical intermediate conformation on the membrane and undergoing a structural transition to the β-conformation of amyloid fibrils. This review also outlines the structural polymorphism of Aβ amyloid fibrils depending on environmental factors. A comprehensive understanding of the energy landscape of amyloid formation considering various environmental factors will promote drug discovery and therapeutic strategies by controlling the fibril formation pathway and targeting the consequent morphology of aggregated structures.
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Lashuel, Hilal A., and Peter T. Lansbury. "Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?" Quarterly Reviews of Biophysics 39, no. 2 (May 2006): 167–201. http://dx.doi.org/10.1017/s0033583506004422.
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1. Introduction 22. What is the significance of the shared structural properties of disease-associated protein fibrils? 32.1 Mechanism of amyloid fibril formation in vitro 62.1.1 In vitro fibril formation involves transient population of ordered aggregates of intermediate stability, or protofibrils 63. Toxic properties of protofibrils 73.1 Protofibrils, rather than fibrils, are likely to be pathogenic 73.2 The toxic protofibril may be a mixture of related species 83.3 Morphological similarities of protofibrils suggest a common mechanism of toxicity 93.4 Are the amyloid diseases a subset of a much larger class of previously unrecognized protofibril diseases? 93.5 Fibrils, in the form of aggresomes, may function to sequester toxic protofibrils 94. Amyloid pores, a common structural link among protein aggregation neurodegenerative diseases 104.1 Mechanistic studies of amyloid fibril formation reveal common features, including pore-like protofibrils 104.1.1 Amyloid-β (Aβ) (Alzheimer's disease) 104.1.2 α-Synuclein (PD and diffuse Lewy body disease) 124.1.3 ABri (familial British dementia) 134.1.4 Superoxide dismutase-1 (amyotrophic lateral sclerosis) 134.1.5 Prion protein (Creutzfeldt–Jakob disease, bovine spongiform encephalopathy, etc.) 144.1.6 Huntingtin (Huntington's disease) 144.2 Amyloidogenic proteins that are not linked to disease also from pore-like protofibrils 154.3 Amyloid proteins form non-fibrillar aggregates that have properties of protein channels or pores 154.3.1 Aβ ‘channels’ 154.3.2 α-Synuclein ‘pores’ 164.3.3 PrP ‘channels’ 164.3.4 Polyglutamine ‘channels’ 174.4 Nature uses β-strand-mediated protein oligomerization to construct pore-forming toxins 175. Mechanisms of protofibril induced toxicity in protein aggregation diseases 195.1 The amyloid pore can explain the age-association and cell-type selectivity of the neurodegenerative diseases 195.2 Protofibrils may promote their own accumulation by inhibiting the proteasome 206. Testing the amyloid pore hypothesis by attempting to disprove it 217. Acknowledgments 228. References 22Protein fibrillization is implicated in the pathogenesis of most, if not all, age-associated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ‘amyloid pore’. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.
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GALZITSKAYA, OXANA V., SERGIY O. GARBUZYNSKIY, and MICHAIL YU. LOBANOV. "IS IT POSSIBLE TO PREDICT AMYLOIDOGENIC REGIONS FROM SEQUENCE ALONE?" Journal of Bioinformatics and Computational Biology 04, no. 02 (April 2006): 373–88. http://dx.doi.org/10.1142/s0219720006002004.
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Identification of potentially amyloidogenic regions in polypeptide chains is very important because the amyloid fibril formation can be induced in most normal proteins. In our work we suggest a new method to detect amyloidogenic regions in protein sequence. It is based on the assumption that packing is tight inside an amyloid and therefore regions which could potentially pack well would have a tendency to form amyloids. This means that the regions with strong expected packing of residues would be responsible for the amyloid formation. We use this property to identify potentially amyloidogenic regions in proteins basing on their amino acid sequences only. Our predictions are consistent with known disease-related amyloidogenic regions for 8 of 11 amyloid-forming proteins and peptides in which the positions of amyloidogenic regions have been revealed experimentally. Predictions of the regions which are responsible for the formation of amyloid fibrils in proteins unrelated to disease have been also done.
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Toleikis, Zigmantas, Mantas Ziaunys, Lina Baranauskiene, Vytautas Petrauskas, Kristaps Jaudzems, and Vytautas Smirnovas. "S100A9 Alters the Pathway of Alpha-Synuclein Amyloid Aggregation." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7972. http://dx.doi.org/10.3390/ijms22157972.
Full textAbstract:
The formation of amyloid fibril plaques in the brain creates inflammation and neuron death. This process is observed in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Alpha-synuclein is the main protein found in neuronal inclusions of patients who have suffered from Parkinson’s disease. S100A9 is a calcium-binding, pro-inflammation protein, which is also found in such amyloid plaques. To understand the influence of S100A9 on the aggregation of α-synuclein, we analyzed their co-aggregation kinetics and the resulting amyloid fibril structure by Fourier-transform infrared spectroscopy and atomic force microscopy. We found that the presence of S100A9 alters the aggregation kinetics of α-synuclein and stabilizes the formation of a particular amyloid fibril structure. We also show that the solution’s ionic strength influences the interplay between S100A9 and α-synuclein, stabilizing a different structure of α-synuclein fibrils.
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Hoepfner, Jeannine, Mandy Kleinsorge, Oliver Papp, Susanne Alfken, Robin Heiringhoff, Andreas Pich, Vanessa Sauer, et al. "In vitro modelling of familial amyloidotic polyneuropathy allows quantitative detection of transthyretin amyloid fibril-like structures in hepatic derivatives of patient-specific induced pluripotent stem cells." Biological Chemistry 398, no. 8 (July 26, 2017): 939–54. http://dx.doi.org/10.1515/hsz-2016-0258.
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Abstract The transthyretin protein is thermodynamically destabilised by mutations in the transthyretin gene, promoting the formation of amyloid fibrils in various tissues. Consequently, impaired autonomic organ function is observed in patients suffering from transthyretin-related familial amyloidotic polyneuropathy (FAP). The influence of individual genetic backgrounds on fibril formation as a potential cause of genotype-phenotype variations needs to be investigated in order to ensure efficient patient-specific therapies. We reprogrammed FAP patient fibroblasts to induced pluripotent stem (iPS) cells and differentiated these cells into transthyretin-expressing hepatocyte-like cells (HLCs). HLCs differentiated from FAP iPS cells and healthy control iPS cells secreted the transthyretin protein in similar concentrations. Mass spectrometry revealed the presence of mutant transthyretin protein in FAP HLC supernatants. In comparison to healthy control iPS cells, we demonstrated the formation of transthyretin amyloid fibril-like structures in FAP HLC supernatants using the amyloid-specific dyes Congo red and thioflavin T. These dyes were also applicable for the quantitative determination of in vitro formed transthyretin fibril-like structures. Moreover, we confirmed the inhibition of fibril formation by the TTR kinetic stabiliser diclofenac. Thioflavin T fluorescence intensity measurements even allowed the quantification of amyloid fibril-like structures in 96-well plate formats as a prerequisite for patient-specific drug screening approaches.
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Xue, Christine, Tiffany Yuwen Lin, Dennis Chang, and Zhefeng Guo. "Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation." Royal Society Open Science 4, no. 1 (January 2017): 160696. http://dx.doi.org/10.1098/rsos.160696.
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Formation of amyloid fibrils underlies a wide range of human disorders, including Alzheimer's and prion diseases. The amyloid fibrils can be readily detected thanks to thioflavin T (ThT), a small molecule that gives strong fluorescence upon binding to amyloids. Using the amyloid fibrils of Aβ40 and Aβ42 involved in Alzheimer's disease, and of yeast prion protein Ure2, here we study three aspects of ThT binding to amyloids: quantification of amyloid fibrils using ThT, the optimal ThT concentration for monitoring amyloid formation and the effect of ThT on aggregation kinetics. We show that ThT fluorescence correlates linearly with amyloid concentration over ThT concentrations ranging from 0.2 to 500 µM. At a given amyloid concentration, the plot of ThT fluorescence versus ThT concentration exhibits a bell-shaped curve. The maximal fluorescence signal depends mostly on the total ThT concentration, rather than amyloid to ThT ratio. For the three proteins investigated, the maximal fluorescence is observed at ThT concentrations of 20–50 µM. Aggregation kinetics experiments in the presence of different ThT concentrations show that ThT has little effect on aggregation at concentrations of 20 µM or lower. ThT at concentrations of 50 µM or more could affect the shape of the aggregation curves, but this effect is protein-dependent and not universal.
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Hori, Yukiko, Tadafumi Hashimoto, Yosuke Wakutani, Katsuya Urakami, Kenji Nakashima, Margaret M. Condron, Satoshi Tsubuki, Takaomi C. Saido, David B. Teplow, and Takeshi Iwatsubo. "The Tottori (D7N) and English (H6R) Familial Alzheimer Disease Mutations Accelerate Aβ Fibril Formation without Increasing Protofibril Formation." Journal of Biological Chemistry 282, no. 7 (December 14, 2006): 4916–23. http://dx.doi.org/10.1074/jbc.m608220200.
Full textAbstract:
A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid β-protein precursor or presenilins. Whereas some amyloid β-protein precursor mutations alter its metabolism through effects on Aβ production, the pathogenic effects of those that alter amino acid residues within the Aβ sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Aβ mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Aβ production, synthetic Aβ(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Aβ(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R Aβ were markedly inhibited despite enhanced fibril formation. These N-terminal Aβ mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Aβ peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.
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Tarabara, Uliana, Olga Zhytniakivska, Kateryna Vus, Valeriya Trusova, and Galyna Gorbenko. "Fluorescence Study of the Interactions Between Insulin Amyloid Fibrils and Proteins." 1, no. 1 (March 17, 2022): 96–104. http://dx.doi.org/10.26565/2312-4334-2022-1-13.
Full textAbstract:
Self-assembly of proteins and peptides into amyloid fibrils is the subject of intense research due to association of this process with multiple human disorders. Despite considerable progress in understanding the nature of amyloid cytotoxicity, the role of cellular components, in particular proteins, in the cytotoxic action of amyloid aggregates is still poorly investigated. The present study was focused on exploring the fibril-protein interactions between the insulin amyloid fibrils and several proteins differing in their structure and physicochemical properties. To this end, the fluorescence spectral properties of the amyloid-sensitive fluorescent phosphonium dye TDV have been measured in the insulin fibrils (InsF) and their mixtures with serum albumin (SA) in its native solution state, lysozyme (Lz) and insulin (Ins) partially unfolded at low pH. It was found that the binding of TDV to the insulin amyloid fibrils is followed by considerable increase of the fluorescence intensity. In the system (InsF + TDV) the TDV fluorescence spectra were decomposed into three spectral components centered at ~ 572 nm, 608 nm and 649 nm. The addition of SA, Lz or Ins to the mixture (InsF + TDV) resulted in the changes of the fluorescence intensity, the maximum position and relative contributions (f1,3) of the first and third spectral components into the overall spectra. The Förster resonance energy transfer between the TDV as a donor and a squaraine dye SQ1 as an acceptor was used to gain further insights into the interaction between the insulin amyloid fibrils and proteins. It was found that the presence of SA do not change the FRET efficiency compared with control system (InsF + chromophores), while the addition of Lz and Ins resulted in the FRET efficiency decrease. The changes in the TDV fluorescence response in the protein-fibril systems were attributed to the probe redistribution between the binding sites located at InsF, the non-fibrillized Ins, SA or Lz and protein-protein interface
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Musteikyte, Greta, Mantas Ziaunys, and Vytautas Smirnovas. "Methylene blue inhibits nucleation and elongation of SOD1 amyloid fibrils." PeerJ 8 (August 14, 2020): e9719. http://dx.doi.org/10.7717/peerj.9719.
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Protein aggregation into highly-structured amyloid fibrils is linked to several neurodegenerative diseases. Such fibril formation by superoxide dismutase I (SOD1) is considered to be related to amyotrophic lateral sclerosis, a late-onset and fatal disorder. Despite much effort and the discovery of numerous anti-amyloid compounds, no effective cure or treatment is currently available. Methylene blue (MB), a phenothiazine dye, has been shown to modulate the aggregation of multiple amyloidogenic proteins. In this work we show its ability to inhibit both the spontaneous amyloid aggregation of SOD1 as well as elongation of preformed fibrils.
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Est, Chandler B., Parth Mangrolia, and Regina M. Murphy. "ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides." Protein Engineering, Design and Selection 32, no. 2 (February 2019): 47–57. http://dx.doi.org/10.1093/protein/gzz016.
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Abstract β-amyloid oligomers are thought to be the most toxic species formed en route to fibril deposition in Alzheimer’s disease. Transthyretin is a natural sequestering agent of β-amyloid oligomers: the binding site to β-amyloid has been traced to strands G/H of the inner β-sheet of transthyretin. A linear peptide, with the same primary sequence as the β-amyloid binding domain on transthyretin, was moderately effective at inhibiting β-amyloid fibril growth. Insertion of a β-turn template and cyclization greatly increased stability against proteolysis and improved efficacy as an amyloid inhibitor. However, the cyclic peptide still contained a significant amount of disorder. Using the Simple Cyclic Peptide Application within ROSETTA as an in silico predictor of cyclic peptide conformation and stability, we investigated putative structural enhancements, including stabilization by disulfide linkages and insertion of a second β-turn template. Several candidates were synthesized and tested for secondary structure and ability to inhibit β-amyloid aggregation. The results demonstrate that cyclization, β-sheet structure and conformational homogeneity are all preferable design features, whereas disulfide bond formation across the two β-strands is not preferable.
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Selivanova, O. M., V. V. Rogachevsky, A. K. Syrin, and O. V. Galzitskaya. "Molecular mechanism of amyloid formation by Ab peptide: review of own works." Biomeditsinskaya Khimiya 64, no. 1 (January 2018): 94–109. http://dx.doi.org/10.18097/pbmc20186401094.
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TA characteristic feature of amyloid structures is polymorphism. The study of amyloid structures and their formation process was carried out for synthetic and recombinant Ab(1-40) and Ab(1-42) peptide preparations. In the study of these peptides, we recognized fibrils of different morphologies. We observed fibrillar formations in the form of single fibrils, ribbons, bundles, bunches, and clusters. Polymorphism of fibrils was observed not only when the environmental conditions changed, but under the same conditions and this was a common characteristics of all amyloid formations. Fibrils of Ab(1-40) peptides tended to form aggregates of fibrils in the form of ribbons, while Ab(1-42) peptide under the same conditions polymerized in the form of rough fibrils of different diameters and tends to branch. We assume that the formation of fibrils of Ab(1-40) and Ab(1-42) peptides occurs according to a simplified scheme: a destabilized monomer ® a ring oligomer ® a mature fibril consisting of ring oligomers. Proceeding from the proposition that the ring oligomer is the main building block of amyloid fibril (similar to the cell in the body), it is easy to explain fibril polymorphism, as well as fragmentation of mature fibrils under various external influences, branching and irregularity of diameter (surface roughness) of fibrils. One aspect of the study of amyloidogenesis is the determination of the regions of the protein chain forming the core of the amyloid fibril. We theoretically predicted amyloidogenic regions for two isoforms of Ab peptides capable of forming an amyloid structure: 16-21 and 32-36 residues. Using the method of tandem mass spectrometry, these regions were determined experimentally. It was shown that the regions of Ab(1-40) peptide from 16 to 22 and from 28 to 40 residues were resistant to the action of proteases, i.e. its formed the core of the amyloid fibril. For Ab(1-42) peptide the whole sequence is not available for the action of proteases, which indicates a different way of associating ring oligomers in the formation of fibrils. Based on electron microscopy and mass spectrometry data we proposed a molecular model of the fibril formed by Ab(1-40) and Ab(1-42) peptides.
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Ecroyd, Heath, David C. Thorn, Yanqin Liu, and John A. Carver. "The dissociated form of κ-casein is the precursor to its amyloid fibril formation." Biochemical Journal 429, no. 2 (June 28, 2010): 251–60. http://dx.doi.org/10.1042/bj20091949.
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Bovine milk κ-casein forms a self-associating oligomeric micelle-like species, in equilibrium with dissociated forms. In its native form, intra- and inter-molecular disulfide bonds lead to the formation of multimeric species ranging from monomers to decamers. When incubated under conditions of physiological pH and temperature, both reduced and non-reduced κ-casein form highly structured β-sheet amyloid fibrils. We investigated whether the precursor to κ-casein fibril formation is a dissociated state of the protein or its oligomeric micelle-like form. We show that reduced κ-casein is capable of forming fibrils well below its critical micelle concentration, i.e. at concentrations where only dissociated forms of the protein are present. Moreover, by regulating the degree of disulfide linkages, we were able to investigate how oligomerization of κ-casein influences its propensity for fibril formation under conditions of physiological pH and temperature. Thus, using fractions containing different proportions of multimeric species, we demonstrate that the propensity of the disulfide-linked multimers to form fibrils is inversely related to their size, with monomeric κ-casein being the most aggregation prone. We conclude that dissociated forms of κ-casein are the amyloidogenic precursors to fibril formation rather than oligomeric micelle-like species. The results highlight the role of oligomerization and natural binding partners in preventing amyloid fibril formation by disease-related proteins in vivo.
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Tan, S. Y., I. E. Murdoch, T. J. Sullivan, J. E. Wright, Oanh Truong, J. J. Hsuan, P. N. Hawkins, and M. B. Pepys. "Primary Localized Orbital Amyloidosis Composed of the Immunoglobulin γ Heavy Chain CH3 Domain." Clinical Science 87, no. 5 (November 1, 1994): 487–91. http://dx.doi.org/10.1042/cs0870487.
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1. Primary orbital amyloidosis is a rare form of localized amyloidosis in which the precursor protein has not previously been identified. We report here the first extraction of amyloid fibrils from a tissue biopsy containing orbital amyloid, and characterization of the fibril protein. 2. The N-terminal nine residues were identical with residues 278–286 and 275–283 of the third constant (CH3) domains of IgG1 and IgG4 γ heavy chains, respectively. The mass of the fibril subunit protein was 6125 Da by time-of-flight mass spectrometry, compared with the expected masses of 6169.9 Da and 6214.9 Da for the CH3 domains of γ1 from residue 278 and γ4 from residue 275, respectively. The fibril protein thus appeared to consist exclusively of an immunoglobulin heavy chain constant domain. 3. Only two examples of immunoglobulin heavy chain derived amyloid have been reported previously and both of these, as well as all published cases of the usual immunoglobulin light chain derived amyloid, contained variable domain sequence. The present case therefore represents a form of local, presumably clonal, B-cell/plasma-cell disorder characterized uniquely by deposition of an amyloidogenic immunoglobulin heavy chain constant domain fragment.
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Ogawa, Kenjirou, Ayumi Ishii, Aimi Shindo, Kunihiro Hongo, Tomohiro Mizobata, Tetsuya Sogon, and Yasushi Kawata. "Spearmint Extract Containing Rosmarinic Acid Suppresses Amyloid Fibril Formation of Proteins Associated with Dementia." Nutrients 12, no. 11 (November 13, 2020): 3480. http://dx.doi.org/10.3390/nu12113480.
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Neurological dementias such as Alzheimer’s disease and Lewy body dementia are thought to be caused in part by the formation and deposition of characteristic insoluble fibrils of polypeptides such as amyloid beta (Aβ), Tau, and/or α-synuclein (αSyn). In this context, it is critical to suppress and remove such aggregates in order to prevent and/or delay the progression of dementia in these ailments. In this report, we investigated the effects of spearmint extract (SME) and rosmarinic acid (RA; the major component of SME) on the amyloid fibril formation reactions of αSyn, Aβ, and Tau proteins in vitro. SME or RA was added to soluble samples of each protein and the formation of fibrils was monitored by thioflavin T (ThioT) binding assays and transmission electron microscopy (TEM). We also evaluated whether preformed amyloid fibrils could be dissolved by the addition of RA. Our results reveal for the first time that SME and RA both suppress amyloid fibril formation, and that RA could disassemble preformed fibrils of αSyn, Aβ, and Tau into non-toxic species. Our results suggest that SME and RA may potentially suppress amyloid fibrils implicated in the progression of Alzheimer’s disease and Lewy body dementia in vivo, as well.
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Tarabara, Uliana, Olga Zhytniakivska, Kateryna Vus, Valeriya Trusova, and Galyna Gorbenko. "Multiple Docking of Fluorescent Dyes to Fibrillar Insulin." 3, no. 3 (September 2, 2022): 115–20. http://dx.doi.org/10.26565/2312-4334-2022-3-15.
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The co-localization of the donor and acceptor fluorophores capable of transferring the energy by the Fӧrster mechanism, on the molecular scaffold of amyloid fibrils offers new opportunities not only for refinement of the amyloid detection and structural analysis, but also for designing photonic nanodevices on their basis. The assembly of these systems involves the non-covalent dye-protein interactions which can hardly be characterized in terms of a precise dye location within the fibril structure that is required for fabricating the FRET-based light harvesting systems or photonic nanowires. In view of this, the dye-fibril binding process deserves a detailed in silico study. In the previous molecular docking studies of the FRET donors and acceptors interacting with the insulin model fibrils we considered only one ligand during the simulation procedure. However, the real situation is much more complicated, when the multiple ligands can compete for the same binding site, a direct complexation between the dyes on the fibril scaffold can take place, the spatial distribution of the bound fluorophores can be unfavorable for the energy transfer, etc. In addition, the mutual orientation of the donor and acceptor molecules essentially contribute to the efficiency of the Förster resonance energy transfer (FRET) in the investigated systems. The present study was undertaken to gain molecular docking insight into the binding of the donor (Thioflavin T) and acceptor (Congo Red or a phosphonium dye TDV) fluorophores to the insulin amyloid fibrils using the multiple docking approach. The employed PatcDock and SwissDock webserves provided evidence for the preferable association of all dyes with the fibril grooves. The protein-ligand interaction profiler (PLIP) was employed for analyzing the (InsF + ThT +CR) and (InsF + ThT + TDV) systems. The revealed binding modes and the types of the dye-fibril interactions may be of importance for a more detailed analysis of the FRET process in amyloid systems and may serve as a background for further in silico studies of the cascade FRET on the amyloid fibril scaffold.
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Kisilevsky, R. "From arthritis to Alzheimer's disease: current concepts on the pathogenesis of amyloidosis." Canadian Journal of Physiology and Pharmacology 65, no. 9 (September 1, 1987): 1805–15. http://dx.doi.org/10.1139/y87-282.
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Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits which all have common morphologic properties, staining characteristics, and x-ray diffraction and infrared spectra. This review considers the new classification of amyloids, based on the underlying peptides forming the protein fibril, and their diversity. The pathogenesis of inflammation-associated amyloid and its relationship to high density lipoprotein metabolism is examined in detail. The lessons learned from models of inflammation-associated amyloid are extended to the other amyloids (e.g., Alzheimer's disease), and potential reasons for the common structural properties of all amyloids are explored.
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Yu, Kun-Hua, and Cheng-I. Lee. "Quercetin Disaggregates Prion Fibrils and Decreases Fibril-Induced Cytotoxicity and Oxidative Stress." Pharmaceutics 12, no. 11 (November 11, 2020): 1081. http://dx.doi.org/10.3390/pharmaceutics12111081.
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Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by misfolding and aggregation of prion protein (PrP). Previous studies have demonstrated that quercetin can disaggregate some amyloid fibrils, such as amyloid β peptide (Aβ) and α-synuclein. However, the disaggregating ability is unclear in PrP fibrils. In this study, we examined the amyloid fibril-disaggregating activity of quercetin on mouse prion protein (moPrP) and characterized quercetin-bound moPrP fibrils by imaging, proteinase resistance, hemolysis assay, cell viability, and cellular oxidative stress measurements. The results showed that quercetin treatment can disaggregate moPrP fibrils and lead to the formation of the proteinase-sensitive amorphous aggregates. Furthermore, quercetin-bound fibrils can reduce the membrane disruption of erythrocytes. Consequently, quercetin-bound fibrils cause less oxidative stress, and are less cytotoxic to neuroblastoma cells. The role of quercetin is distinct from the typical function of antiamyloidogenic drugs that inhibit the formation of amyloid fibrils. This study provides a solution for the development of antiamyloidogenic therapy.
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Krebs, Mark R. H., Kristin R. Domike, and Athene M. Donald. "Protein aggregation: more than just fibrils." Biochemical Society Transactions 37, no. 4 (July 22, 2009): 682–86. http://dx.doi.org/10.1042/bst0370682.
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The aggregation of misfolded proteins into amyloid fibrils, and the importance of this step for various diseases, is well known. However, it is becoming apparent that the fibril is not the only structure that aggregating proteins of widely different types may adopt. Around the isoelectric point, when the net charge is essentially zero, rather monodisperse and quasi-amorphous nanoscale particles form. These particles are found to contain limited runs of β-sheet structure, but their overall organization is random. These nanoparticles have the potential to be useful for such applications as the slow release of drugs. The amyloid fibrils form away from the isoelectric point, but over certain ranges of, e.g., pH, the fibrils themselves do not exist freely, but form suprafibrillar aggregates termed spherulites. These consist of fibrils radiating from a central nucleus, and form by new species attaching to the ends of growing fibrils, rather than by the aggregation of pre-existing fibrils. Under the polarizing light microscope, they exhibit a Maltese cross shape due to their symmetry. The rate of aggregation is determined by factors involving (at least) protein size, concentration, presence of salt and charge. The occurrence of spherulites, which have been found in vivo as well as in vitro, appears to be generic, although the factors which determine the equilibrium between free fibril and spherulite are not as yet clear.
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Ziaunys, Mantas, Andrius Sakalauskas, Kamile Mikalauskaite, Ruta Snieckute, and Vytautas Smirnovas. "Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils." International Journal of Molecular Sciences 22, no. 10 (May 11, 2021): 5075. http://dx.doi.org/10.3390/ijms22105075.
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Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein forms multiple, conformationally and morphologically distinct structures. Considering that such structural variations can greatly complicate the search for potential antiamyloid compounds, either by having specific propagation properties or stability, it is important to better understand this aggregation event. We have recently reported the ability of prion protein fibrils to obtain at least two distinct conformations under identical conditions, which raised the question if this occurrence is tied to only certain environmental conditions. In this work, we examined a large sample size of prion protein aggregation reactions under a range of temperatures and analyzed the resulting fibril dye-binding, secondary structure and morphological properties. We show that all temperature conditions lead to the formation of more than one fibril type and that this variability may depend on the state of the initial prion protein molecules.
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Khan, Mohammad Ashhar I., Ulrich Weininger, Sven Kjellström, Shashank Deep, and Mikael Akke. "Adsorption of unfolded Cu/Zn superoxide dismutase onto hydrophobic surfaces catalyzes its formation of amyloid fibrils." Protein Engineering, Design and Selection 32, no. 2 (February 2019): 77–85. http://dx.doi.org/10.1093/protein/gzz033.
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Abstract Intracellular aggregates of superoxide dismutase 1 (SOD1) are associated with amyotrophic lateral sclerosis. In vivo, aggregation occurs in a complex and dense molecular environment with chemically heterogeneous surfaces. To investigate how SOD1 fibril formation is affected by surfaces, we used an in vitro model system enabling us to vary the molecular features of both SOD1 and the surfaces, as well as the surface area. We compared fibril formation in hydrophilic and hydrophobic sample wells, as a function of denaturant concentration and extraneous hydrophobic surface area. In the presence of hydrophobic surfaces, SOD1 unfolding promotes fibril nucleation. By contrast, in the presence of hydrophilic surfaces, increasing denaturant concentration retards the onset of fibril formation. We conclude that the mechanism of fibril formation depends on the surrounding surfaces and that the nucleating species might correspond to different conformational states of SOD1 depending on the nature of these surfaces.