Journal articles: 'Protein Conformers'

1

Schneider, Bohdan, Jiří Černý, Daniel Svozil, Petr Čech, Jean-Christophe Gelly, and Alexandre G. de Brevern. "Bioinformatic analysis of the protein/DNA interface." Nucleic Acids Research 42, no. 5 (December 11, 2013): 3381–94. http://dx.doi.org/10.1093/nar/gkt1273.

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Abstract To investigate the principles driving recognition between proteins and DNA, we analyzed more than thousand crystal structures of protein/DNA complexes. We classified protein and DNA conformations by structural alphabets, protein blocks [de Brevern, Etchebest and Hazout (2000) (Bayesian probabilistic approach for predicting backbone structures in terms of protein blocks. Prots. Struct. Funct. Genet., 41:271–287)] and dinucleotide conformers [Svozil, Kalina, Omelka and Schneider (2008) (DNA conformations and their sequence preferences. Nucleic Acids Res., 36:3690–3706)], respectively. Assembling the mutually interacting protein blocks and dinucleotide conformers into ‘interaction matrices’ revealed their correlations and conformer preferences at the interface relative to their occurrence outside the interface. The analyzed data demonstrated important differences between complexes of various types of proteins such as transcription factors and nucleases, distinct interaction patterns for the DNA minor groove relative to the major groove and phosphate and importance of water-mediated contacts. Water molecules mediate proportionally the largest number of contacts in the minor groove and form the largest proportion of contacts in complexes of transcription factors. The generally known induction of A-DNA forms by complexation was more accurately attributed to A-like and intermediate A/B conformers rare in naked DNA molecules.

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Verdonk, Marcel L., Paul N. Mortenson, Richard J. Hall, Michael J. Hartshorn, and Christopher W. Murray. "Protein−Ligand Docking against Non-Native Protein Conformers." Journal of Chemical Information and Modeling 48, no. 11 (October 28, 2008): 2214–25. http://dx.doi.org/10.1021/ci8002254.

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Xu, Aoshuang, Fenglei Li, Howard Robinson, and Edward S. Yeung. "Can Protein Conformers Be Fractionated by Crystallization?" Analytical Chemistry 85, no. 13 (June 12, 2013): 6372–77. http://dx.doi.org/10.1021/ac400762x.

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Mahajan, Swapnil, and Yves-Henri Sanejouand. "Jumping between protein conformers using normal modes." Journal of Computational Chemistry 38, no. 18 (May 3, 2017): 1622–30. http://dx.doi.org/10.1002/jcc.24803.

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Ma, Jiyan, Jingjing Zhang, and Runchuan Yan. "Recombinant Mammalian Prions: The “Correctly” Misfolded Prion Protein Conformers." Viruses 14, no. 9 (August 31, 2022): 1940. http://dx.doi.org/10.3390/v14091940.

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Generating a prion with exogenously produced recombinant prion protein is widely accepted as the ultimate proof of the prion hypothesis. Over the years, a plethora of misfolded recPrP conformers have been generated, but despite their seeding capability, many of them have failed to elicit a fatal neurodegenerative disorder in wild-type animals like a naturally occurring prion. The application of the protein misfolding cyclic amplification technique and the inclusion of non-protein cofactors in the reaction mixture have led to the generation of authentic recombinant prions that fully recapitulate the characteristics of native prions. Together, these studies reveal that recPrP can stably exist in a variety of misfolded conformations and when inoculated into wild-type animals, misfolded recPrP conformers cause a wide range of outcomes, from being completely innocuous to lethal. Since all these recPrP conformers possess seeding capabilities, these results clearly suggest that seeding activity alone is not equivalent to prion activity. Instead, authentic prions are those PrP conformers that are not only heritable (the ability to seed the conversion of normal PrP) but also pathogenic (the ability to cause fatal neurodegeneration). The knowledge gained from the studies of the recombinant prion is important for us to understand the pathogenesis of prion disease and the roles of misfolded proteins in other neurodegenerative disorders.

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de Groot, J., and H. H. J. de Jongh. "The presence of heat-stable conformers of ovalbumin affects properties of thermally formed aggregates." Protein Engineering Design and Selection 16, no. 12 (December 1, 2003): 1035–40. http://dx.doi.org/10.1093/protein/gzg123.

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Beglov, Dmitri, David R. Hall, Ryan Brenke, Maxim V. Shapovalov, Roland L. Dunbrack, Dima Kozakov, and Sandor Vajda. "Minimal ensembles of side chain conformers for modeling protein-protein interactions." Proteins: Structure, Function, and Bioinformatics 80, no. 2 (November 22, 2011): 591–601. http://dx.doi.org/10.1002/prot.23222.

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Orellana, Laura, Johan Gustavsson, Cathrine Bergh, Ozge Yoluk, and Erik Lindahl. "eBDIMS server: protein transition pathways with ensemble analysis in 2D-motion spaces." Bioinformatics 35, no. 18 (February 19, 2019): 3505–7. http://dx.doi.org/10.1093/bioinformatics/btz104.

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Abstract Summary Understanding how proteins transition between different conformers, and how conformers relate to each other in terms of structure and function, is not trivial. Here, we present an online tool for transition pathway generation between two protein conformations using Elastic Network Driven Brownian Dynamics Importance Sampling, a coarse-grained simulation algorithm, which spontaneously predicts transition intermediates trapped experimentally. In addition to path-generation, the server provides an interactive 2D-motion landscape graphical representation of the transitions or any additional conformers to explore their structural relationships. Availability and implementation eBDIMS is available online: http://ebdims.biophysics.se/ or as standalone software: https://github.com/laura-orellana/eBDIMS, https://github.com/cabergh/eBDIMS. Supplementary information Supplementary data are available at Bioinformatics online.

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Walsh, Daniel J., Abigail M. Schwind, Geoffrey P. Noble, and Surachai Supattapone. "Conformational diversity in purified prions produced in vitro." PLOS Pathogens 19, no. 1 (January 10, 2023): e1011083. http://dx.doi.org/10.1371/journal.ppat.1011083.

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Prion diseases are caused by misfolding of either wild-type or mutant forms of the prion protein (PrP) into self-propagating, pathogenic conformers, collectively termed PrPSc. Both wild-type and mutant PrPSc molecules exhibit conformational diversity in vivo, but purified prions generated by the serial protein misfolding cyclic amplification (sPMCA) technique do not display this same diversity in vitro. This discrepancy has left a gap in our understanding of how conformational diversity arises at the molecular level in both types of prions. Here, we use continuous shaking instead of sPMCA to generate conformationally diverse purified prions in vitro. Using this approach, we show for the first time that wild type prions initially seeded by different native strains can propagate as metastable PrPSc conformers with distinguishable strain properties in purified reactions containing a single active cofactor. Propagation of these metastable PrPSc conformers requires appropriate shaking conditions, and changes in these conditions cause all the different PrPSc conformers to converge irreversibly into the same single conformer as that produced in sPMCA reactions. We also use continuous shaking to show that two mutant PrP molecules with different pathogenic point mutations (D177N and E199K) adopt distinguishable PrPSc conformations in reactions containing pure protein substrate without cofactors. Unlike wild-type prions, the conformations of mutant prions appear to be dictated by substrate sequence rather than seed conformation. Overall, our studies using purified substrates in shaking reactions show that wild-type and mutant prions use fundamentally different mechanisms to generate conformational diversity at the molecular level.

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10

Barreca, Maria, Nunzio Iraci, Silvia Biggi, Violetta Cecchetti, and Emiliano Biasini. "Pharmacological Agents Targeting the Cellular Prion Protein." Pathogens 7, no. 1 (March 7, 2018): 27. http://dx.doi.org/10.3390/pathogens7010027.

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Prion diseases are associated with the conversion of the cellular prion protein (PrPC), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrPSc) that accumulates in brain tissues of affected individuals. PrPSc is a self-catalytic protein assembly capable of recruiting native conformers of PrPC, and causing their rearrangement into new PrPSc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrPSc, and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrPSc might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrPC, the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrPC in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrPC, discussing pharmacological properties and therapeutic potentials of each chemical class.

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Sahini, Victor, and Gabriela Ionita. "Evidence of changes in hydrophilic/hydrophobic balance and in chemical activity of HSA induced by thermal treatments." Open Chemistry 9, no. 2 (April 1, 2011): 245–52. http://dx.doi.org/10.2478/s11532-010-0148-2.

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AbstractSamples of human serum albumin (HSA) obtained as a result of heat denaturation followed by refolding controlled by a cooling of the protein solution were studied by several methods: chromatographic measurements, kinetic of the reaction with a water soluble free radical and by electron paramagnetic resonance (EPR) spectroscopy. In this context the interaction of this protein with β-cyclodextrin (β-CD) and sodium dodecyl sulfate (SDS) was also investigated. Reversed phase thin layer chromatography (RP-TLC) showed changes in lipophylicity of HSA, which are related with the existence of different ensembles of conformers. The UV-Vis absorption spectra had shown the broadening of absorption band of the protein and a hyperchrom effect in the presence of SDS; β-CD reduces the effect of SDS on protein UV-Vis spectra.Kinetic measurements related to the reaction of HSA with a water soluble DPPH type free radical provided evidence that reactivity of the HSA denaturated conformers is higher compared with the natural conformer. The affinity of SDS to the albumins surface and the effect of β-CD on the SDS/protein aggregates were also evident by changes in the EPR spectra of the spin probe CAT16.

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Guo, Xiang, Jincheng Han, Ray Luo, and Hai-Feng Chen. "Conformation dynamics of the intrinsically disordered protein c-Myb with the ff99IDPs force field." RSC Advances 7, no. 47 (2017): 29713–21. http://dx.doi.org/10.1039/c7ra04133k.

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13

Chen, Shih-Cheng, and René C. L. Olsthoorn. "In Vitro and In Vivo Studies of the RNA Conformational Switch in Alfalfa Mosaic Virus." Journal of Virology 84, no. 3 (November 18, 2009): 1423–29. http://dx.doi.org/10.1128/jvi.01443-09.

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ABSTRACT The 3′ termini of Alfalfa mosaic virus (AMV) RNAs adopt two mutually exclusive conformations, a coat protein binding (CPB) and a tRNA-like (TL) conformer, which consist of a linear array of stem-loop structures and a pseudoknot structure, respectively. Previously, switching between CPB and TL conformers has been proposed as a mechanism to regulate the competing processes of translation and replication of the viral RNA (R. C. L. Olsthoorn et al., EMBO J. 18:4856-4864, 1999). In the present study, the switch between CPB and TL conformers was further investigated. First, we showed that recognition of the AMV 3′ untranslated region (UTR) by a tRNA-specific enzyme (CCA-adding enzyme) in vitro is more efficient when the distribution is shifted toward the TL conformation. Second, the recognition of the 3′ UTR by the viral replicase was similarly dependent on the ratio of CBP and TL conformers. Furthermore, the addition of CP, which is expected to shift the distribution toward the CPB conformer, inhibited recognition by the CCA-adding enzyme and the replicase. Finally, we monitored how the binding affinity to CP is affected by this conformational switch in the yeast three-hybrid system. Here, disruption of the pseudoknot enhanced the binding affinity to CP by shifting the balance in favor of the CPB conformer, whereas stabilizing the pseudoknot did the reverse. Together, the in vitro and in vivo data clearly demonstrate the existence of the conformational switch in the 3′ UTR of AMV RNAs.

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14

Futamura, Akinori, Sotaro Hieda, Yukiko Mori, Kensaku Kasuga, Azusa Sugimoto, Hideyo Kasai, Takeshi Kuroda, et al. "Toxic Amyloid-β42 Conformer May Accelerate the Onset of Alzheimer’s Disease in the Preclinical Stage." Journal of Alzheimer's Disease 80, no. 2 (March 23, 2021): 639–46. http://dx.doi.org/10.3233/jad-201407.

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Background: Toxic amyloid-β protein (Aβ) conformers play an important role in the progression of Alzheimer’s disease (AD). The ratio of toxic conformer to total Aβ42 in cerebrospinal fluid (CSF) was significantly high in AD and mild cognitive impairment (MCI) due to AD using an enzyme-linked immunosorbent assay kit with a 24B3 antibody. Objective: We compared the toxic Aβ42, conformer at different stages of AD to identify its contribution to AD pathogenesis. Methods: We compared 5 patients with preclinical AD, 11 patients with MCI due to AD, 21 patients with AD, and 5 healthy controls to measure CSF levels of total Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), and toxic Aβ conformers. All were classified using the Clinical Dementia Rating. Cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE-J). Results: Toxic Aβ conformer level was insignificant between groups, but its ratio to Aβ42 was significantly higher in AD than in preclinical AD (p < 0.05). Toxic Aβ42 conformer correlated positively with p-tau (r = 0.67, p < 0.01) and p-tau correlated negatively with MMSE-J (r = –0.38, p < 0.05). Conclusion: Toxic Aβ conformer triggers tau accumulation leading to neuronal impairment in AD pathogenesis.

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Ghaemmaghami, Sina, Julie Ullman, Misol Ahn, Susan St. Martin, and Stanley B. Prusiner. "Chemical Induction of Misfolded Prion Protein Conformers in Cell Culture." Journal of Biological Chemistry 285, no. 14 (December 2, 2009): 10415–23. http://dx.doi.org/10.1074/jbc.m109.045112.

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16

Young, Lawrence J., and Lewis M. Siegel. "Activated conformers of Escherichia coli sulfite reductase heme protein subunit." Biochemistry 27, no. 14 (July 12, 1988): 4991–99. http://dx.doi.org/10.1021/bi00414a007.

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Kuprowski, Mark C., and Lars Konermann. "Signal Response of Coexisting Protein Conformers in Electrospray Mass Spectrometry." Analytical Chemistry 79, no. 6 (March 2007): 2499–506. http://dx.doi.org/10.1021/ac0620056.

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Nowalk, Andrew J., Kevin G. Vaughan, Billy W. Day, Sarah B. Tencza, and Timothy A. Mietzner. "Metal-Dependent Conformers of the Periplasmic Ferric Ion Binding Protein†." Biochemistry 36, no. 42 (October 1997): 13054–59. http://dx.doi.org/10.1021/bi971413o.

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Bouvignies, Guillaume, Pramodh Vallurupalli, and Lewis E. Kay. "Visualizing Side Chains of Invisible Protein Conformers by Solution NMR." Journal of Molecular Biology 426, no. 3 (February 2014): 763–74. http://dx.doi.org/10.1016/j.jmb.2013.10.041.

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20

Smirnova, Irina, Vladimir Kasho, Xiaoxu Jiang, Els Pardon, Jan Steyaert, and H. Ronald Kaback. "Transient conformers of LacY are trapped by nanobodies." Proceedings of the National Academy of Sciences 112, no. 45 (October 28, 2015): 13839–44. http://dx.doi.org/10.1073/pnas.1519485112.

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The lactose permease of Escherichia coli (LacY), a highly dynamic membrane protein, catalyzes symport of a galactopyranoside and an H+ by using an alternating access mechanism, and the transport cycle involves multiple conformational states. Single-domain camelid nanobodies (Nbs) developed against a LacY mutant immobilized in an outward (periplasmic)-open conformation bind to the flexible WT protein and stabilize the open-outward conformation(s). Here, we use site-directed, distance-dependent Trp quenching/unquenching of fluorescent probes inserted on opposite surfaces of LacY to assess the conformational states of the protein complexed with each of eight unique Nbs that bind exclusively to the periplasmic side and block transport, but increase the accessibility of the sugar-binding site. Nb binding involves conformational selection of LacY molecules with exposed binding epitopes. Each of eight Nbs induces quenching with three pairs of cytoplasmic Trp/fluorophore probes, indicating closing of cytoplasmic cavity. In reciprocal fashion, the same Nbs induce unquenching of fluorescence in three pairs of periplasmic probes due to opening of the periplasmic cavity. Because the extent of fluorescence change with various Nbs differs and the differences correlate with changes in the rate of sugar binding, it is also concluded that the Nbs stabilize several different outward-open conformations of LacY.

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Xu, Xingjian, Igor Dikiy, Matthew R. Evans, Leandro P. Marcelino, and Kevin H. Gardner. "Fragile protein folds: sequence and environmental factors affecting the equilibrium of two interconverting, stably folded protein conformations." Magnetic Resonance 2, no. 1 (March 10, 2021): 63–76. http://dx.doi.org/10.5194/mr-2-63-2021.

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Abstract. Recent research on fold-switching metamorphic proteins has revealed some notable exceptions to Anfinsen's hypothesis of protein folding. We have previously described how a single point mutation can enable a well-folded protein domain, one of the two PAS (Per-ARNT-Sim) domains of the human ARNT (aryl hydrocarbon receptor nuclear translocator) protein, to interconvert between two conformers related by a slip of an internal β strand. Using this protein as a test case, we advance the concept of a “fragile fold”, a protein fold that can reversibly rearrange into another fold that differs by a substantial number of hydrogen bonds, entailing reorganization of single secondary structure elements to more drastic changes seen in metamorphic proteins. Here we use a battery of biophysical tests to examine several factors affecting the equilibrium between the two conformations of the switching ARNT PAS-B Y456T protein. Of note is that we find that factors which impact the HI loop preceding the shifted Iβ strand affect both the equilibrium levels of the two conformers and the denatured state which links them in the interconversion process. Finally, we describe small molecules that selectively bind to and stabilize the wild-type conformation of ARNT PAS-B. These studies form a toolkit for studying fragile protein folds and could enable ways to modulate the biological functions of such fragile folds, both in natural and engineered proteins.

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Akasaka, Kazuyuki. "Exploring the entire conformational space of proteins by high-pressure NMR." Pure and Applied Chemistry 75, no. 7 (January 1, 2003): 927–36. http://dx.doi.org/10.1351/pac200375070927.

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A protein in solution is a thermodynamic entity, spanning, in principle, the entire allowed conformational space from the fully folded N to the fully unfolded U. Although some alternately or partially folded higher-energy conformers may coexist with N and U, they are seldom detected spectroscopically because their populations are usually quite low under physiological conditions. I describe here a new type of experiment, a combination of multidimensional NMR spectroscopy with pressure, that is capable of detecting and analyzing structures and thermodynamic stability of these higher-energy conformers. The idea is based on the finding that under physiological conditions the conformational order of a globular protein normally decreases in parallel with its partial molar volume (negative δV), so that under equilibrium conditions, the population is shifted to a less and-less-ordered conformer with increasing pressure. In principle, with the high space resolution of the multidimensional NMR, the method enables one to explore protein structure and stability in atomic detail in a wide conformational space from N to U with pressure and temperature as variables. The method will provide us with a strong basis for understanding the fundamental phenomena of proteins:function, folding, and aggregation.

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Maki, Takahito, Masahito Sawahata, Ichiro Akutsu, Shohei Amaike, Genki Hiramatsu, Daisuke Uta, Naotaka Izuo, Takahiko Shimizu, Kazuhiro Irie, and Toshiaki Kume. "APP Knock-In Mice Produce E22P-Aβ Exhibiting an Alzheimer’s Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression." International Journal of Molecular Sciences 23, no. 21 (October 31, 2022): 13259. http://dx.doi.org/10.3390/ijms232113259.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that requires further pathological elucidation to establish effective treatment strategies. We previously showed that amyloid β (Aβ) toxic conformer with a turn at positions 22–23 is essential for forming highly toxic oligomers. In the present study, we evaluated phenotypic changes with aging in AD model AppNL-P-F/NL-P-F (NL-P-F) mice with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Aβ, a mimic of toxic conformer utilizing the knock-in technique. Furthermore, the role of the toxic conformer in AD pathology was investigated. NL-P-F mice produced soluble toxic conformers from an early age. They showed impaired synaptic plasticity, glial cell activation, and cognitive decline, followed by the accumulation of Aβ plaques and tau hyperphosphorylation. In addition, the protein expression of hypoxia-inducible factor (HIF)-1α was increased, and gene expression of HIF-3α was decreased in NL-P-F mice. HIF dysregulation due to the production of soluble toxic conformers may be involved in AD pathology in NL-P-F mice. This study could reveal the role of a highly toxic Aβ on AD pathogenesis, thereby contributing to the development of a novel therapeutic strategy targeting the toxic conformer.

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Hromadkova, Lenka, Mohammad Khursheed Siddiqi, He Liu, and Jiri G. Safar. "Populations of Tau Conformers Drive Prion-like Strain Effects in Alzheimer’s Disease and Related Dementias." Cells 11, no. 19 (September 26, 2022): 2997. http://dx.doi.org/10.3390/cells11192997.

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Recent findings of diverse populations of prion-like conformers of misfolded tau protein expand the prion concept to Alzheimer’s disease (AD) and monogenic frontotemporal lobar degeneration (FTLD)-MAPT P301L, and suggest that distinct strains of misfolded proteins drive the phenotypes and progression rates in many neurodegenerative diseases. Notable progress in the previous decades has generated many lines of proof arguing that yeast, fungal, and mammalian prions determine heritable as well as infectious traits. The extraordinary phenotypic diversity of human prion diseases arises from structurally distinct prion strains that target, at different progression speeds, variable brain structures and cells. Although human prion research presents beneficial lessons and methods to study the mechanism of strain diversity of protein-only pathogens, the fundamental molecular mechanism by which tau conformers are formed and replicate in diverse tauopathies is still poorly understood. In this review, we summarize up to date advances in identification of diverse tau conformers through biophysical and cellular experimental paradigms, and the impact of heterogeneity of pathological tau strains on personalized structure- and strain-specific therapeutic approaches in major tauopathies.

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Gumerov, Dmitry R., Andras Dobo, and Igor A. Kaltashov. "Protein—Ion Charge-State Distributions in Electrospray Ionization Mass Spectrometry: Distinguishing Conformational Contributions from Masking Effects." European Journal of Mass Spectrometry 8, no. 2 (April 2002): 123–29. http://dx.doi.org/10.1255/ejms.480.

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Electrospray ionization mass spectrometry (ESI-MS) is often used to monitor protein conformational dynamics in solution, for example acid unfolding, by following the changes in positive-ion charge-state distributions in response to changes of ambient conditions, for example solution pH. Deconvolution of these charge-state distributions often reveals the presence of multiple protein conformers coexisting in solution in equilibrium. The ion signal corresponding to each conformer depends on its size (which determines the average charge state of the protein ions) and heterogeneity (which determines the spread of the ion signal). In the present work, we seek to explore how the ion signal of individual protein conformers can be influenced by other factors not related to protein shape, with particular attention being paid to contributions from solution acid-base chemistry. The composition of the buffer was found to exert a significant influence on the ion signal by inducing apparent charge reduction of the protein ions. This effect was ascribed to protein-base (anion) complex formation in solution followed by dissociation of the neutral conjugated acid from the complex in the gas-phase. The resulting shift in the charge-state distribution occurs in the pH range from p Ka to approximately (p Ka −1.5) and is induced by the elevated concentration of the anion in solution. On the other hand, intrinsic charges on the protein in solution have been shown to have no effect on the appearance of the charge-state distributions, lending further credibility to the notion that protein shape is the only structural determinant of the ion signal in ESI-MS.

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Kurpiewska, Katarzyna, and Krzysztof Lewiński. "High pressure macromolecular crystallography for structural biology: a review." Open Life Sciences 5, no. 5 (October 1, 2010): 531–42. http://dx.doi.org/10.2478/s11535-010-0044-y.

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AbstractIn recent years, significant progress in high pressure macromolecular crystallography has been observed. It can be attributed both to the developments in experimental techniques, as well as to recognition of importance of high pressure protein studies in biochemistry and biophysics. The number of protein structures determined at pressure up to 1 GPa is growing. The unique advantages of this method can greatly improve the investigation of higher energy conformers of functional significance and our understanding of functionally important conformers, protein folding processes and the structural base of conformational diseases.

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Scott, M. R., D. Groth, J. Tatzelt, M. Torchia, P. Tremblay, S. J. DeArmond, and S. B. Prusiner. "Propagation of prion strains through specific conformers of the prion protein." Journal of virology 71, no. 12 (1997): 9032–44. http://dx.doi.org/10.1128/jvi.71.12.9032-9044.1997.

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Broersen, Kerensa, Mireille Weijers, Jolan de Groot, Rob J. Hamer, and de Jongh. "Effect of Protein Charge on the Generation of Aggregation-Prone Conformers." Biomacromolecules 8, no. 5 (May 2007): 1648–56. http://dx.doi.org/10.1021/bm0612283.

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Muir, T. W., M. J. Williams, and S. B. H. Kent. "Detection of Synthetic Protein Isomers and Conformers by Electrospray Mass Spectrometry." Analytical Biochemistry 224, no. 1 (January 1995): 100–109. http://dx.doi.org/10.1006/abio.1995.1013.

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Yan, Xin, and Robert B. Denman. "Conformational-Dependent and Independent RNA Binding to the Fragile X Mental Retardation Protein." Journal of Nucleic Acids 2011 (2011): 1–14. http://dx.doi.org/10.4061/2011/246127.

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The interaction between the fragile X mental retardation protein (FMRP) and BC1 RNA has been the subject of controversy. We probed the parameters of RNA binding to FMRP in several ways. Nondenaturing agarose gel analysis showed that BC1 RNA transcripts produced by in vitro transcription contain a population of conformers, which can be modulated by preannealing. Accordingly, FMRP differentially binds to the annealed and unannealed conformer populations. Using partial RNase digestion, we demonstrate that annealed BC1 RNA contains a unique conformer that FMRP likely binds. We further demonstrate that this interaction is 100-fold weaker than that the binding of eEF-1A mRNA and FMRP, and that preannealing is not a general requirement for FMRP's interaction with RNA. In addition, binding does not require the N-terminal 204 amino acids of FMRP, methylated arginine residues and can be recapitulated by both fragile X paralogs. Altogether, our data continue to support a model in which BC1 RNA functions independently of FMRP.

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Pogonin, Aleksandr E., George A. Gamov, Maksim N. Zavalishin, and Valentin A. Sharnin. "CONFORMATIONAL BEHAVIOR OF HYDRAZONE DERIVED FROM PYRIDOXAL 5’-PHOSPHATE AND ISONIAZID." IZVESTIYA VYSSHIKH UCHEBNYKH ZAVEDENIY KHIMIYA KHIMICHESKAYA TEKHNOLOGIYA 61, no. 12 (December 12, 2018): 101–7. http://dx.doi.org/10.6060/ivkkt.20186112.5846.

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The hydrazones derived from pyridoxal or pyridoxal 5’-phosphate and heterocyclic hydrazides are of interest due to their potential biological activity and metal sensing properties. These characteristics of hydrazones could be dependent on the conformation equilibria of molecule since the most stable conformer could differ from the one with the highest affinity towards biomolecule or metal ion. In the present contribution, deprotonated hydrazone formed by pyridoxal 5’-phosphate and isoniazid (PLP-INH3-) was studied by means of quantum chemistry. Three rotations leading to eight conformers are possible for this hydrazone; however, four of those species obtained by rotation of pyridine ring of isoniazid residue are degenerated. The geometry of different non-degenerated rotation conformers of the hydrazine (differing by the mutual arrangement of carbonyl group of the isoniazid residue and oxygen in 3’-site of PLP moiety) was optimized using density functional theory (B3LYP/6-311++G(d,p)). Activation barriers were evaluated. Changes in energy and geometry of conformers as well as transition states are discussed. Quantitative QTAIM (Quantum Theory of Atoms in Molecules) analysis was performed in order to check the intermolecular hydrogen bonding existence. The species capable of forming the complex with the metal ions differs from the most stable (according to the total energy values) conformer. The preliminary prediction of biological activity of PLP-INH3- hydrazone and the docking for the hydrazone and G-protein-coupled receptor kinase were performed and the preferable conformation for ligand binding to the kinase active site was found.

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Champenois, E. G., D. M. Sanchez, J. Yang, J. P. Figueira Nunes, A. Attar, M. Centurion, R. Forbes, et al. "Conformer-specific photochemistry imaged in real space and time." Science 374, no. 6564 (October 8, 2021): 178–82. http://dx.doi.org/10.1126/science.abk3132.

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Conformer-specific dynamics Conformation-dependent dynamics play an important role in organic chemistry syntheses such as electrocyclic reactions, as well as in biological processes such as protein folding. However, current time-resolved experimental methods struggle to distinguish conformers from each other, and conformational isomerism is usually analyzed through reactant and product distributions. Using a combination of mega–electron volt ultrafast electron diffraction and quantum wave packet simulations, Champenois et al . directly followed the photochemical electrocyclic ring opening of the molecule α-phellandrene with femtosecond time resolution and confirmed that the transformation of a specific molecular conformer follows the famous Woodward-Hoffmann rules. The proposed method is potentially a powerful tool to follow conformer specificity in various organic and biological systems in real time. —YS

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Rolfsson, Ottar, Katerina Toropova, Victoria Morton, Simona Francese, Gabriella Basnak, Gary S. Thompson, Stephen W. Homans, et al. "RNA Packing Specificity and Folding during Assembly of the Bacteriophage MS2." Computational and Mathematical Methods in Medicine 9, no. 3-4 (2008): 339–49. http://dx.doi.org/10.1080/17486700802168445.

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Using a combination of biochemistry, mass spectrometry, NMR spectroscopy and cryo-electron microscopy (cryo-EM), we have been able to show that quasi-equivalent conformer switching in the coat protein (CP) of an RNA bacteriophage (MS2) is controlled by a sequence-specific RNA–protein interaction. The RNA component of this complex is an RNA stem-loop encompassing just 19 nts from the phage genomic RNA, which is 3569 nts in length. This binding results in the conversion of a CP dimer from a symmetrical conformation to an asymmetric one. Only when both symmetrical and asymmetrical dimers are present in solution is assembly of theT = 3 phage capsid efficient. This implies that the conformers, we have characterized by NMR correspond to the two distinct quasi-equivalent conformers seen in the 3D structure of the virion. An icosahedrally-averaged single particle cryo-EM reconstruction of the wild-type phage (to ∼9 Å resolution) has revealed icosahedrally ordered density encompassing up to 90% of the single-stranded RNA genome. The RNA is seen with a novel arrangement of two concentric shells, with connections between them along the 5-fold symmetry axes. RNA in the outer shell interacts with each of the 90 CP dimers in theT = 3 capsid and although the density is icosahedrally averaged, there appears to be a different average contact at the different quasi-equivalent protein dimers: precisely the result that would be expected if protein conformer switching is RNA-mediated throughout the assembly pathway. This unprecedented RNA structure provides new constraints for models of viral assembly and we describe experiments aimed at probing these. Together, these results suggest that viral genomic RNA folding is an important factor in efficient assembly, and further suggest that RNAs that could sequester viral CPs but not fold appropriately could act as potent inhibitors of viral assembly.

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Nikiforovich, G. V., S. Galaktionov, J. Balodis, and G. R. Marshall. "Novel approach to computer modeling of seven-helical transmembrane proteins: current progress in the test case of bacteriorhodopsin." Acta Biochimica Polonica 48, no. 1 (March 31, 2001): 53–64. http://dx.doi.org/10.18388/abp.2001_5111.

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G-protein coupled receptors (GPCRs) are thought to be proteins with 7-membered transmembrane helical bundles (7TM proteins). Recently, the X-ray structures have been solved for two such proteins, namely for bacteriorhodopsin (BR) and rhodopsin (Rh), the latter being a GPCR. Despite similarities, the structures are different enough to suggest that 3D models for different GPCRs cannot be obtained directly employing 3D structures of BR or Rh as a unique template. The approach to computer modeling of 7TM proteins developed in this work was capable of reproducing the experimental X-ray structure of BR with great accuracy. A combination of helical packing and low-energy conformers for loops most close to the X-ray structure possesses the r.m.s.d. value of 3.13 A. Such a level of accuracy for the 3D-structure prediction for a 216-residue protein has not been achieved, so far, by any available ab initio procedure of protein folding. The approach may produce also other energetically consistent combinations of helical bundles and loop conformers, creating a variety of possible templates for 3D structures of 7TM proteins, including GPCRs. These templates may provide experimentalists with various plausible options for 3D structure of a given GPCR; in our view, only experiments will determine the final choice of the most reasonable 3D template.

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Ahinko, Mira, Sami T. Kurkinen, Sanna P. Niinivehmas, Olli T. Pentikäinen, and Pekka A. Postila. "A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening." International Journal of Molecular Sciences 20, no. 11 (June 6, 2019): 2779. http://dx.doi.org/10.3390/ijms20112779.

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Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users.

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Hsueh, Shu-Shun, S. S. (Steven) Wang, Shu-Han Chen, Chia-Lin Wang, W. (Josephine) Wu, and Ta-Hsien Lin. "Insights to Human γD-Crystallin Unfolding by NMR Spectroscopy and Molecular Dynamics Simulations." International Journal of Molecular Sciences 23, no. 3 (January 29, 2022): 1591. http://dx.doi.org/10.3390/ijms23031591.

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Human γD-crystallin (HGDC) is an abundant lens protein residing in the nucleus of the human lens. Aggregation of this and other structural proteins within the lens leads to the development of cataract. Much has been explored on the stability and aggregation of HGDC and where detailed investigation at the atomic resolution was needed, the X-ray structure was used as an initial starting conformer for molecular modeling. In this study, we implemented NMR-solution HGDC structures as starting conformers for molecular dynamics simulations to provide the missing pieces of the puzzle on the very early stages of HGDC unfolding leading up to the domain swap theories proposed by past studies. The high-resolution details of the conformational dynamics also revealed additional insights to possible early intervention for cataractogenesis.

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Yu, Hongjun, Tania J. Lupoli, Amanda Kovach, Xing Meng, Gongpu Zhao, Carl F. Nathan, and Huilin Li. "ATP hydrolysis-coupled peptide translocation mechanism of Mycobacterium tuberculosis ClpB." Proceedings of the National Academy of Sciences 115, no. 41 (September 26, 2018): E9560—E9569. http://dx.doi.org/10.1073/pnas.1810648115.

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The protein disaggregase ClpB hexamer is conserved across evolution and has two AAA+-type nucleotide-binding domains, NBD1 and NBD2, in each protomer. In M. tuberculosis (Mtb), ClpB facilitates asymmetric distribution of protein aggregates during cell division to help the pathogen survive and persist within the host, but a mechanistic understanding has been lacking. Here we report cryo-EM structures at 3.8- to 3.9-Å resolution of Mtb ClpB bound to a model substrate, casein, in the presence of the weakly hydrolyzable ATP mimic adenosine 5′-[γ-thio]triphosphate. Mtb ClpB existed in solution in two closed-ring conformations, conformers 1 and 2. In both conformers, the 12 pore-loops on the 12 NTDs of the six protomers (P1–P6) were arranged similarly to a staircase around the bound peptide. Conformer 1 is a low-affinity state in which three of the 12 pore-loops (the protomer P1 NBD1 and NBD2 loops and the protomer P2 NBD1 loop) are not engaged with peptide. Conformer 2 is a high-affinity state because only one pore-loop (the protomer P2 NBD1 loop) is not engaged with the peptide. The resolution of the two conformations, along with their bound substrate peptides and nucleotides, enabled us to propose a nucleotide-driven peptide translocation mechanism of a bacterial ClpB that is largely consistent with several recent unfoldase structures, in particular with the eukaryotic Hsp104. However, whereas Hsp104’s two NBDs move in opposing directions during one step of peptide translocation, in Mtb ClpB the two NBDs move only in the direction of translocation.

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Josefson, Rebecca, Rebecca Andersson, and Thomas Nyström. "How and why do toxic conformers of aberrant proteins accumulate during ageing?" Essays in Biochemistry 61, no. 3 (May 24, 2017): 317–24. http://dx.doi.org/10.1042/ebc20160085.

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Ageing can be defined as a gradual decline in cellular and physical functions accompanied by an increased sensitivity to the environment and risk of death. The increased risk of mortality is causally connected to a gradual, intracellular accumulation of so-called ageing factors, of which damaged and aggregated proteins are believed to be one. Such aggregated proteins also contribute to several age-related neurodegenerative disorders e.g. Alzheimer’s, Parkinson’s, and Huntington’s diseases, highlighting the importance of protein quality control (PQC) in ageing and its associated diseases. PQC consists of two interrelated systems: the temporal control system aimed at refolding, repairing, and/or removing aberrant proteins and their aggregates and the spatial control system aimed at harnessing the potential toxicity of aberrant proteins by sequestering them at specific cellular locations. The accumulation of toxic conformers of aberrant proteins during ageing is often declared to be a consequence of an incapacitated temporal PQC system—i.e. a gradual decline in the activity of chaperones and proteases. Here, we review the current knowledge on PQC in relation to ageing and highlight that the breakdown of both temporal and spatial PQC may contribute to ageing and thus comprise potential targets for therapeutic interventions of the ageing process.

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Laine, Roney O., and Alfred F. Esser. "Detection of refolding conformers of complement protein C9 during insertion into membranes." Nature 341, no. 6237 (September 1989): 63–65. http://dx.doi.org/10.1038/341063a0.

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Shvartsburg, Alexandre A., and Richard D. Smith. "Separation of Protein Conformers by Differential Ion Mobility in Hydrogen-Rich Gases." Analytical Chemistry 85, no. 14 (June 25, 2013): 6967–73. http://dx.doi.org/10.1021/ac4015963.

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Cavatorta, P., L. Masotti, A. G. Szabo, D. Juretic, P. Piccio, and E. Quagliariello. "Fluorescence spectral resolution of myelin basic protein conformers in complexes with lysophosphatidylcholine." Cell Biophysics 13, no. 3 (December 1988): 201–15. http://dx.doi.org/10.1007/bf02918376.

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Jung, Byung Chul, Yoon-Ju Lim, Eun-Jin Bae, Jun Sung Lee, Min Sun Choi, Michael K. Lee, He-Jin Lee, Yoon Suk Kim, and Seung-Jae Lee. "Amplification of distinct α-synuclein fibril conformers through protein misfolding cyclic amplification." Experimental & Molecular Medicine 49, no. 4 (April 2017): e314-e314. http://dx.doi.org/10.1038/emm.2017.1.

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Purves, Randy W., Barbara Ells, David A. Barnett, and Roger Guevremont. "Combining HD exchange and ESI-FAIMS-MS for detecting gas-phase conformers of equine cytochrome c." Canadian Journal of Chemistry 83, no. 11 (November 1, 2005): 1961–68. http://dx.doi.org/10.1139/v05-215.

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Conformers of equine cytochrome c were investigated in the gas phase using a combination of high-field asymmetric waveform ion mobility spectrometry (FAIMS) and hydrogendeuterium (HD) exchange. Electrospray generated ions of equine cytochrome c were exposed to a low concentration of D2O vapour while being transported by a flow of nitrogen through a FAIMS device. During this transport period of about 250 ms in the FAIMS analyzer, the various conformers of multiply charged ions of cytochrome c were simultaneously undergoing HD exchange and being separated from each other. The extent of HD exchange was calculated from the observed m/z of conformers after exposure to D2O vapour in FAIMS. The complementary nature of these two methods resulted in observations supporting a greater number of conformers (e.g., at least 11 conformers were identified for the +16 charge state) than would be expected by analyzing the FAIMS data and the HD exchange data independently.Key words: FAIMS, HD exchange, mass spectrometry, protein conformations, electrospray ionization.

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44

Rother, Kristian, Mathias Dunkel, Elke Michalsky, Silke Trissl, Andrean Goede, Ulf Leser, and Robert Preissner. "A structural keystone for drug design." Journal of Integrative Bioinformatics 3, no. 1 (June 1, 2006): 21–31. http://dx.doi.org/10.1515/jib-2006-19.

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Abstract 3D-structures of proteins and potential ligands are the cornerstones of rational drug design. The first brick to build upon is selecting a protein target and finding out whether biologically active compounds are known. Both tasks require more information than the structures themselves provide. For this purpose we have built a web resource bridging protein and ligand databases. It consists of three parts: i) A data warehouse on annotation of protein structures that integrates many well-known databases such as Swiss-Prot, SCOP, ENZYME and others. ii) A conformational library of structures of approved drugs. iii) A conformational library of ligands from the PDB, linking the realms of proteins and small molecules. The data collection contains structures of 30,000 proteins, 5,000 different ligands from 70,000 ligand-protein complexes, and 2,500 known drugs. Sets of protein structures can be refined by criteria like protein fold, family, metabolic pathway, resolution and textual annotation. The structures of organic compounds (drugs and ligands) can be searched considering chemical formula, trivial and trade names as well as medical classification codes for drugs (ATC). Retrieving structures by 2D-similarity has been implemented for all small molecules using Tanimoto coefficients. For the drug structures, 110,000 structural conformers have been calculated to account for structural flexibility. Two substances can be compared online by 3D-superimposition, where the pair of conformers that fits best is detected. Together, these web-accessible resources can be used to identify promising drug candidates. They have been used in-house to find alternatives to substances with a known binding activity but adverse side effects.

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Panicker, Sumith R., Indranil Biswas, Hemant Giri, Xiaofeng Cai, and Alireza R. Rezaie. "PKC (Protein Kinase C)-δ Modulates AT (Antithrombin) Signaling in Vascular Endothelial Cells." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 7 (July 2020): 1748–62. http://dx.doi.org/10.1161/atvbaha.120.314479.

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Objective: Native and latent conformers of AT (antithrombin) induce anti-inflammatory and proapoptotic signaling activities, respectively, in vascular endothelial cells by unknown mechanisms. Synd-4 (syndecan-4) has been identified as a receptor that is involved in transmitting signaling activities of AT in endothelial cells. Approach and Results: In this study, we used flow cytometry, signaling assays, immunoblotting and confocal immunofluorescence microscopy to investigate the mechanism of the paradoxical signaling activities of high-affinity heparin (native) and low-affinity heparin (latent) conformers of AT in endothelial cells. We discovered that native AT binds to glycosaminoglycans on vascular endothelial cells via its heparin-binding D-helix to induce anti-inflammatory signaling responses by recruiting PKC (protein kinase C)-δ to the plasma membrane and promoting phosphorylation of the Synd-4 cytoplasmic domain at Ser179. By contrast, the binding of latent AT to endothelial cells to a site(s), which is not competed by the native AT, induces a proapoptotic effect by localizing PKC-δ to the perinuclear/nuclear compartment in endothelial cells. Overexpression of a dominant-negative form of PKC-δ resulted in inhibition of anti-inflammatory and proapoptotic signaling activities of both native and latent AT. Conclusions: These results indicate that the native and latent conformers of AT may exert their distinct intracellular signaling effects through differentially modulating the subcellular localization of PKC-δ in endothelial cells.

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Duque Velásquez, Camilo, Chae Kim, Tracy Haldiman, Chiye Kim, Allen Herbst, Judd Aiken, Jiri G. Safar, and Debbie McKenzie. "Chronic wasting disease (CWD) prion strains evolve via adaptive diversification of conformers in hosts expressing prion protein polymorphisms." Journal of Biological Chemistry 295, no. 15 (February 28, 2020): 4985–5001. http://dx.doi.org/10.1074/jbc.ra120.012546.

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Chronic wasting disease (CWD) is caused by an unknown spectrum of prions and has become enzootic in populations of cervid species that express cellular prion protein (PrPC) molecules varying in amino acid composition. These PrPC polymorphisms can affect prion transmission, disease progression, neuropathology, and emergence of new prion strains, but the mechanistic steps in prion evolution are not understood. Here, using conformation-dependent immunoassay, conformation stability assay, and protein-misfolding cyclic amplification, we monitored the conformational and phenotypic characteristics of CWD prions passaged through deer and transgenic mice expressing different cervid PrPC polymorphisms. We observed that transmission through hosts with distinct PrPC sequences diversifies the PrPCWD conformations and causes a shift toward oligomers with defined structural organization, replication rate, and host range. When passaged in host environments that restrict prion replication, distinct co-existing PrPCWD conformers underwent competitive selection, stabilizing a new prion strain. Nonadaptive conformers exhibited unstable replication and accumulated only to low levels. These results suggest a continuously evolving diversity of CWD conformers and imply a critical interplay between CWD prion plasticity and PrPC polymorphisms during prion strain evolution.

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Yuan, Jue, Xiangzhu Xiao, John McGeehan, Zhiqian Dong, Ignazio Cali, Hisashi Fujioka, Qingzhong Kong, Geoff Kneale, Pierluigi Gambetti, and Wen-Quan Zou. "Insoluble Aggregates and Protease-resistant Conformers of Prion Protein in Uninfected Human Brains." Journal of Biological Chemistry 281, no. 46 (September 20, 2006): 34848–58. http://dx.doi.org/10.1074/jbc.m602238200.

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Given, James A., and Michael K. Gilson. "A hierarchical method for generating low-energy conformers of a protein-ligand complex." Proteins: Structure, Function, and Genetics 33, no. 4 (December 1, 1998): 475–95. http://dx.doi.org/10.1002/(sici)1097-0134(19981201)33:4<475::aid-prot3>3.0.co;2-b.

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Ohkawa, Kousaku, Masakazu Hachisu, Takaomi Nomura, Ryoichi Arai, Kimio Hirabayashi, Masuhiro Tsukada, and Koji Abe. "Chain Conformational Study on Underwater Silk Proteins from Caddisfly, Stenopsyche marmorata - Implication of a Fiber-Forming Mechanism." Advanced Materials Research 796 (September 2013): 3–8. http://dx.doi.org/10.4028/www.scientific.net/amr.796.3.

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Larval silk/cement proteins from a caddisfly, Stenopsyche marmorata, were isolated as a protein mixture of Smsp-1, 2, 3 and 4. Smsp-1 is a giant phosphorylated protein, which occupies ca. 45%-mass of the silk gland content, and composed of a long-range periodic amino acid sequences, involving 8 kinds of characteristic segments. The silk protein film was prepared and drawn in water up to 9-folds of the initial axis length, then the drawn film was subjected to polarized FT-IR and WAXD. The results implied that the Smsp-1 backbone adopts two different conformations, one of which was the β-turn-like conformers. The molecular mechanic studies were separately performed to evaluate the solid-state chain structures of the hydrophobic/Pro-rich segments 3 and 4, which are enriched in the primary sequence of Smsp-1, and the results were coincident with those from the vibration spectra and WAXD. The molecular dynamic (MD) studies were also carried out in order to estimate their preferred chain conformations in a solution state. The MD trajectory suggests that the segments 3 and 4 tend to adopt a turn-like conformation, which is a potential precursor of the β-turn-like conformers. In conclusion, the underwater silk proteins have a fiber-forming mechanism, which is substantially different from a silkworm, Bombyx mori.

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Costanzo, Maddalena, and Chiara Zurzolo. "The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration." Biochemical Journal 452, no. 1 (April 25, 2013): 1–17. http://dx.doi.org/10.1042/bj20121898.

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The misfolding and aggregation of specific proteins is a common hallmark of many neurodegenerative disorders, including highly prevalent illnesses such as Alzheimer's and Parkinson's diseases, as well as rarer disorders such as Huntington's and prion diseases. Among these, only prion diseases are ‘infectious’. By seeding misfolding of the PrPC (normal conformer prion protein) into PrPSc (abnormal disease-specific conformation of prion protein), prions spread from the periphery of the body to the central nervous system and can also be transmitted between individuals of the same or different species. However, recent exciting data suggest that the transmissibility of misfolded proteins within the brain is a property that goes way beyond the rare prion diseases. Evidence indicates that non-prion aggregates [tau, α-syn (α-synuclein), Aβ (amyloid-β) and Htt (huntingtin) aggregates] can also move between cells and seed the misfolding of their normal conformers. These findings have enormous implications. On the one hand they question the therapeutical use of transplants, and on the other they indicate that it may be possible to bring these diseases to an early arrest by preventing cell-to-cell transmission. To better understand the prion-like spread of these protein aggregates it is essential to identify the underlying cellular and molecular factors. In the present review we analyse and discuss the evidence supporting prion-like spreading of amyloidogenic proteins, especially focusing on the cellular and molecular mechanisms and their significance.

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Journal articles on the topic 'Protein Conformers'

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