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1
NEMOTO, Takayuki, and Nobuko SATO. "Oligomeric forms of the 90-kDa heat shock protein." Biochemical Journal 330, no. 2 (March 1, 1998): 989–95. http://dx.doi.org/10.1042/bj3300989.
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Two isoforms of the 90-kDa heat shock protein, HSP90α and HSP90β, are present in the cytosol of mammalian cells. Analysis by polyacrylamide gel electrophoresis under nondenaturing conditions (native PAGE) revealed that HSP90α predominantly exists as a homodimer and that HSP90β is present mainly as a monomer [Minami, Kawasaki, Miyata, Suzuki and Yahara (1991) J. Biol. Chem. 266, 10099-10103]. However, only the dimeric form has been observed under other analytical conditions such as gradient centrifugation. In this study, therefore, we investigated native forms of HSP90 by use of immunochemical techniques with isoform-specific monoclonal antibodies recently developed in our laboratory. Glycerol gradient centrifugation at the physiological salt concentration as well as native PAGE analysis of rat liver cytosol revealed oligomeric forms of HSP90α sedimenting at 8-10S as predominant ones. On the other hand, the glycerol gradient centrifugation revealed multiple forms of HSP90β oligomers sedimenting at 6-12S. All of the HSP90β oligomers, however, migrated at 100-kDa monomer and 190-kDa dimer positions on native PAGE. A novel two-dimensional double native PAGE revealed that the entity was converted from the HSP90β dimer to monomers during the electrophoresis. The same PAGE further revealed that the HSP90α oligomer also dissociated into dimers during the electrophoresis. Full-length form of bacterially-expressed human HSP90α migrated as dimers, but a considerable amount did not penetrate into the gel under native PAGE conditions, indicating the existence of oligomeric forms. Electrophoretic studies of deletion mutants of HSP90 demonstrated that the C-terminal 200 amino acids were capable of forming oligomers. Taken together, we conclude that both of the HSP90 isoforms predominantly exist as oligomeric forms in the cytosol even under unstressed conditions but that they artificially dissociate into smaller forms when subjected to native PAGE.
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Harrison, R. A. "Preliminary characterization of the multiple forms of ram sperm hyaluronidase." Biochemical Journal 252, no. 3 (June 15, 1988): 875–82. http://dx.doi.org/10.1042/bj2520875.
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An investigation was made of the inter-relationships and characteristics of various hyaluronidase forms isolated from ram spermatozoa. They were shown to be members of an oligomeric series, apparently formed by intermolecular disulphide cross-linking. Two monomer species were detected, alpha (Mr 89,600) and beta (Mr 81,200). Although the alpha species predominated, the two were evenly distributed throughout the oligomer population, and they shared antigenic determinants; the beta species did not arise from the alpha species as a result of catabolism following cell disruption. The oligomeric series was of the form [Hyal]n, where n = 1, 2, 4, 5, 6, 7 etc.; no trimer was detectable. Though essentially cationic, part of the hyaluronidase population also had anionic characteristics, probably due to oxidation of free thiol groups. In the anionic subpopulation tetramers and higher oligomers predominated, whereas the non-anionic subpopulation was composed of monomers, dimers and tetramers. The pH optimum of the monomer was 4.3 in 0.2 M-NaCl/0.1 M-sodium citrate, whereas that of the anionic oligomers was 4.9. Both serum albumin and polylysine stimulated enzyme activity at pH 4.0 in the absence of NaCl; polylysine was particularly effective. NaCl diminished the stimulatory effects, and essentially suppressed them above the pH optimum. The specific activities of different oligomer populations were the same as that of the monomer, and conversion of oligomers into monomer by reduction had likewise no effect upon the specific activity. Low concentrations of poly(vinyl alcohol), poly(ethylene glycol) or polyvinylpyrrolidone stabilized soluble hyaluronidase activity by preventing the enzyme's binding to surfaces; solutions of anionic oligomers were further stabilized by NaCl. Enzyme preparations were stable for several months frozen in the presence of poly(vinyl alcohol) and salt.
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Larson, Megan E., Susan J. Greimel, Fatou Amar, Michael LaCroix, Gabriel Boyle, Mathew A. Sherman, Hallie Schley, et al. "Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits." Proceedings of the National Academy of Sciences 114, no. 23 (May 22, 2017): E4648—E4657. http://dx.doi.org/10.1073/pnas.1704698114.
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Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression.
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You, Young Suk, Jae-Hoon Kim, Jong-Soo Lee, and Hyeseong Cho. "The mitochodnrial E3 ligase MARCH5 resolves RIG-I and MAVS aggregates in innate immunity." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 222.13. http://dx.doi.org/10.4049/jimmunol.198.supp.222.13.
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Abstract Ubiquitin proteasome system (UPS) on the mitochondrial is one of quality control systems that works as a first line of defense barrier against aggregated or misfolded proteins. In innate immunity formation of the MAVS(Mitochondrial anti-viral signaling protein) oligomers elicits robust type-I interferon induction upon viral infection and however, persistent RIG-I and MAVS complex rather leads to host immunopathology. We recently reported that mitochondria-resident E3 ligase, MARCH5, recognizes the oligomeric form of RIG-I and MAVS complex. MARCH5+/− mice and MARCH5 deficient immune cells exhibited low viral replication and elevated type-I interferon response to viral infection. MARCH5 bound RIG-I and MAVS complex only during viral infection when MAVS forms oligomer. MARCH5 mediates Lys-48-linked poly-ubiquitination chain addition to RIG-I and MAVS oligomer and induces the RIG-I/MAVS monomer. Next, we studies have suggested that a novel function of MARCH5 in inflammation signaling. Together, these data demonstrates that MARCH5 regulates oligomeric RIG-I and MAVS complex.
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Cerf, Emilie, Rabia Sarroukh, Shiori Tamamizu-Kato, Leonid Breydo, Sylvie Derclaye, Yves F. Dufrêne, Vasanthy Narayanaswami, Erik Goormaghtigh, Jean-Marie Ruysschaert, and Vincent Raussens. "Antiparallel β-sheet: a signature structure of the oligomeric amyloid β-peptide." Biochemical Journal 421, no. 3 (July 15, 2009): 415–23. http://dx.doi.org/10.1042/bj20090379.
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AD (Alzheimer's disease) is linked to Aβ (amyloid β-peptide) misfolding. Studies demonstrate that the level of soluble Aβ oligomeric forms correlates better with the progression of the disease than the level of fibrillar forms. Conformation-dependent antibodies have been developed to detect either Aβ oligomers or fibrils, suggesting that structural differences between these forms of Aβ exist. Using conditions which yield well-defined Aβ-(1–42) oligomers or fibrils, we studied the secondary structure of these species by ATR (attenuated total reflection)–FTIR (Fouriertransform infrared) spectroscopy. Whereas fibrillar Aβ was organized in a parallel β-sheet conformation, oligomeric Aβ displayed distinct spectral features, which were attributed to an antiparallel β-sheet structure. We also noted striking similarities between Aβ oligomers spectra and those of bacterial outer membrane porins. We discuss our results in terms of a possible organization of the antiparallel β-sheets in Aβ oligomers, which may be related to reported effects of these highly toxic species in the amyloid pathogenesis associated with AD.
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Tian, Huilai, Eliot Davidowitz, Patricia Lopez, Sharareh Emadi, James Moe, and Michael Sierks. "Trimeric Tau Is Toxic to Human Neuronal Cells at Low Nanomolar Concentrations." International Journal of Cell Biology 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/260787.
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In Alzheimer’s disease (AD), tau aggregates into fibrils and higher order neurofibrillary tangles, a key histopathological feature of AD. However, soluble oligomeric tau species may play a more critical role in AD progression since these tau species correlate better with neuronal loss and cognitive dysfunction. Recent studies show that extracellular oligomeric tau can inhibit memory formation and synaptic function and also transmit pathology to neighboring neurons. However, the specific forms of oligomeric tau involved in toxicity are still unknown. Here, we used two splice variants of recombinant human tau and generated monomeric, dimeric, and trimeric fractions of each isoform. The composition of each fraction was verified chromatographically and also by atomic force microscopy. The toxicity of each fraction toward both human neuroblastoma cells and cholinergic-like neurons was assessed. Trimeric, but not monomeric or dimeric, tau oligomers of both splice variants were neurotoxic at low nanomolar concentrations. Further characterization of tau oligomer species with disease-specific modifications and morphologies is necessary to identify the best targets for the development of biomarker and therapeutic development for AD and related tauopathies.
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Sonnen, Andreas F. P., Jürgen M. Plitzko, and Robert J. C. Gilbert. "Incomplete pneumolysin oligomers form membrane pores." Open Biology 4, no. 4 (April 2014): 140044. http://dx.doi.org/10.1098/rsob.140044.
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Pneumolysin is a member of the cholesterol-dependent cytolysin (CDC) family of pore-forming proteins that are produced as water-soluble monomers or dimers, bind to target membranes and oligomerize into large ring-shaped assemblies comprising approximately 40 subunits and approximately 30 nm across. This pre-pore assembly then refolds to punch a large hole in the lipid bilayer. However, in addition to forming large pores, pneumolysin and other CDCs form smaller lesions characterized by low electrical conductance. Owing to the observation of arc-like (rather than full-ring) oligomers by electron microscopy, it has been hypothesized that smaller oligomers explain smaller functional pores. To investigate whether this is the case, we performed cryo-electron tomography of pneumolysin oligomers on model lipid membranes. We then used sub-tomogram classification and averaging to determine representative membrane-bound low-resolution structures and identified pre-pores versus pores by the presence of membrane within the oligomeric curve. We found pre-pore and pore forms of both complete (ring) and incomplete (arc) oligomers and conclude that arc-shaped oligomeric assemblies of pneumolysin can form pores. As the CDCs are evolutionarily related to the membrane attack complex/perforin family of proteins, which also form variably sized pores, our findings are of relevance to that class of proteins as well.
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Center, Rob J., Richard D. Leapman, Jacob Lebowitz, Larry O. Arthur, Patricia L. Earl, and Bernard Moss. "Oligomeric Structure of the Human Immunodeficiency Virus Type 1 Envelope Protein on the Virion Surface." Journal of Virology 76, no. 15 (August 1, 2002): 7863–67. http://dx.doi.org/10.1128/jvi.76.15.7863-7867.2002.
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ABSTRACT The envelope protein (Env) of human immunodeficiency virus type 1 forms homo-oligomers in the endoplasmic reticulum. The oligomeric structure of Env is maintained after cleavage in a Golgi compartment and transport to the surfaces of infected cells, where incorporation into budding virions takes place. Here, we use biophysical techniques to assess the oligomeric valency of virion-associated Env prior to fusion activation. Virion-associated Env oligomers were stabilized by chemical cross-linking prior to detergent extraction and were purified by immunoaffinity chromatography. Gel filtration revealed a single predominant oligomeric species, and sedimentation equilibrium analysis-derived mass values indicated a trimeric structure. Determination of the masses of individual Env molecules by scanning transmission electron microscopy demonstrated that virion-associated Env was trimeric, and a triangular morphology was observed in 20 to 30% of the molecules. These results, which firmly establish the oligomeric structure of human immunodeficiency virus virion-associated Env, parallel those of our previous analysis of the simian immunodeficiency virus Env.
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Kvansakul, Marc, Ivan Poon, Amy Baxter, Fung Lay, Grant Mills, Christopher Adda, Jennifer Payne, et al. "NaD1 forms oligomeric complexes with phosphatidylinositol to lyse cell membranes." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1049. http://dx.doi.org/10.1107/s2053273314089505.
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Cationic antimicrobial peptides (CAPs) are innate defense molecules produced by essentially all living species and represent a rich source of novel therapeutic molecules for the treatment of human diseases including cancer. Although several CAPs (mainly from amphibians and vertebrates) have been shown to exhibit direct toxicity against tumor cells, the underlying molecular mechanisms are not well understood. Nicotiana alata (ornamental tobacco) defensin 1, NaD1, is a Class II solanaceous plant defensin in the CAP family that exhibits antifungal activities. We have identified NaD1 as a potent molecule in killing mammalian tumour cells. Microscopy analyses have revealed that NaD1 induces cytolysis of tumor cells via the formation of large plasma membrane blebs. NaD1 was demonstrated to bind directly to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2 or PIP2) resulting in disruption of cytoskeleton-membrane interactions and subsequent plasma membrane blebbing. To define the molecular basis of the interaction between NaD1 and PIP2, we determined the crystal structure of a NaD1:PIP2 complex. Strikingly, NaD1 forms a unique arch-shaped oligomer comprised of seven NaD1 dimers and 14 PIP2. The structure of the protein:lipid complex indicates that the presence of PIP2 is critical for oligomerisation of NaD1. Formation of NaD1:PIP2 oligomers was further confirmed by protein-protein crosslinking and transmission electron microscopy. Based on these data we propose that NaD1 is an innate pattern recognition molecule for PIP2 and forms a unique protein-lipid oligomeric complex that mediates permeabilisation of both microbes and tumour cells.
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Wojciechowska, Daria, Michał Taube, Karolina Rucińska, Joanna Maksim, and Maciej Kozak. "Oligomerization of Human Cystatin C—An Amyloidogenic Protein: An Analysis of Small Oligomeric Subspecies." International Journal of Molecular Sciences 23, no. 21 (November 3, 2022): 13441. http://dx.doi.org/10.3390/ijms232113441.
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Human cystatin C (HCC), an amyloidogenic protein, forms dimers and higher oligomers (trimers, tetramers and donut like large oligomers) via a domain-swapping mechanism. The aim of this study was the characterization of the HCC oligomeric states observed within the pH range from 2.2 to 10.0 and also in conditions promoting oligomerization. The HCC oligomeric forms obtained in different conditions were characterized using size exclusion chromatography, dynamic light scattering and small-angle X-ray scattering. The marked ability of HCC to form tetramers at low pH (2.3 or 3.0) and dimers at pH 4.0–5.0 was observed. HCC remains monomeric at pH levels above 6.0. Based on the SAXS data, the structure of the HCC tetramer was proposed. Changes in the environment (from acid to neutral) induced a breakdown of the HCC tetramers to dimers. The tetrameric forms of human cystatin C are formed by the association of the dimers without a domain-swapping mechanism. These observations were confirmed by their dissociation to dimers at pH 7.4.
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ZEINELDIN, Reema, Suzanne EKBORG, and John BAKER. "Oligomeric forms of the 148 kDa cartilage matrix protein." Biochemical Journal 328, no. 2 (December 1, 1997): 665–68. http://dx.doi.org/10.1042/bj3280665.
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The 148 kDa cartilage matrix protein (CMP), composed of three disulphide-bonded subunits, is a cartilage-specific glycoprotein found in association with fibrils of type II collagen and possibly with aggrecan. It is probable that CMP serves a structural role. As cartilage ages, an increasing proportion of the CMP becomes insoluble and resistant to extraction. In the present study, the isolation of CMP has been improved by inclusion of a hydrophobic chromatography step, thereby removing the remaining traces of collagen and proteoglycan. Evidence of self-association of CMP is presented. Higher-molecular-mass forms of CMP, ranging in apparent molecular mass from 270 to 510 kDa and separated by SDS/PAGE, were located using a specific anti-CMP monoclonal antibody. Both CMP and its oligomeric forms are reducible to 52 kDa subunits, and only trace amounts of other proteins. The formation of oligomers, which may constitute 23% of the total cartilage matrix protein, could occur as a byproduct of the normal biosynthetic trimerization of subunits. Alternatively, the oligomers may represent a step toward the age-related cross-linking and insolubilization of CMP.
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Gyparaki, Melina Theoni, Arian Arab, Elena M. Sorokina, Adriana N. Santiago-Ruiz, Christopher H. Bohrer, Jie Xiao, and Melike Lakadamyali. "Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates." Proceedings of the National Academy of Sciences 118, no. 19 (May 5, 2021): e2021461118. http://dx.doi.org/10.1073/pnas.2021461118.
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Tau is a microtubule-associated protein, which promotes neuronal microtubule assembly and stability. Accumulation of tau into insoluble aggregates known as neurofibrillary tangles (NFTs) is a pathological hallmark of several neurodegenerative diseases. The current hypothesis is that small, soluble oligomeric tau species preceding NFT formation cause toxicity. However, thus far, visualizing the spatial distribution of tau monomers and oligomers inside cells under physiological or pathological conditions has not been possible. Here, using single-molecule localization microscopy, we show that tau forms small oligomers on microtubules ex vivo. These oligomers are distinct from those found in cells exhibiting tau aggregation and could be precursors of aggregated tau in pathology. Furthermore, using an unsupervised shape classification algorithm that we developed, we show that different tau phosphorylation states are associated with distinct tau aggregate species. Our work elucidates tau’s nanoscale composition under nonaggregated and aggregated conditions ex vivo.
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Österlund, Nicklas, Martin Lundqvist, Leopold L. Ilag, Astrid Gräslund, and Cecilia Emanuelsson. "Amyloid-β oligomers are captured by the DNAJB6 chaperone: Direct detection of interactions that can prevent primary nucleation." Journal of Biological Chemistry 295, no. 24 (April 29, 2020): 8135–44. http://dx.doi.org/10.1074/jbc.ra120.013459.
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A human molecular chaperone protein, DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), efficiently inhibits amyloid aggregation. This inhibition depends on a unique motif with conserved serine and threonine (S/T) residues that have a high capacity for hydrogen bonding. Global analysis of kinetics data has previously shown that DNAJB6 especially inhibits the primary nucleation pathways. These observations indicated that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β symbol (Aβ) peptide but with aggregated species. However, these pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here, we employed a native MS-based approach to directly detect oligomeric forms of Aβ formed in solution. We found that WT DNAJB6 considerably reduces the signals from the various forms of Aβ (1–40) oligomers, whereas a mutational DNAJB6 variant in which the S/T residues have been substituted with alanines does not. We also detected signals that appeared to represent DNAJB6 dimers and trimers to which varying amounts of Aβ are bound. These data provide direct experimental evidence that it is the oligomeric forms of Aβ that are captured by DNAJB6 in a manner which depends on the S/T residues. We conclude that, in agreement with the previously observed decrease in primary nucleation rate, strong binding of Aβ oligomers to DNAJB6 inhibits the formation of amyloid nuclei.
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Mishra, Ashish K., Megan Gragg, Michael R. Stoneman, Gabriel Biener, Julie A. Oliver, Przemyslaw Miszta, Slawomir Filipek, Valerică Raicu, and Paul S. H. Park. "Quaternary structures of opsin in live cells revealed by FRET spectrometry." Biochemical Journal 473, no. 21 (October 27, 2016): 3819–36. http://dx.doi.org/10.1042/bcj20160422.
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Rhodopsin is a prototypical G-protein-coupled receptor (GPCR) that initiates phototransduction in the retina. The receptor consists of the apoprotein opsin covalently linked to the inverse agonist 11-cis retinal. Rhodopsin and opsin have been shown to form oligomers within the outer segment disc membranes of rod photoreceptor cells. However, the physiological relevance of the observed oligomers has been questioned since observations were made on samples prepared from the retina at low temperatures. To investigate the oligomeric status of opsin in live cells at body temperatures, we utilized a novel approach called Förster resonance energy transfer spectrometry, which previously has allowed the determination of the stoichiometry and geometry (i.e. quaternary structure) of various GPCRs. In the current study, we have extended the method to additionally determine whether or not a mixture of oligomeric forms of opsin exists and in what proportion. The application of this improved method revealed that opsin expressed in live Chinese hamster ovary (CHO) cells at 37°C exists as oligomers of various sizes. At lower concentrations, opsin existed in an equilibrium of dimers and tetramers. The tetramers were in the shape of a near-rhombus. At higher concentrations of the receptor, higher-order oligomers began to form. Thus, a mixture of different oligomeric forms of opsin is present in the membrane of live CHO cells and oligomerization occurs in a concentration-dependent manner. The general principles underlying the concentration-dependent oligomerization of opsin may be universal and apply to other GPCRs as well.
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Corti, A., G. Fassina, F. Marcucci, E. Barbanti, and G. Cassani. "Oligomeric tumour necrosis factor α slowly converts into inactive forms at bioactive levels." Biochemical Journal 284, no. 3 (June 15, 1992): 905–10. http://dx.doi.org/10.1042/bj2840905.
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The stability of oligomeric human tumour necrasis factor alpha (TNF) at bioactive levels has been studied by two immunoenzymatic assays: one able to specifically detect oligomeric and not monomeric TNF (O-e.l.i.s.a.) and the other able to detect both forms (OM-e.l.i.s.a.). The selectivity of O-e.l.i.s.a. and OM-e.l.i.s.a. for oligomeric and monomeric TNF was demonstrated with isolated forms prepared by partial dissociation of recombinant TNF with 10% (v/v) dimethyl sulphoxide and gel-filtration h.p.l.c. Evidence for instability of oligomeric TNF were obtained in physiological buffers, as well as in serum and cell-culture supernatants, as a function of TNF concentration. In particular, only a half of the TNF antigen was recovered in the oligomeric form after 72 h incubation (37 degrees C) at 0.12 nM, whereas no apparent dissociation was detected at 4 nM. The structural changes observed at picomolar concentrations were rapidly reversed by raising the concentration of TNF to about 2 nM by ultrafiltration, suggesting that subunit dissociation and reassociation reactions occur in the picomolar and nanomolar range respectively. The cytolytic activity of L-M cells correlates with oligomeric-TNF levels after incubation at picomolar concentrations. Moreover, isolated oligomeric TNF was cytotoxic towards L-M cells, whereas monomeric TNF was virtually inactive. In conclusion, the results suggest that bioactive oligomeric TNF is unstable at picomolar levels and slowly converts into inactive monomers, supporting the hypothesis that quaternary-structure changes in TNF may contribute to the fine regulation of TNF cytotoxicity.
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Gurevich, Vsevolod V. "Do arrestin oligomers have specific functions?" Cell Signaling 1, no. 1 (August 11, 2023): 42–46. http://dx.doi.org/10.46439/signaling.1.009.
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Arrestins are a small family of versatile regulators of cell signaling. Arrestins regulate signaling and trafficking of G protein-coupled receptors, regulate and direct to particular subcellular compartments numerous protein kinases, ubiquitin ligases, etc. Three out of four arrestin subtypes expressed in vertebrates self-associate, each forming oligomers of a distinct size and shape. While the structures of the solution oligomers of arrestin-1, -2, and -3 have been elucidated, no function specific for the oligomeric form of either of these three subtypes has been identified thus far. Considering how multi-functional average-sized (~45 kDa) arrestin proteins were found to be, it appears likely that certain functions are predominantly or exclusively fulfilled by monomeric and oligomeric forms of each subtype.
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Martellucci, Stefano, Letizia Clementi, Samantha Sabetta, Paola Muzi, Vincenzo Mattei, Mauro Bologna, and Adriano Angelucci. "Tau oligomers accumulation sensitizes prostate cancer cells to docetaxel treatment." Journal of Cancer Research and Clinical Oncology 147, no. 7 (April 2, 2021): 1957–71. http://dx.doi.org/10.1007/s00432-021-03598-3.
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Abstract Purpose Human tau is a highly dynamic, multifunctional protein expressed in different isoforms and conformers, known to modulate microtubule turnover. Tau oligomers are considered pathologic forms of the protein able to initiate specific protein accumulation diseases, called tauopathies. In our study, we investigated the potential association between autophagy and tau oligomers accumulation and its role in the response of prostate cancer cells to docetaxel. Methods We evaluated in vitro the expression of tau oligomers in prostate cancer cell lines, PC3 and DU145, in presence of autophagy inhibitors and investigated the role of tau oligomers accumulation in resistance to docetaxel treatment. Results Tau protein was basally expressed in prostate cancer lines as several monomeric and oligomeric forms. The pharmacologic inhibition of autophagy induced in cancer cells the accumulation of tau protein, with a prevalent expression of oligomeric forms. Immunofluorescence analysis of untreated cells revealed that tau was visible mainly in dividing cells where it was localized on the mitotic spindle. Inhibition of autophagy determined an evident upregulation of tau signal in dividing cells and the presence of aberrant monoastral mitotic spindles. The accumulation of tau oligomers was associated with DNA DSB and increased cytotoxic effect by docetaxel. Conclusions Our data indicate that autophagy could exert a promoting role in cancer growth and during chemotherapy facilitating degradation of tau protein and thus blocking the antimitotic effect of accumulated tau oligomers. Thus, therapeutic strategies aimed at stimulating tau oligomers formation, such as autophagy inhibition, could be an effective adjuvant in cancer therapy.
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Di Gennaro, Patrizia, Valentina Sabatini, Silvia Fallarini, Roberto Pagliarin, and Guido Sello. "Polyphenol Polymerization by an Alternative Oxidative Microbial Enzyme and Characterization of the Biological Activity of Oligomers." BioMed Research International 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/3828627.
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The recombinant catalase-peroxidase HPI from E. coli was used as an alternative enzyme in polymerization reactions for the production of (−) epicatechin oligomers and their biological activity was characterized. The enzyme was prepared in two forms: a purified and an immobilized form. Both were tested for their activity in oxidative polymerization reactions, and their stability and reusability were assessed. The polymerization reactions were followed by SEC-HPLC analyses, and the substrate was completely converted into one or more polymerization products depending on the reactions conditions. Results showed that the utilized conditions allowed for the isolation of some oligomers of different molecular weight: the oligomers containing 6 and 7 units of epicatechin substrate are the heaviest ones. Epicatechin was also used in reactions catalyzed by HRP in the same reaction conditions for comparison. In addition, one selected oligomer obtained by HPI enzyme catalysis was shown to act as in vitro inhibitor of tumor cell growth, like one oligomer deriving from epicatechin by HRP catalysis. These data confirm that epicatechin oligomeric form is more effective than its monomer in biological activity and suggest the use of HPI as an alternative enzyme in reactions for the production of epicatechin oligomers.
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Mielecki, Marcin, Marcin Ziemniak, Magdalena Ozga, Radosław Borowski, Jarosław Antosik, Angelika Kaczyńska, and Beata Pająk. "Structure–Activity Relationship of the Dimeric and Oligomeric Forms of a Cytotoxic Biotherapeutic Based on Diphtheria Toxin." Biomolecules 12, no. 8 (August 12, 2022): 1111. http://dx.doi.org/10.3390/biom12081111.
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Protein aggregation is a well-recognized problem in industrial preparation, including biotherapeutics. These low-energy states constantly compete with a native-like conformation, which is more pronounced in the case of macromolecules of low stability in the solution. A better understanding of the structure and function of such aggregates is generally required for the more rational development of therapeutic proteins, including single-chain fusion cytotoxins to target specific receptors on cancer cells. Here, we identified and purified such particles as side products of the renaturation process of the single-chain fusion cytotoxin, composed of two diphtheria toxin (DT) domains and interleukin 13 (IL-13), and applied various experimental techniques to comprehensively understand their molecular architecture and function. Importantly, we distinguished soluble purified dimeric and fractionated oligomeric particles from aggregates. The oligomers are polydisperse and multimodal, with a distribution favoring lower and even stoichiometries, suggesting they are composed of dimeric building units. Importantly, all these oligomeric particles and the monomer are cystine-dependent as their innate disulfide bonds have structural and functional roles. Their reduction triggers aggregation. Presumably the dimer and lower oligomers represent the metastable state, retaining the native disulfide bond. Although significantly reduced in contrast to the monomer, they preserve some fraction of bioactivity, manifested by their IL-13RA2 receptor affinity and selective cytotoxic potency towards the U-251 glioblastoma cell line. These molecular assemblies probably preserve structural integrity and native-like fold, at least to some extent. As our study demonstrated, the dimeric and oligomeric cytotoxin may be an exciting model protein, introducing a new understanding of its monomeric counterpart’s molecular characteristics.
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Verrey, F., and K. Drickamer. "Determinants of oligomeric structure in the chicken liver glycoprotein receptor." Biochemical Journal 292, no. 1 (May 15, 1993): 149–55. http://dx.doi.org/10.1042/bj2920149.
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The oligomeric state of the chicken liver receptor (chicken hepatic lectin), which mediates endocytosis of glycoproteins terminating with N-acetylglucosamine, has been investigated using physical methods as well as chemical cross-linking. Receptor isolated from liver and from transfected rat fibroblasts expressing the full-length polypeptide is a homotrimer immediately following solubilization in non-ionic detergent, but forms the previously observed hexamer during purification. These results are most consistent with the presence of a trimer of receptor polypeptides in liver membranes and in transfected cells. Analysis of truncated receptors reveals that the C-terminal extracellular portion of this type-II transmembrane protein does not form stable oligomers when isolated from the membrane anchor and cytoplasmic tail. The behaviour of chimeric receptors, in which the cytoplasmic tail of the glycoprotein receptor is replaced with the corresponding segments of rat liver asialoglycoprotein receptor or the beta-subunit of Na+,K(+)-ATPase, or with unrelated sequences from globin, indicates that the cytoplasmic tail influences oligomer stability. Replacement of N-terminal portions of the receptor with corresponding segments of influenza virus neuraminidase results in formation of tetramers, suggesting that the membrane anchor and flanking sequences are important determinants of oligomer formation.
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Eisenberg, David, Arthur Laganowsky, Cong Liu, Michael Sawaya, Julian Whitelegge, Minglei Zhao, Angela Soriaga, et al. "Structural Studies of the Amyloid State of Proteins." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C797. http://dx.doi.org/10.1107/s205327331409202x.
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Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. At the morphological level, these fibers appear similar and are termed "amyloid." We found that the adhesive segments of amyloid fibers are short protein sequences which form pairs of interdigitated, in-register beta sheets. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that in the neurodegenerative diseases, smaller, often transient and polymorphic oligomers are the toxic entities. We have identified a segment of the amyloid-forming protein, alphaB crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: beta-sheet-rich structure, cytotoxicity, and recognition by an anti-oligomer antibody. The X-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six anti-parallel, out-of-register protein strands, which we term a cylindrin. The cylindrin structure is compatible with sequence segments from the Abeta protein of Alzheimer's disease and from other amyloid proteins. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers, and are distinct in structure from amyloid fibrils.
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Schirrmann, Thomas, Christian Menzel, Michael Hust, Jessica Prilop, Thomas Jostock, and Stefan Dübel. "Oligomeric forms of single chain immunoglobulin (scIgG)." mAbs 2, no. 1 (January 2010): 73–76. http://dx.doi.org/10.4161/mabs.2.1.10784.
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Abskharon, Romany, Paul M. Seidler, Michael R. Sawaya, Duilio Cascio, Tianxiao P. Yang, Stephan Philipp, Christopher Kazu Williams, et al. "Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease." Journal of Biological Chemistry 295, no. 31 (June 3, 2020): 10662–76. http://dx.doi.org/10.1074/jbc.ra120.013638.
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Soluble oligomers of aggregated tau accompany the accumulation of insoluble amyloid fibrils, a histological hallmark of Alzheimer disease (AD) and two dozen related neurodegenerative diseases. Both oligomers and fibrils seed the spread of Tau pathology, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. Here, we report the formation of in vitro tau oligomers formed by an ionic liquid (IL15). Using IL15-induced recombinant tau oligomers and a dot blot assay, we discovered a mAb (M204) that binds oligomeric tau, but not tau monomers or fibrils. M204 and an engineered single-chain variable fragment (scFv) inhibited seeding by IL15-induced tau oligomers and pathological extracts from donors with AD and chronic traumatic encephalopathy. This finding suggests that M204-scFv targets pathological structures that are formed by tau in neurodegenerative diseases. We found that M204-scFv itself partitions into oligomeric forms that inhibit seeding differently, and crystal structures of the M204-scFv monomer, dimer, and trimer revealed conformational differences that explain differences among these forms in binding and inhibition. The efficiency of M204-scFv antibodies to inhibit the seeding by brain tissue extracts from different donors with tauopathies varied among individuals, indicating the possible existence of distinct amyloid polymorphs. We propose that by binding to oligomers, which are hypothesized to be the earliest seeding-competent species, M204-scFv may have potential as an early-stage diagnostic for AD and tauopathies, and also could guide the development of promising therapeutic antibodies.
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Rodriguez Camargo, Diana C., Divita Garg, Katalin Buday, Andras Franko, Andres Rodriguez Camargo, Fabian Schmidt, Sarah J. Cox, et al. "hIAPP forms toxic oligomers in plasma." Chemical Communications 54, no. 43 (2018): 5426–29. http://dx.doi.org/10.1039/c8cc03097a.
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Zheng, Weihua, Min-Yeh Tsai, Mingchen Chen, and Peter G. Wolynes. "Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)." Proceedings of the National Academy of Sciences 113, no. 42 (October 3, 2016): 11835–40. http://dx.doi.org/10.1073/pnas.1612362113.
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A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1–40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer’s disease.
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Bernabeu-Zornoza, Adela, Raquel Coronel, Charlotte Palmer, Victoria López-Alonso, and Isabel Liste. "Oligomeric and Fibrillar Species of Aβ42 Diversely Affect Human Neural Stem Cells." International Journal of Molecular Sciences 22, no. 17 (September 2, 2021): 9537. http://dx.doi.org/10.3390/ijms22179537.
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Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.
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Gigant, Benoit, Frédéric Iseni, Yves Gaudin, Marcel Knossow, and Danielle Blondel. "Neither phosphorylation nor the amino-terminal part of rabies virus phosphoprotein is required for its oligomerization." Microbiology 81, no. 7 (July 1, 2000): 1757–61. http://dx.doi.org/10.1099/0022-1317-81-7-1757.
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Rabies virus (PV strain) phosphoprotein (P) was expressed in bacteria. This recombinant protein binds specifically to the nucleoprotein–RNA complex purified from infected cells. Chemical cross-linking and gel-filtration studies indicated that the P protein forms oligomers. Analytical centrifugation data demonstrated the co-existence of monomeric and oligomeric forms of rabies virus P protein and suggested that there is an equilibrium between these species. As P expressed in bacteria is not phosphorylated, this result indicates that P phosphorylation is not required for its oligomerization. Although an alignment of several rhabdovirus P sequences revealed that the amino-terminal domain of P has a conserved predicted propensity to form helical coiled coils, an amino-terminally truncated form of P protein, lacking the first 52 residues, was also shown to be oligomeric. Therefore, the amino-terminal domain of rabies virus P is not necessary for its oligomerization.
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Caldwell, Brian J., Andrew Norris, Ekaterina Zakharova, Christopher E. Smith, Carter T. Wheat, Deepanshu Choudhary, Marcos Sotomayor, Vicki H. Wysocki, and Charles E. Bell. "Oligomeric complexes formed by Redβ single strand annealing protein in its different DNA bound states." Nucleic Acids Research 49, no. 6 (March 8, 2021): 3441–60. http://dx.doi.org/10.1093/nar/gkab125.
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Abstract Redβ is a single strand annealing protein from bacteriophage λ that binds loosely to ssDNA, not at all to pre-formed dsDNA, but tightly to a duplex intermediate of annealing. As viewed by electron microscopy, Redβ forms oligomeric rings on ssDNA substrate, and helical filaments on the annealed duplex intermediate. However, it is not clear if these are the functional forms of the protein in vivo. We have used size-exclusion chromatography coupled with multi-angle light scattering, analytical ultracentrifugation and native mass spectrometry (nMS) to characterize the size of the oligomers formed by Redβ in its different DNA-bound states. The nMS data, which resolve species with the highest resolution, reveal that Redβ forms an oligomer of 12 subunits in the absence of DNA, complexes ranging from 4 to 14 subunits on 38-mer ssDNA, and a much more distinct and stable complex of 11 subunits on 38-mer annealed duplex. We also measure the concentration of Redβ in cells active for recombination and find it to range from 7 to 27 μM. Collectively, these data provide new insights into the dynamic nature of the complex on ssDNA, and the more stable and defined complex on annealed duplex.
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Верлов, Н. А., Л. С. Гулина, И. В. Бендт, С. Б. Ланда, А. П. Трашков, and В. Л. Эмануэль. "Changes in the urinary content of uromodulin oligomeric forms in rats during development of urolithiasis." Zhurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia», no. 4 (December 28, 2021): 89–96. http://dx.doi.org/10.25557/0031-2991.2021.04.89-96.
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Введение. Изучение роли олигомерных форм уромодулина в развитии уролитиаза является важной фундаментальной и прикладной задачей. Несмотря на разнообразие моделей уролитиаза на лабораторных животных в настоящее время отсутствует информация относительно динамики концентрации и фракционного состава олигомерных форм уромодулина в моче животных на различных этапах развития патологического процесса. Цель - исследование динамики содержания олигомерных форм уромодулина в моче животных на фоне развития гипероксалатного уролитиаза индуцированного экзогенным введением 1% раствора этиленгликоля в качестве безальтернативного источника питья. Методика. Проводили общеклинический и биохимический анализ образцов крови и мочи на различных этапах развития патологического процесса. До начала моделирования патологии и на фоне экзогенного введения этиленгликоля был исследован осадок мочи. Оценка содержания олигомерных форм уромодулина в моче животных проводилась методом анализа треков наночастиц и динамического рассеяния света. Результаты. Показано, что на фоне развития патологии наблюдается уменьшение концентрации олигомерных форм уромодулина в моче, на начальных этапах развития патологии за счёт увеличения фракции крупных частиц (более 200 нм, олигомерная форма 28 МДа). При дальнейшем развитии патологического процесса на завершающем этапе наблюдается радикальное уменьшение концентрации частиц в моче (более чем в 2 раза). Заключение. Полученные данные показали относительно низкую корреляцию между длительностью моделирования патологии и тяжестью проявления уролитиаза (r-Пирсона = 0,49, p-value = 0,0003). Концентрация олигомеров уромодулина в моче животных уменьшается на фоне увеличения количества кристаллов в осадке мочи, что вероятно связанно с включением уромодулина в структуру кристаллов осадка. Studying uromodulin oligomeric forms in urolithiasis development is important fundamental and applied problem. Despite the variety of in vivo models of urolithiasis, there is currently no information about concentration dynamics and fractional composition of uromodulin oligomeric forms in urine for animals at various stages of pathological process developmen. The purpose We investigate dynamics uromodulin oligomeric forms in urine of animals against the background of development hyperoxalate urolithiasis induced by exogenous administration of 1% ethylene glycol solution as a non-alternative source of drinking. Methods. For urine samples at various stages of pathogenesis, general clinical and biochemical analysis were carried out, for urine samples before the start of pathology modeling and against the background of exogenous administration of ethylene glycol, urine sediment was examined. The study of urine sediment and content uromodulin oligomeric forms was carried out on 0th, 7th, 14th, 21st and 28th days of pathology modeling. Evaluation of the content of uromodulin oligomeric forms in urine of animals was carried out by nanoparticles track analysing and dynamic light scattering. Results. It is shown that against the background of the pathology development there is a decrease in the concentration of oligomeric forms of uromodulin in the urine, at the initial stages of pathology development due to an increase in the fraction of large particles (over 200 nm, oligomeric form 28 МDa). With further development of the pathological process at the final stage, there is a radical decrease in the concentration of particles in the urine (more than 2-fold). Conclusion. The obtained data showed a relatively low correlation between the duration of pathology modeling and the severity of urolithiasis manifestation (Pearson's r = 0.49, p-value = 0.0003). Concentration of uromodulin oligomers in animals urine decreases with an increase in the amount of crystals in urine sediment, which is probably associated with inclusion of uromodulin in structure of sediment crystals.
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Arroyo, Raquel, Mercedes Echaide, Robert Wilmanowski, Alejandro Martín-González, Emma Batllori, Alberto Galindo, Jan S. Rosenbaum, Fernando Moreno-Herrero, Paul S. Kingma, and Jesús Pérez-Gil. "Structure and activity of human surfactant protein D from different natural sources." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 1 (July 1, 2020): L148—L158. http://dx.doi.org/10.1152/ajplung.00007.2020.
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Surfactant protein D (SP-D) is a C-type lectin that participates in the innate immune defense of lungs. It binds pathogens through its carbohydrate recognition domain in a calcium-dependent manner. Human surfactant protein D (hSP-D) has been routinely obtained from bronchoalveolar lavage of patients suffering from pulmonary alveolar proteinosis (PAP) and from amniotic fluid (AF). As a consequence of the disease, hSP-D obtained from PAP is found in higher amounts and is mainly composed of higher order oligomeric forms. However, PAP-hSP-D has never been directly compared with nonpathological human protein in terms of structure and biological activity. Moreover, the quantitative distribution of the different hSP-D oligomeric forms in human protein obtained from a natural source has never been evaluated. In this work, we have determined the quantitative distribution of AF-hSP-D oligomers, characterized the sugars attached through the N-glycosylation site of the protein, and compared the activity of hSP-D from AF and PAP with respect to their ability to bind and agglutinate bacteria. We have found that fuzzy balls (40%) are the most abundant oligomeric form in AF-hSP-D, very closely followed by dodecamers (33%), with both together constituting 73% of the protein mass. The glycan attached to the N-glycosylation site was found to be composed of fucose, galactose, sialic acid, and N-acetylglucosamine. Finally, in the functional assays performed, hSP-D obtained from PAP showed higher potency, probably as a consequence of its higher proportion of large oligomers compared with hSP-D from AF.
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Wallis, Russell, and Jason Y. T. Cheng. "Molecular Defects in Variant Forms of Mannose-Binding Protein Associated with Immunodeficiency." Journal of Immunology 163, no. 9 (November 1, 1999): 4953–59. http://dx.doi.org/10.4049/jimmunol.163.9.4953.
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Abstract Distinct molecular mechanisms underlying immunodeficiency caused by three different naturally occurring point mutations within the collagen-like domain of human mannose-binding protein (MBP; also known as mannose-binding lectin) have been revealed by introduction of analogous mutations into rat serum MBP. The change Arg23→Cys results in a lower proportion of the large oligomers most efficient at activating the complement cascade. The presence of cysteine at position 23, which forms aberrant interchain disulfide bonds, causes disruption of the normal oligomeric state. The deficiency in MBPs containing Gly25→Asp and Gly28→Glu substitutions also results in part from reduced formation of higher oligomers. However, decreased ability to interact with downstream components of the complement cascade due to changes in both the N-terminal disulfide-bonding arrangement and the local structure of the collagenous domain make more important contributions to the loss of activity in these mutants.
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Верлов, Н. А., С. Б. Ланда, В. В. Егоров, Ю. В. Эмануэль, and В. Л. Эмануэль. "Uromodulin: Relationship of protein oligomeric forms and functions." Zhurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia», no. 1 (March 31, 2021): 133–40. http://dx.doi.org/10.25557/0031-2991.2021.01.133-140.
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Введение. Уромодулин является основным белком присутствующим в моче в норме, его физиологическая роль очень разнообразна. Оценка его вклада в стабилизацию коллоида мочи в норме и при различных патологических состояниях требует детального исследования олигомерных форм, присутствующих в моче, их структуры и функций. Цель работы - изучение структурных особенностей олигомерных форм белка уромодулина в моче здоровых добровольцев и пациентов с подтверждённым уролитиазом и выявление связи структуры белка и его роли в стабилизации коллоида мочи. Методика. Методом динамического рассеяния света, анализом треков наночастиц и измерением дзета-потенциала изучены биофизические свойства изоформ уромодулина (UM), присутствующего в нативной моче в виде олигомерных форм, из которых можно выделить 2 основные: UM(7) - глобулярная молекула массой 7MDa, характеризуется гидродинамическим радиусом Rh=90-100 нм и отрицательным поверхностным зарядом величиной 25 - 30 мВ; UM(28) - массой 28MDa обладает палочкоподобной структурой с гидродинамическим радиусом Rh=200-300 нм и существенно меньшим по величине поверхностным зарядом 0 - -7 мВ. Результаты. В норме в моче UM(7) является доминантной формой, при этом вклад UM(28) либо отсутствует, либо незначителен. При уролитиазе доля UM(7) радикально уменьшается и вклад UM(28) становится основным. В модельных экспериментах показаны различия этих переходов в моче здоровых лиц и пациентов с уролитиазом в зависимости от величины pH и концентрации одновалентных катионов: натрия, калия и аммония. Заключение. На основании полученных данных существенно расширено представление о саногенетической системе коллоидного гомеостаза мочеобразования и патогенезе кристаллогенеза. Аппроксимация выдвинутой концепции развития патологического кристаллогенеза в клиническую практику расширяют информативность превентивной диагностики уролитиаза. Introduction. Uromodulin is the major protein, which is normally present in urine and plays multiple physiological roles. Evaluation of the uromodulin contribution to stabilization of urinary colloids in normal and various pathological conditions requires a comprehensive study of uromodulin oligomeric forms occurring in urine, their structure and functions. The aim of this work was studying structural features of uromodulin oligomeric forms in the urine of healthy volunteers and patients with confirmed urolithiasis and identifying a relationship between the protein structure and role in stabilization of urinary colloids. Methods. Dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), and measurement of zeta potential were used to study biophysical properties of uromodulin (UM) isoforms. UM is present in native urine as oligomeric forms, including two major ones: i) UM (7), a 7MDa globular molecule characterized by a hydrodynamic radius Rh = 90-100 nm and a negative surface charge of 25-30 mV and ii) UM (28), a rod-like 28MDa molecule with a hydrodynamic radius of Rh=200-300 nm and a significantly lower surface charge of 0 --7 mV. Results. Normally, UM (7) is a dominant form in urine whereas the UM (28) contribution is either non-existent or minor. In urolithiasis, the proportion of UM (7) decreases drastically, and the contribution of UM (28) becomes primary. Model experiments showed differences between these transitions in the urine of healthy individuals and patients with urolithiasis depending on pH values and concentrations of monovalent cations, including sodium, potassium, and ammonium. Conclusion. The study results considerably expanded the concept of the sanogenetic system of colloidal homeostasis in urine formation and the pathogenesis of crystallogenesis. Approximating the proposed concept of pathological crystallogenesis in clinical practice expands the informative value of preventive diagnosis of urolithiasis.
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Palczewski, Krzysztof. "Oligomeric forms of G protein-coupled receptors (GPCRs)." Trends in Biochemical Sciences 35, no. 11 (November 2010): 595–600. http://dx.doi.org/10.1016/j.tibs.2010.05.002.
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Emadi, Sharareh, Srinath Kasturirangan, Min S. Wang, Philip Schulz, and Michael R. Sierks. "Detecting Morphologically Distinct Oligomeric Forms of α-Synuclein." Journal of Biological Chemistry 284, no. 17 (January 13, 2009): 11048–58. http://dx.doi.org/10.1074/jbc.m806559200.
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Gurevich, Vsevolod V., and Eugenia V. Gurevich. "Solo vs Chorus: Monomers and Oligomers of Arrestin Proteins." International Journal of Molecular Sciences 23, no. 13 (June 29, 2022): 7253. http://dx.doi.org/10.3390/ijms23137253.
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Three out of four subtypes of arrestin proteins expressed in mammals self-associate, each forming oligomers of a distinct kind. Monomers and oligomers have different subcellular localization and distinct biological functions. Here we summarize existing evidence regarding arrestin oligomerization and discuss specific functions of monomeric and oligomeric forms, although too few of the latter are known. The data on arrestins highlight biological importance of oligomerization of signaling proteins. Distinct modes of oligomerization might be an important contributing factor to the functional differences among highly homologous members of the arrestin protein family.
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Demuro, Angelo, Martin Smith, and Ian Parker. "Single-channel Ca2+ imaging implicates Aβ1–42 amyloid pores in Alzheimer’s disease pathology." Journal of Cell Biology 195, no. 3 (October 24, 2011): 515–24. http://dx.doi.org/10.1083/jcb.201104133.
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Oligomeric forms of Aβ peptides are implicated in Alzheimer’s disease (AD) and disrupt membrane integrity, leading to cytosolic calcium (Ca2+) elevation. Proposed mechanisms by which Aβ mediates its effects include lipid destabilization, activation of native membrane channels, and aggregation of Aβ into Ca2+-permeable pores. We distinguished between these using total internal reflection fluorescence (TIRF) microscopy to image Ca2+ influx in Xenopus laevis oocytes. Aβ1–42 oligomers evoked single-channel Ca2+ fluorescence transients (SCCaFTs), which resembled those from classical ion channels but which were not attributable to endogenous oocyte channels. SCCaFTs displayed widely variable open probabilities (Po) and stepwise transitions among multiple amplitude levels reminiscent of subconductance levels of ion channels. The proportion of high Po, large amplitude SCCaFTs grew with time, suggesting that continued oligomer aggregation results in the formation of highly toxic pores. We conclude that formation of intrinsic Ca2+-permeable membrane pores is a major pathological mechanism in AD and introduce TIRF imaging for massively parallel single-channel studies of the incorporation, assembly, and properties of amyloidogenic oligomers.
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Theoni Gyparaki, Melina, Arian Arab, Elena M. Sorokina, Adriana N. Santiago-Ruiz, Christopher H. Bohrer, Jie Xiao, and Melike Lakadamyali. "Tau Forms Oligomeric Complexes on Microtubules that are Distinct from Pathological Oligomers in Disease." Biophysical Journal 120, no. 3 (February 2021): 31a. http://dx.doi.org/10.1016/j.bpj.2020.11.442.
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Tran, Ngoc-Han, Stephen D. Carter, Ann De Mazière, Avi Ashkenazi, Judith Klumperman, Peter Walter, and Grant J. Jensen. "The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes." Science 374, no. 6563 (October 2021): 52–57. http://dx.doi.org/10.1126/science.abh2474.
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Keeping tabs on ER stress In the endoplasmic reticulum (ER), oligomerization is a central step in modulating signaling during the unfolded protein response. Tran et al . visualized the active, oligomeric form of the ER stress sensor IRE1α residing in an ER subdomain in stressed human cells. This ER region was composed of narrow (diameter about 28 nanometers) anastomosing ER tubes with a high degree of branching and was continuous with surrounding ER structures. Within the lumen of these narrow IRE1α subdomain tubes, regular protein densities were observed, consistent with ordered oligomers of the lumenal stress–sensing domain of IRE1α. This arrangement may suggest a positive feedback mechanism involved in signaling by IRE1α. —SMH
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Gamblin, Clémence L., Frédérique Parent-Prévost, Kévin Jacquet, Cornélia Biehler, Alexandra Jetté, and Patrick Laprise. "Oligomerization of the FERM-FA protein Yurt controls epithelial cell polarity." Journal of Cell Biology 217, no. 11 (August 6, 2018): 3853–62. http://dx.doi.org/10.1083/jcb.201803099.
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Drosophila melanogaster Yurt (Yrt) and its mammalian orthologue EPB41L5 limit apical membrane growth in polarized epithelia. EPB41L5 also supports epithelial–mesenchymal transition and metastasis. Yrt and EPB41L5 contain a four-point-one, ezrin, radixin, and moesin (FERM) domain and a FERM-adjacent (FA) domain. The former contributes to the quaternary structure of 50 human proteins, whereas the latter defines a subfamily of 14 human FERM proteins and fulfills unknown roles. In this study, we show that both Yrt and EPB41L5 oligomerize. Our data also establish that the FERM-FA unit forms an oligomeric interface and that multimerization of Yrt is crucial for its function in epithelial cell polarity regulation. Finally, we demonstrate that aPKC destabilizes the Yrt oligomer to repress its functions, thereby revealing a mechanism through which this kinase supports apical domain formation. Overall, our study highlights a conserved biochemical property of fly and human Yrt proteins, describes a novel function of the FA domain, and further characterizes the molecular mechanisms sustaining epithelial cell polarity.
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Jackowski, Grzegorz, and Ewa Kluck. "The Oligomeric Arrangement of the Light-Harvesting Chlorophyll a/6-Protein Complex of Photosystem II." Zeitschrift für Naturforschung C 49, no. 5-6 (June 1, 1994): 337–42. http://dx.doi.org/10.1515/znc-1994-5-610.
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Abstract The light-harvesting chlorophyll a/b-protein complex of photosystem II (LHC II) was isolated from carnation (Dianthus caryophyllus L.) leaves by K+-induced aggregation of n-hep-tylthioglucoside-treated photosystem II particles. When solubilized with a mixture of lithium docedyl sulphate, octyl-β-D-glucopyranoside and dodecyl-β-D-maltoside the LHC II was re solved by mild sodium dodecyl sulphate-polyacrylamide gel electrophoresis into four oligomeric forms and a monomeric one. LHC II contained five major polypeptides only two of which (27 and 26 kDa) were found to be its authentic components. The oligomeric forms of LHC II were found to differ in the stoichiometric ratios of the polypeptides present. The 26 kD a polypeptide was enriched in the largest oligomeric forms while the 27 kDa polypeptide tended to form a monomer or to assemble as lower oligomeric states of LHC II.
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Lloyd-Jones, G. C., S. C. Stephen, I. J. S. Fairlamb, Aina Martorell, Beatriz Dominguez, P. M. Tomlin, M. Murray, et al. "Coordination of the Trost modular ligand to palladium allyl fragments: Oligomers, monomers and memory effects in catalysis." Pure and Applied Chemistry 76, no. 3 (January 1, 2004): 589–601. http://dx.doi.org/10.1351/pac200476030589.
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Reaction of the C2-symmetric "Trost modular ligand" with cationic Pd(II) allyl fragments allows isolation of air- and bench-stable pro-catalysts for the asymmetric allylic alkylation of racemic cycloalkenyl esters. In solution, three distinct complexation modes are observed. When mixed in a ligand/Pd ratio of 1/2, a binuclear bis-P,O-chelate complex is generated. This species does not induce enantioselectivity in the reaction. In contrast, with a ligand/Pd ratio of 1/1, a highly enantioselective, P,P-coordinated pro-catalyst system is generated in which there are two basic coordination modes: monomeric and oligomeric. The monomeric form is mononuclear and exists as two 13-membered chelates, isomeric through loss of C2-symmetry in the ligand. The oligomeric form is polynuclear and forms chains and rings of alternating ligand and cationic Pd(allyl) units, one of which was identified by single-crystal X-ray diffraction. In solution, the monomeric and oligomeric species are in dynamic equilibrium with populations and interconversion rates controlled by concentration, temperature, and counterion. Isotopic desymmetrization analysis suggests that the monomer-oligomer equilibrium plays a crucial role in both the selectivity and efficiency of the asymmetric allylic alkylation reaction.
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Sedman, Juhan, and Arne Stenlund. "The Papillomavirus E1 Protein Forms a DNA-Dependent Hexameric Complex with ATPase and DNA Helicase Activities." Journal of Virology 72, no. 8 (August 1, 1998): 6893–97. http://dx.doi.org/10.1128/jvi.72.8.6893-6897.1998.
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ABSTRACT The E1 protein from bovine papillomavirus has site-specific DNA binding activity, DNA helicase activity, and DNA-dependent ATPase activity consistent with the properties of an initiator protein. Here we have identified and characterized a novel oligomeric form of E1 that is associated with the ATPase and DNA helicase activities and whose formation is strongly stimulated by single-stranded DNA. This oligomeric form corresponds to a hexamer of E1.
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Diociaiuti, Marco, Laura Zanetti Polzi, Luisa Valvo, Fiorella Malchiodi-Albedi, Cecilia Bombelli, and Maria Cristina Gaudiano. "Calcitonin Forms Oligomeric Pore-Like Structures in Lipid Membranes." Biophysical Journal 91, no. 6 (September 2006): 2275–81. http://dx.doi.org/10.1529/biophysj.105.079475.
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Alushin, Gregory M., Vincent H. Ramey, Sebastiano Pasqualato, David A. Ball, Nikolaus Grigorieff, Andrea Musacchio, and Eva Nogales. "The Ndc80 kinetochore complex forms oligomeric arrays along microtubules." Nature 467, no. 7317 (October 2010): 805–10. http://dx.doi.org/10.1038/nature09423.
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Giorgio, Valentina, Dimitri Dunin, Maria Eugenia Soriano, Elena Bisetto, Federica Dabbeni-Sala, Valeria Petronilli, Paolo Bernardi, and Giovanna Lippe. "Cyclophilin D interaction with the ATP synthase oligomeric forms." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 (July 2010): 36. http://dx.doi.org/10.1016/j.bbabio.2010.04.124.
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Chavarría, Cecilia, Sebastián Rodríguez-Bottero, Celia Quijano, Patricia Cassina, and José M. Souza. "Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons." Biochemical Journal 475, no. 19 (October 12, 2018): 3153–69. http://dx.doi.org/10.1042/bcj20180297.
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Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of aggregated and fibrillar forms of alpha-synuclein (α-syn). Here, we analyze the effect of different species of α-syn, including monomeric, oligomeric and fibrillar forms of the protein, on rat astrocytes. Astrocytes treated with these distinct forms of α-syn showed an increase in long and thin processes and glial fibrillary acidic protein expression, indicating cell activation, high levels of intracellular oxidants and increased expression of cytokines. Moreover, astrocytes incubated with the different species induced hippocampal neuronal death in co-culture, and cytotoxicity was particularly enhanced by exposure to fibrillar α-syn. Further exploration of the mechanisms behind astrocyte activation and cytotoxicity revealed differences between the assessed α-syn species. Only oligomers induced mitochondrial dysfunction in astrocytes and significantly increased extracellular hydrogen peroxide production by these cells. Besides, TNF-α and IL-1β (interleukin 1β) expression presented different kinetics and levels depending on which species induced the response. Our data suggest that α-syn species (monomeric, oligomeric and fibrillar) induce astrocyte activation that can lead to neuronal death. Nevertheless, the tested α-syn species act through different preferential mechanisms and potency. All together these results help to understand the effect of α-syn species on astrocyte function and their potential impact on the pathogenesis of Parkinson's disease and related α-synucleinopathies.
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Pokrajac, Lisa, J. Robin Harris, Naghmeh Sarraf, and Michael Palmer. "Oligomerization and hemolytic properties of the C-terminal domain of pyolysin, a cholesterol-dependent cytolysin." Biochemistry and Cell Biology 91, no. 2 (April 2013): 59–66. http://dx.doi.org/10.1139/bcb-2012-0065.
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Pyolysin (PLO) belongs to the homologous family of the cholesterol-dependent cytolysins (CDCs), which bind to cell membranes containing cholesterol to form oligomeric pores of large size. The CDC monomer structure consists of 4 domains. Among these, the C-terminal domain 4 has been implicated in membrane binding of the monomer, while the subsequent processes of oligomerization and membrane insertion have primarily been assigned to other domains of the molecule. Recombinantly expressed or proteolytic fragments that span domain 4 of the CDCs streptolysin O and perfringolysin O bind to membranes but fail to oligomerize, and they inhibit the activity of the respective wild-type toxins. We report here that the isolated domain 4 of pyolysin (PLO-D4) not only binds to membranes but also forms oligomers with itself, as well as hybrid oligomers with the full-length toxin. As expected, the pure PLO-D4 oligomers are devoid of pore-forming activity. Surprisingly, however, within hybrid oligomers, PLO-D4 not only fails to inhibit, but even amplifies the hemolytic activity of the full-length toxin, to an extent similar to that of doubling the amount of the full-length toxin alone. We propose that this amplification may be related to the kinetics of the oligomerization reaction. Overall, our findings indicate a greater role of domain 4 in the oligomerization of CDCs than previously demonstrated.
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Shahnawaz, Mohammad, and Claudio Soto. "Microcin Amyloid Fibrils A Are Reservoir of Toxic Oligomeric Species." Journal of Biological Chemistry 287, no. 15 (February 15, 2012): 11665–76. http://dx.doi.org/10.1074/jbc.m111.282533.
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Microcin E492 (Mcc), a low molecular weight bacteriocin produced by Klebsiella pneumoniae RYC492, has been shown to exist in two forms: soluble forms that are believed to be toxic to the bacterial cell by forming pores and non-toxic fibrillar forms that share similar biochemical and biophysical properties with amyloids associated with several human diseases. Here we report that fibrils polymerized in vitro from soluble forms sequester toxic species that can be released upon changing environmental conditions such as pH, ionic strength, and upon dilution. Our results indicate that basic pH (≥8.5), low NaCl concentrations (≤50 mm), and dilution (>10-fold) destabilize Mcc fibrils into more soluble species that are found to be toxic to the target cells. Additionally, we also found a similar conversion of non-toxic fibrils into highly toxic oligomers using Mcc aggregates produced in vivo. Moreover, the soluble protein released from fibrils is able to rapidly polymerize into amyloid fibrils under fibril-forming conditions and to efficiently seed aggregation of monomeric Mcc. Our findings indicate that fibrillar forms of Mcc constitute a reservoir of toxic oligomeric species that is released into the medium upon changing the environmental conditions. These findings may have substantial implications to understand the dynamic process of interconversion between toxic and non-toxic aggregated species implicated in protein misfolding diseases.
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Di Domizio, Jeremy, Ran Zhang, Ming Zhuo, Loren Stagg, John Ladbury, Michel Gilliet, and Wei Cao. "A novel class of host-derived etiological agent for autoimmunity: oligomers of endogenous proteins bind to self-nucleic acids and trigger type I IFN production by plasmacytoid dendritic cells (44.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 44.2. http://dx.doi.org/10.4049/jimmunol.186.supp.44.2.
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Abstract Under certain conditions, some soluble endogenous proteins can form ordered oligomeric structures leading to the assembly of stable insoluble amyloids, a process that increases with age. The presence of such structures is associated with cellular toxicity and diseases development, e.g. Alzheimer disease, type II diabetes. Recent studies clearly show that the primary toxic species in such pathologies is the soluble oligomers of proteins, precursors of amyloids. Yet, it is unknown if such aberrant forms of proteins would elicit any immune reaction. Here we obtained oligomers derived from several human endogenous proteins and characterized their biochemical and immunological functions. The oligomeric proteins preferentially bind to both DNA and RNA and can be effectively internalized by cells. Surprisingly, the soluble protein oligomers enable prominent IFNα production by PBMCs to self-DNA, self-RNA and necrotic cell debris in a pDC-dependent manner. Consistently, peptides from amyloid β and prion protein, two known etiological agents associated with amyloid diseases, display similar innate immune functions by complexing with nucleic acids and inducing IFN production by pDCs. Therefore, oligomers of endogenous proteins formed during the aging process may strongly promote the host’s type I IFN response to self-nucleic acids, a reaction likely favoring the development of autoimmunity, such as SLE where strong type I IFN presence correlates with disease pathology.
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Rodigast, Maria, Anke Mutzel, and Hartmut Herrmann. "A quantification method for heat-decomposable methylglyoxal oligomers and its application on 1,3,5-trimethylbenzene SOA." Atmospheric Chemistry and Physics 17, no. 6 (March 23, 2017): 3929–43. http://dx.doi.org/10.5194/acp-17-3929-2017.
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Abstract. Methylglyoxal forms oligomeric compounds in the atmospheric aqueous particle phase, which could establish a significant contribution to the formation of aqueous secondary organic aerosol (aqSOA). Thus far, no suitable method for the quantification of methylglyoxal oligomers is available despite the great effort spent for structure elucidation. In the present study a simplified method was developed to quantify heat-decomposable methylglyoxal oligomers as a sum parameter. The method is based on the thermal decomposition of oligomers into methylglyoxal monomers. Formed methylglyoxal monomers were detected using PFBHA (o-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride) derivatisation and gas chromatography–mass spectrometry (GC/MS) analysis. The method development was focused on the heating time (varied between 15 and 48 h), pH during the heating process (pH = 1–7), and heating temperature (50, 100 °C). The optimised values of these method parameters are presented. The developed method was applied to quantify heat-decomposable methylglyoxal oligomers formed during the OH-radical oxidation of 1,3,5-trimethylbenzene (TMB) in the Leipzig aerosol chamber (LEipziger AerosolKammer, LEAK). Oligomer formation was investigated as a function of seed particle acidity and relative humidity. A fraction of heat-decomposable methylglyoxal oligomers of up to 8 % in the produced organic particle mass was found, highlighting the importance of those oligomers formed solely by methylglyoxal for SOA formation. Overall, the present study provides a new and suitable method for quantification of heat-decomposable methylglyoxal oligomers in the aqueous particle phase.