2007
DOI: 10.1021/bi7014053
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Role of Different Regions of α-Synuclein in the Assembly of Fibrils

Abstract: Elucidating the details of the assembly of amyloid fibrils is a key step to understanding the mechanism of amyloid deposition diseases including Parkinson's disease. Although several models have been proposed, based on analyses of polypeptides and short peptides, a detailed understanding of the structure and mechanism of alpha-synuclein fibrillation remains elusive. In this study, we used trypsin and endoproteinase GluC to digest intact alpha-synuclein fibrils and to analyze the detailed morphology of the resu… Show more

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Cited by 97 publications
(121 citation statements)
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“…Despite the reported variability, all aSyn species share a common aggregation core with a less-compacted region mainly composed by the C terminus of the polypeptide. This finding is in agreement with previous data reporting the poor participation of the C-terminal domain in fibril formation, which indeed remains mainly disordered instead of acquiring the typical β-sheet structure (46). The definition of aSyn as a prion-like protein is intimately linked to an intrinsic seeding activity of, at least, some misfolded conformations.…”
Section: Discussionsupporting
confidence: 92%
“…Despite the reported variability, all aSyn species share a common aggregation core with a less-compacted region mainly composed by the C terminus of the polypeptide. This finding is in agreement with previous data reporting the poor participation of the C-terminal domain in fibril formation, which indeed remains mainly disordered instead of acquiring the typical β-sheet structure (46). The definition of aSyn as a prion-like protein is intimately linked to an intrinsic seeding activity of, at least, some misfolded conformations.…”
Section: Discussionsupporting
confidence: 92%
“…We therefore propose that the RPT domain plays a regulatory function in vivo, rather than serving a structural role as the core of the fibrils. A comparable regulatory role for a repeat-rich domain has been observed for other amyloids, such as Sup35 and ␣-synuclein, in which repeated sequences have been found to influence the kinetics of fibril formation but are not completely sequestered in the amyloid core itself (53)(54)(55)(56)(57)(58)(59).…”
Section: Discussionmentioning
confidence: 56%
“…For example, it may prevent M␣ from aggregating until reaching the endosome, where proteolytic maturation and a decreased pH might release the RPT domain and thus uncover the amyloidogenic domain within the NTR and/or PKD domains for the initiation of fibrillogenesis. Interestingly, deletion of the N-terminal repeats of ␣-synuclein by either mutation or protease digestion does not affect protofilament generation, but it results in thinner protofilaments that assemble less efficiently into protofibrils (58). Similarly, deletion of repeats within Sup35 retards fibril assembly (56).…”
Section: Discussionmentioning
confidence: 99%
“…Intra-and intermolecular contacts can be detected in monomeric, unfolded αS and are implicated in modulating the aggregation propensity (Bertoncini et al, 2005;Dedmon et al, 2005;Outeiro et al, 2008;Wu and Baum, 2010). The negatively charged C-terminus remains disordered in several conformational states such as monomeric, fibrillar and membrane-bound αS (Del Mar et al, 2005;Eliezer et al, 2001;Qin et al, 2007;Ulmer et al, 2005;Vilar et al, 2008). In Lewy õbodies, 90% of αS is estimated to be phosphorylated at S129 in the C-terminus (Fujiwara et al, 2002).…”
mentioning
confidence: 99%