2013
DOI: 10.1016/j.bpj.2013.07.044
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Identification of Fibril-Like Tertiary Contacts in Soluble Monomeric α-Synuclein

Abstract: Structural conversion of the presynaptic, intrinsically disordered protein α-synuclein into amyloid fibrils underlies neurotoxicity in Parkinson's disease. The detailed mechanism by which this conversion occurs is largely unknown. Here, we identify a discrete pattern of transient tertiary interactions in monomeric α-synuclein involving amino acid residues that are, in the fibrillar state, part of β-strands. Importantly, this pattern of pairwise interactions does not correspond to that found in the amyloid stat… Show more

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Cited by 61 publications
(101 citation statements)
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References 64 publications
(112 reference statements)
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“…4C), it still could be interacting with other residues in the protein. This hypothesis is in line with the fact that ␤5 region establishes long range tertiary contacts in the monomeric protein (9) and that position 90 is shielded from the solvent and protected from a soluble quencher in Trp-engineered oligomers (16).…”
Section: Discussionsupporting
confidence: 73%
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“…4C), it still could be interacting with other residues in the protein. This hypothesis is in line with the fact that ␤5 region establishes long range tertiary contacts in the monomeric protein (9) and that position 90 is shielded from the solvent and protected from a soluble quencher in Trp-engineered oligomers (16).…”
Section: Discussionsupporting
confidence: 73%
“…4D. A number of transient tertiary contacts are present in the soluble monomeric protein, which could direct the formation of early aggregation-prone species (9). Then, antiparallel ␤-sheet-rich oligomeric intermediates are buildup (15), probably involving ␤1-␤1, ␤2-␤2, and ␤4-␤4 intermolecular interactions (this work).…”
Section: Discussionmentioning
confidence: 84%
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“…Based on the antiparallel five β-strand fibrillary α-Syn model28, Salvatella et al proposed that the transient interactions of hydrophobic regions (β4–β5 strands etc.) lead to early aggregate formation29. The C-terminal region (residues 104–130) contacts residues comprising β4 and β5 in monomeric α-Syn29, which is important in modulating the early aggregation process.…”
Section: Discussionmentioning
confidence: 99%
“…lead to early aggregate formation29. The C-terminal region (residues 104–130) contacts residues comprising β4 and β5 in monomeric α-Syn29, which is important in modulating the early aggregation process. The implication is that phosphorylation at Ser129 may interfere with the transient interactions, increase conformational flexibility30, and break the autoinhibitory conformation, which are compatible with the influence in fibrillization exerted by phosphorylation of Ser129 and could characterize structural difference between α-Syn WT and PS fibers.…”
Section: Discussionmentioning
confidence: 99%