+検索条件
-Structure paper
タイトル | A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion. |
---|---|
ジャーナル・号・ページ | J Am Chem Soc, Vol. 146, Issue 18, Page 12702-12711, Year 2024 |
掲載日 | 2024年5月8日 |
著者 | Jaime Santos / Jorge Cuellar / Irantzu Pallarès / Emily J Byrd / Alons Lends / Fernando Moro / Muhammed Bilal Abdul-Shukkoor / Jordi Pujols / Lorea Velasco-Carneros / Frank Sobott / Daniel E Otzen / Antonio N Calabrese / Arturo Muga / Jan Skov Pedersen / Antoine Loquet / Jose María Valpuesta / Sheena E Radford / Salvador Ventura / |
PubMed 要旨 | Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is ...Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations. |
リンク | J Am Chem Soc / PubMed:38683963 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 18.3 Å |
構造データ | EMDB-16466: The structural architecture of alpha-synuclein oligomer EMDB-16528: 3D reconstruction of alpha-synuclein oligomer-PSMa3 complex |
由来 |
|