8A4L

Lipidic alpha-synuclein fibril - polymorph L2A

8A4L の概要

• エントリーDOI: 10.2210/pdb8a4l/pdb
• EMDBエントリー: 15148
• 分子名称: Alpha-synuclein (1 entity in total)
• 機能のキーワード: amyloid fibril, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 15
• 化学式量合計: 217141.62

構造登録者

Frieg, B.,Antonschmidt, L.,Dienemann, C.,Geraets, J.A.,Najbauer, E.E.,Matthes, D.,de Groot, B.L.,Andreas, L.B.,Becker, S.,Griesinger, C.,Schroeder, G.F. (登録日: 2022-06-12, 公開日: 2022-08-17, 最終更新日: 2024-07-24)

主引用文献

Frieg, B.,Antonschmidt, L.,Dienemann, C.,Geraets, J.A.,Najbauer, E.E.,Matthes, D.,de Groot, B.L.,Andreas, L.B.,Becker, S.,Griesinger, C.,Schroder, G.F.
The 3D structure of lipidic fibrils of alpha-synuclein.
Nat Commun, 13:6810-6810, 2022

PubMed Abstract: α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson's disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson's patients revealed that lipids and membranous organelles are also a significant component. Interactions between α-synuclein and lipids have been previously identified as relevant for Parkinson's disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six α-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of α-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions.

PubMed: 36357403
DOI: 10.1038/s41467-022-34552-7

実験手法

ELECTRON MICROSCOPY (2.68 Å)