9D5C

Cryo-EM structure of serine 87 O-GlcNAc-modified alpha-synuclein fibrils

9D5C の概要

• エントリーDOI: 10.2210/pdb9d5c/pdb
• 関連するPDBエントリー: 8GF7
• EMDBエントリー: 29980
• 分子名称: Alpha-synuclein, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• 機能のキーワード: alpha-synuclein, o-glcnac, amyloid, fibril, posttranslational modification, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 58531.07

構造登録者

Balana, J.A.,Nguyen, A.B.,Sawaya, M.,Murzin, A.G.,Saelices, L.,Pratt, R.M. (登録日: 2024-08-13, 公開日: 2025-03-12)

主引用文献

Balana, A.T.,Mahul-Mellier, A.L.,Nguyen, B.A.,Horvath, M.,Javed, A.,Hard, E.R.,Jasiqi, Y.,Singh, P.,Afrin, S.,Pedretti, R.,Singh, V.,Lee, V.M.,Luk, K.C.,Saelices, L.,Lashuel, H.A.,Pratt, M.R.
O-GlcNAc forces an alpha-synuclein amyloid strain with notably diminished seeding and pathology.
Nat.Chem.Biol., 20:646-655, 2024

PubMed Abstract: Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.

PubMed: 38347213
DOI: 10.1038/s41589-024-01551-2

実験手法

ELECTRON MICROSCOPY (4.8 Å)