7K3C

SGMGGIT segment 58-64 from Keratin-8

7K3C の概要

• エントリーDOI: 10.2210/pdb7k3c/pdb
• 分子名称: SGMGGIT segment 58-64 from the low complexity domain of Keratin-8, ETHANOL, TRIETHYLENE GLYCOL, ... (4 entities in total)
• 機能のキーワード: amyloid filament, low complexity sequence, protein fibril
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 1485.72

構造登録者

Murray, K.A.,Sawaya, M.R.,Eisenberg, D.S. (登録日: 2020-09-11, 公開日: 2021-11-10, 最終更新日: 2024-05-22)

主引用文献

Murray, K.A.,Hughes, M.P.,Hu, C.J.,Sawaya, M.R.,Salwinski, L.,Pan, H.,French, S.W.,Seidler, P.M.,Eisenberg, D.S.
Identifying amyloid-related diseases by mapping mutations in low-complexity protein domains to pathologies.
Nat.Struct.Mol.Biol., 29:529-536, 2022

PubMed Abstract: Proteins including FUS, hnRNPA2, and TDP-43 reversibly aggregate into amyloid-like fibrils through interactions of their low-complexity domains (LCDs). Mutations in LCDs can promote irreversible amyloid aggregation and disease. We introduce a computational approach to identify mutations in LCDs of disease-associated proteins predicted to increase propensity for amyloid aggregation. We identify several disease-related mutations in the intermediate filament protein keratin-8 (KRT8). Atomic structures of wild-type and mutant KRT8 segments confirm the transition to a pleated strand capable of amyloid formation. Biochemical analysis reveals KRT8 forms amyloid aggregates, and the identified mutations promote aggregation. Aggregated KRT8 is found in Mallory-Denk bodies, observed in hepatocytes of livers with alcoholic steatohepatitis (ASH). We demonstrate that ethanol promotes KRT8 aggregation, and KRT8 amyloids co-crystallize with alcohol. Lastly, KRT8 aggregation can be seeded by liver extract from people with ASH, consistent with the amyloid nature of KRT8 aggregates and the classification of ASH as an amyloid-related condition.

PubMed: 35637421
DOI: 10.1038/s41594-022-00774-y

実験手法

X-RAY DIFFRACTION (1.1 Å)