5VOS

VGSNKGAIIGL from Amyloid Beta determined by MicroED

5VOS の概要

• エントリーDOI: 10.2210/pdb5vos/pdb
• 関連するPDBエントリー: 5KNZ
• EMDBエントリー: 8720
• 分子名称: Amyloid beta A4 protein (2 entities in total)
• 機能のキーワード: amyloid, steric zipper, protein fibril
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 1029.21

構造登録者

Rodriguez, J.A.,Sawaya, M.R.,Cascio, D.,Eisenberg, D.S.,Griner, S.L.,Gonen, T. (登録日: 2017-05-03, 公開日: 2018-01-03, 最終更新日: 2024-03-13)

主引用文献

Krotee, P.,Griner, S.L.,Sawaya, M.R.,Cascio, D.,Rodriguez, J.A.,Shi, D.,Philipp, S.,Murray, K.,Saelices, L.,Lee, J.,Seidler, P.,Glabe, C.G.,Jiang, L.,Gonen, T.,Eisenberg, D.S.
Common fibrillar spines of amyloid-beta and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors.
J. Biol. Chem., 293:2888-2902, 2018

PubMed Abstract: Amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregate to form amyloid fibrils that deposit in tissues and are associated with Alzheimer's disease (AD) and type II diabetes (T2D), respectively. Individuals with T2D have an increased risk of developing AD, and conversely, AD patients have an increased risk of developing T2D. Evidence suggests that this link between AD and T2D might originate from a structural similarity between aggregates of Aβ and hIAPP. Using the cryoEM method microelectron diffraction, we determined the atomic structures of 11-residue segments from both Aβ and hIAPP, termed Aβ(24-34) WT and hIAPP(19-29) S20G, with 64% sequence similarity. We observed a high degree of structural similarity between their backbone atoms (0.96-Å root mean square deviation). Moreover, fibrils of these segments induced amyloid formation through self- and cross-seeding. Furthermore, inhibitors designed for one segment showed cross-efficacy for full-length Aβ and hIAPP and reduced cytotoxicity of both proteins, although by apparently blocking different cytotoxic mechanisms. The similarity of the atomic structures of Aβ(24-34) WT and hIAPP(19-29) S20G offers a molecular model for cross-seeding between Aβ and hIAPP.

PubMed: 29282295
DOI: 10.1074/jbc.M117.806109

実験手法

ELECTRON CRYSTALLOGRAPHY (1.42 Å)