ジャーナル: J Biol Chem / 年: 2018 タイトル: Common fibrillar spines of amyloid-β and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors. 著者: Pascal Krotee / Sarah L Griner / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Dan Shi / Stephan Philipp / Kevin Murray / Lorena Saelices / Ji Lee / Paul Seidler / Charles G Glabe / ...著者: Pascal Krotee / Sarah L Griner / Michael R Sawaya / Duilio Cascio / Jose A Rodriguez / Dan Shi / Stephan Philipp / Kevin Murray / Lorena Saelices / Ji Lee / Paul Seidler / Charles G Glabe / Lin Jiang / Tamir Gonen / David S Eisenberg / 要旨: 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), ...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.
∠α: 90 ° / ∠β: 100.017 ° / ∠γ: 90 ° / A: 18.78 Å / B: 4.73 Å / C: 33.47 Å / 空間群名: P21 / 空間群番号: 4
CTF補正
タイプ: NONE
3次元再構成
解像度の算出法: DIFFRACTION PATTERN/LAYERLINES / 対称性のタイプ: 3D CRYSTAL
原子モデル構築
プロトコル: OTHER / 空間: RECIPROCAL / Target criteria: Maximum likelihood
精密化
構造決定の手法: 分子置換 / 解像度: 1.42→32.96 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.881 / SU B: 2.871 / SU ML: 0.1 / SU R Cruickshank DPI: 0.1152 / 交差検証法: THROUGHOUT / σ(F): 0 / ESU R: 0.115 / ESU R Free: 0.122 詳細: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY