ジャーナル: Nat Struct Mol Biol / 年: 2020 タイトル: Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils. 著者: Christine Röder / Tatsiana Kupreichyk / Lothar Gremer / Luisa U Schäfer / Karunakar R Pothula / Raimond B G Ravelli / Dieter Willbold / Wolfgang Hoyer / Gunnar F Schröder / 要旨: Amyloid deposits consisting of fibrillar islet amyloid polypeptide (IAPP) in pancreatic islets are associated with beta-cell loss and have been implicated in type 2 diabetes (T2D). Here, we applied ...Amyloid deposits consisting of fibrillar islet amyloid polypeptide (IAPP) in pancreatic islets are associated with beta-cell loss and have been implicated in type 2 diabetes (T2D). Here, we applied cryo-EM to reconstruct densities of three dominant IAPP fibril polymorphs, formed in vitro from synthetic human IAPP. An atomic model of the main polymorph, built from a density map of 4.2-Å resolution, reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, essential for IAPP amyloidogenicity, forms the protofilament interface together with Tyr37 and the amidated C terminus. The S-fold resembles polymorphs of Alzheimer's disease (AD)-associated amyloid-β (Aβ) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-Aβ cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of Aβ and support the design of inhibitors and imaging probes for IAPP fibrils.
EMPIAR-11093 (タイトル: Micrographs of IAPP (amylin) amyloid fibrils / Data size: 83.1 Data #1: MotionCor2-aligned single frame of islet amyloid polypeptide fibrils [micrographs - single frame])
フィルム・検出器のモデル: FEI FALCON III (4k x 4k) 検出モード: COUNTING / 撮影したグリッド数: 1 / 実像数: 1330 / 平均露光時間: 46.0 sec. / 平均電子線量: 41.4 e/Å2
電子線
加速電圧: 200 kV / 電子線源: FIELD EMISSION GUN
電子光学系
照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD
実験機器
モデル: Talos Arctica / 画像提供: FEI Company
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画像解析
最終 再構成
使用したクラス数: 1 想定した対称性 - らせんパラメータ - Δz: 2.351 Å 想定した対称性 - らせんパラメータ - ΔΦ: 178.23 ° 想定した対称性 - らせんパラメータ - 軸対称性: C1 (非対称) 解像度のタイプ: BY AUTHOR / 解像度: 4.2 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION (ver. 3.0.5) 詳細: the data set was split by whole fibrils and then refined independently for 25 iterations to yield the two half maps. 使用した粒子像数: 37120
初期モデル
モデルのタイプ: OTHER / 詳細: noise filled cylinder
最終 角度割当
タイプ: NOT APPLICABLE
FSC曲線 (解像度の算出)
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原子モデル構築 1
精密化
空間: REAL / プロトコル: AB INITIO MODEL
得られたモデル
PDB-6y1a: Amyloid fibril structure of islet amyloid polypeptide