2LNQ

40-residue D23N beta amyloid fibril

2LNQ の概要

• エントリーDOI: 10.2210/pdb2lnq/pdb
• NMR情報: BMRB: 18175
• 分子名称: P3(40) (1 entity in total)
• 機能のキーワード: iowa mutant, antiparallel beta sheet, protein fibril
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P05067
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 34678.94

構造登録者

Qiang, W.,Yau, W.,Luo, Y.,Mattson, M.P.,Tycko, R. (登録日: 2012-01-03, 公開日: 2012-02-08, 最終更新日: 2024-05-15)

主引用文献

Qiang, W.,Yau, W.M.,Luo, Y.,Mattson, M.P.,Tycko, R.
Antiparallel beta-sheet architecture in Iowa-mutant beta-amyloid fibrils.
Proc.Natl.Acad.Sci.USA, 109:4443-4448, 2012

PubMed Abstract: Wild-type, full-length (40- and 42-residue) amyloid β-peptide (Aβ) fibrils have been shown by a variety of magnetic resonance techniques to contain cross-β structures in which the β-sheets have an in-register parallel supramolecular organization. In contrast, recent studies of fibrils formed in vitro by the Asp23-to-Asn mutant of 40-residue Aβ (D23N-Aβ(1-40)), which is associated with early onset neurodegeneration, indicate that D23N-Aβ(1-40) fibrils can contain either parallel or antiparallel β-sheets. We report a protocol for producing structurally pure antiparallel D23N-Aβ(1-40) fibril samples and a series of solid state nuclear magnetic resonance and electron microscopy measurements that lead to a specific model for the antiparallel D23N-Aβ(1-40) fibril structure. This model reveals how both parallel and antiparallel cross-β structures can be constructed from similar peptide monomer conformations and stabilized by similar sets of interactions, primarily hydrophobic in nature. We find that antiparallel D23N-Aβ(1-40) fibrils are thermodynamically metastable with respect to conversion to parallel structures, propagate less efficiently than parallel fibrils in seeded fibril growth, and therefore must nucleate more efficiently than parallel fibrils in order to be observable. Experiments in neuronal cell cultures indicate that both antiparallel and parallel D23N-Aβ(1-40) fibrils are cytotoxic. Thus, our antiparallel D23N-Aβ(1-40) fibril model represents a specific "toxic intermediate" in the aggregation process of a disease-associated Aβ mutant.

PubMed: 22403062
DOI: 10.1073/pnas.1111305109

実験手法

SOLID-STATE NMR