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-Structure paper
タイトル | Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface. |
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ジャーナル・号・ページ | Nat Commun, Vol. 10, Issue 1, Page 3357, Year 2019 |
掲載日 | 2019年7月26日 |
著者 | Rebeccah A Warmack / David R Boyer / Chih-Te Zee / Logan S Richards / Michael R Sawaya / Duilio Cascio / Tamir Gonen / David S Eisenberg / Steven G Clarke / |
PubMed 要旨 | Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20- ...Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD. |
リンク | Nat Commun / PubMed:31350392 / PubMed Central |
手法 | EM (電子線結晶学) |
解像度 | 1.05 - 1.1 Å |
構造データ | EMDB-20082, PDB-6oiz: |
化合物 | ChemComp-HOH: |
由来 |
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キーワード | PROTEIN FIBRIL / protofilament / 2 sub 1 screw symmetry / post-translational modification / isoaspartate |