Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, 90095-1569, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095-1570, USA.
Nat Commun. 2019 Jul 26;10(1):3357. doi: 10.1038/s41467-019-11183-z.
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.
淀粉样蛋白-β（Aβ）具有许多翻译后修饰（PTMs），这些修饰可能会影响阿尔茨海默病（AD）的发病机制。在这里，我们展示了分辨率为 1.1Å 的 Aβ 20-34 纤维的 MicroED 结构，其中包括和不包括位置 23 的疾病相关修饰物 L-异天冬氨酸（L-isoAsp23）。野生型和 L-isoAsp23 原纤维都采用 β-螺旋样折叠，核心紧密堆积，类似于全长纤维状 Aβ 结构的核心，并且都通过两个不同的界面进行自我组装。其中一个是由异天冬氨酸修饰强化的独特 Aβ 界面。粉末衍射图谱表明，含有遗传的爱荷华突变（Asp23Asn）的类似片段中的原纤维可能采用类似的结构。与患者中早发性表型一致，Asp23Asn 加速了 Aβ 20-34 的聚集，L-isoAsp23 修饰也是如此。这些结构表明，修饰的 Aβ 片段的增强的淀粉样蛋白形成性也可能降低达到成核所需的浓度，从而有助于促进 AD 的发病机制。
