Structure of amyloid-? (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.

ABSTRACT: Amyloid-? (A?) 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 A? 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 ?-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar A? structures, and both self-associate through two distinct interfaces. One of these is a unique A? 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 A? 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified A? segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD.

SUBMITTER: Warmack RA 

PROVIDER: S-EPMC6659688 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature