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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

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

Warmack Rebeccah A RA Boyer David R DR Zee Chih-Te CT Richards Logan S LS Sawaya Michael R MR Cascio Duilio D Gonen Tamir T Eisenberg David S DS Clarke Steven G SG

Nature communications 20190726 1

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 inte ...[more]

PMID: 31350392

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Project description:Detailed structural studies of amyloid fibrils can elucidate the way in which their constituent polypeptides are folded and self-assemble, and exert their neurotoxic effects in Alzheimer's disease (AD). We have previously reported that when aqueous solutions of the N-terminal hydrophilic peptides of AD beta-amyloid (A beta) are gradually dried in a 2-Tesla magnetic field, they form highly oriented fibrils that are well suited to x-ray fiber diffraction. The longer, more physiologically relevant sequences such as A beta(1-40) have not been amenable to such analysis, owing to their strong propensity to polymerize and aggregate before orientation is achieved. In seeking an efficient and inexpensive method for rapid screening of conditions that could lead to improved orientation of fibrils assembled from the longer peptides, we report here that the birefringence of a small drop of peptide solution can supply information related to the cooperative packing of amyloid fibers and their capacity for magnetic orientation. The samples were examined by electron microscopy (negative and positive staining) and x-ray diffraction. Negative staining showed a mixture of straight and twisted fibers. The average width of both types was approximately 70 A, and the helical pitch of the latter was approximately 460 A. Cross sections of plastic-embedded samples showed a approximately 60-A-wide tubular structure. X-ray diffraction from these samples indicated a cross-beta fiber pattern, characterized by a strong meridional reflection at 4.74 A and a broad equatorial reflection at 8.9 A. Modeling studies suggested that tilted arrays of beta-strands constitute tubular, 30-A-diameter protofilaments, and that three to five of these protofilaments constitute the A beta fiber. This type of structure--a multimeric array of protofilaments organized as a tubular fibril--resembles that formed by the shorter A beta fragments (e.g., A beta(6-25), A beta(11-25), A beta(1-28)), suggesting a common structural motif in AD amyloid fibril organization.

Dataset Information

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

Publications

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

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