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

Warmack, Rebeccah A.; Boyer, David R.; Zee, Chih-Te; Richards, Logan S.; Sawaya, Michael R.; Cascio, Duilio; Gonen, Tamir; Eisenberg, David S.; Clarke, Steven G.

doi:10.1038/s41467-019-11183-z

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

Journal Article · Fri Jul 26 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-11183-z· OSTI ID:1624174

^[1]; Boyer, David R. ^[2]; Zee, Chih-Te ^[2]; Richards, Logan S. ^[2]; ^[2]; ^[2]; ^[2]; ^[2]; Clarke, Steven G. ^[2]

Univ. of California, Los Angeles, CA (United States); DOE/OSTI
Univ. of California, Los Angeles, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: University of California, Los Angeles, CA (United States)

Sponsoring Organization:: Elizabeth and Thomas Plott Chair in Gerontology; Howard Hughes Medical Institute; Life Extension Foundation; National Institutes of Health (NIH); National Science Foundation (NSF); USDOE; USPHS National Research Service Award

OSTI ID:: 1624174

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Alzheimer's disease
biochemistry
electron microscopy
post-translational modifications
science & technology
structural biology

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

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