Structural highlights
Publication Abstract from PubMed
Amyloid-beta (Abeta) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 A resolution MicroED structure of an Abeta 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 beta-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Abeta structures, and both self-associate through two distinct interfaces. One of these is a unique Abeta 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 Abeta 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Abeta segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD.
Structure of amyloid-beta (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.,Warmack RA, Boyer DR, Zee CT, Richards LS, Sawaya MR, Cascio D, Gonen T, Eisenberg DS, Clarke SG Nat Commun. 2019 Jul 26;10(1):3357. doi: 10.1038/s41467-019-11183-z. PMID:31350392[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Warmack RA, Boyer DR, Zee CT, Richards LS, Sawaya MR, Cascio D, Gonen T, Eisenberg DS, Clarke SG. Structure of amyloid-beta (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface. Nat Commun. 2019 Jul 26;10(1):3357. doi: 10.1038/s41467-019-11183-z. PMID:31350392 doi:http://dx.doi.org/10.1038/s41467-019-11183-z
