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TitleStructure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.
Journal, issue, pagesNat Commun, Vol. 10, Issue 1, Page 3357, Year 2019
Publish dateJul 26, 2019
AuthorsRebeccah A Warmack / David R Boyer / Chih-Te Zee / Logan S Richards / Michael R Sawaya / Duilio Cascio / Tamir Gonen / David S Eisenberg / Steven G Clarke /
PubMed AbstractAmyloid-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- ...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.
External linksNat Commun / PubMed:31350392 / PubMed Central
MethodsEM (electron crystallography)
Resolution1.05 - 1.1 Å
Structure data

EMDB-0405, PDB-6nb9:
Amyloid-Beta (20-34) with L-isoaspartate 23
Method: EM (electron crystallography)

EMDB-20082, PDB-6oiz:
Amyloid-Beta (20-34) wild type
Method: EM (electron crystallography)

Chemicals

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / protofilament / 2 sub 1 screw symmetry / post-translational modification / isoaspartate

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