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

Author

Listed:
  • Rebeccah A. Warmack

    (University of California, Los Angeles)

  • David R. Boyer

    (University of California, Los Angeles)

  • Chih-Te Zee

    (University of California, Los Angeles)

  • Logan S. Richards

    (University of California, Los Angeles)

  • Michael R. Sawaya

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Duilio Cascio

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Tamir Gonen

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • David S. Eisenberg

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Steven G. Clarke

    (University of California, Los Angeles
    University of California, Los Angeles)

Abstract

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.

Suggested Citation

  • Rebeccah A. Warmack & David R. Boyer & Chih-Te Zee & Logan S. Richards & Michael R. Sawaya & Duilio Cascio & Tamir Gonen & David S. Eisenberg & Steven G. Clarke, 2019. "Structure of amyloid-β (20-34) with Alzheimer’s-associated isomerization at Asp23 reveals a distinct protofilament interface," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11183-z
    DOI: 10.1038/s41467-019-11183-z
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    Cited by:

    1. Agnes Banreti & Shayon Bhattacharya & Frank Wien & Koichi Matsuo & Matthieu Réfrégiers & Cornelia Meinert & Uwe Meierhenrich & Bruno Hudry & Damien Thompson & Stéphane Noselli, 2022. "Biological effects of the loss of homochirality in a multicellular organism," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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