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An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation

Author

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  • Mireia Seuma

    (The Barcelona Institute of Science and Technology)

  • Ben Lehner

    (Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra (UPF)
    ICREA
    Wellcome Genome Campus)

  • Benedetta Bolognesi

    (The Barcelona Institute of Science and Technology)

Abstract

Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type—amino acid (AA) substitutions—despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate a comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer’s disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.

Suggested Citation

  • Mireia Seuma & Ben Lehner & Benedetta Bolognesi, 2022. "An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34742-3
    DOI: 10.1038/s41467-022-34742-3
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    References listed on IDEAS

    as
    1. Benedetta Bolognesi & Andre J. Faure & Mireia Seuma & Jörn M. Schmiedel & Gian Gaetano Tartaglia & Ben Lehner, 2019. "The mutational landscape of a prion-like domain," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Stephane Emond & Maya Petek & Emily J. Kay & Brennen Heames & Sean R. A. Devenish & Nobuhiko Tokuriki & Florian Hollfelder, 2020. "Accessing unexplored regions of sequence space in directed enzyme evolution via insertion/deletion mutagenesis," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Jung-Eun Shin & Adam J. Riesselman & Aaron W. Kollasch & Conor McMahon & Elana Simon & Chris Sander & Aashish Manglik & Andrew C. Kruse & Debora S. Marks, 2021. "Protein design and variant prediction using autoregressive generative models," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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