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Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

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  • Melissa Birol

    (University of Pennsylvania
    Yale University)

  • Sunil Kumar

    (New York University, Silver Center for Arts and Science)

  • Elizabeth Rhoades

    (University of Pennsylvania)

  • Andrew D. Miranker

    (Yale University)

Abstract

Peptide mediated gain-of-toxic function is central to pathology in Alzheimer’s, Parkinson’s and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here we focus on islet amyloid polypeptide (IAPP) mediated loss-of-insulin secreting cells in patients with diabetes. Newly developed methods enable structure-function enquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two classes of poration occur; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilising non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalisable approach for enquiry applicable to other partially ordered protein assemblies.

Suggested Citation

  • Melissa Birol & Sunil Kumar & Elizabeth Rhoades & Andrew D. Miranker, 2018. "Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03651-9
    DOI: 10.1038/s41467-018-03651-9
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    Cited by:

    1. Jemil Ahmed & Tessa C. Fitch & Courtney M. Donnelly & Johnson A. Joseph & Tyler D. Ball & Mikaela M. Bassil & Ahyun Son & Chen Zhang & Aurélie Ledreux & Scott Horowitz & Yan Qin & Daniel Paredes & Sun, 2022. "Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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