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Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity
Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Biol Chem, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, UCLA DOE Inst, Los Angeles, CA 90095 USA..
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2017 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 6Article in journal (Refereed) Published
Abstract [en]

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic beta-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of beta-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile beta-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.

Place, publisher, year, edition, pages
2017. Vol. 6
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-316042DOI: 10.7554/eLife.19273ISI: 000392186000001OAI: oai:DiVA.org:uu-316042DiVA: diva2:1076822
Funder
NIH (National Institute of Health), R01 AG029430
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-01-13Bibliographically approved

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Oskarsson, Marie E.Westermark, Gunilla T.
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