Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

Krotee, Pascal; Rodriguez, Jose A.; Sawaya, Michael R.; Cascio, Duilio; Reyes, Francis E.; Shi, Dan; Hattne, Johan; Nannenga, Brent L.; Oskarsson, Marie E.; Philipp, Stephan; Griner, Sarah; Jiang, Lin; Glabe, Charles G.; Westermark, Gunilla T.; Gonen, Tamir; Eisenberg, David S.

doi:10.7554/eLife.19273

Title: Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

Journal Article · Tue Jan 03 00:00:00 EST 2017 · eLife

DOI:https://doi.org/10.7554/eLife.19273· OSTI ID:1430326

^[1]; Rodriguez, Jose A. ^[1];

^[1];

^[1]; Reyes, Francis E. ^[2]; Shi, Dan ^[2];

^[2]; Nannenga, Brent L. ^[2]; Oskarsson, Marie E. ^[3]; Philipp, Stephan ^[4]; Griner, Sarah ^[1]; Jiang, Lin ^[5]; Glabe, Charles G. ^[6]; Westermark, Gunilla T. ^[3]; Gonen, Tamir ^[2]; Eisenberg, David S. ^[1]

Howard Hughes Medical Inst., Chevy Chase, MD (United States); Univ. of California, Los Angeles, CA (United States); Univ. of California, Los Angeles, CA (United States). UCLA-DOE Inst.
Howard Hughes Medical Inst., Chevy Chase, MD (United States). Janelia Research Campus
Uppsala Univ. (Sweden)
Univ. of California, Irvine, CA (United States)
Univ. of California, Los Angeles, CA (United States)
Univ. of California, Irvine, CA (United States); King Abdulaziz Univ., Jeddah (Saudi Arabia)

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 β-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 β-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 β-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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE; Cure Alzheimer’s Fund; Swedish Research Council (VR); Swedish Diabetes Foundation

Contributing Organization:: Janelia Research Campus Visitor Program

Grant/Contract Number:: FC03-02ER63421; P41 RR015301; P41 GM103403; AC02-06CH11357

OSTI ID:: 1430326

Journal Information:: eLife, Vol. 6, Issue 01, 2017; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 80 works

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Identification of a hinge residue controlling islet amyloid polypeptide self-assembly and cytotoxicity Godin, Elizabeth; Nguyen, Phuong Trang; Zottig, Ximena Journal of Biological Chemistry, Vol. 294, Issue 21 https://doi.org/10.1074/jbc.ra118.006454	journal	April 2019
Homochiral and racemic MicroED structures of a peptide repeat from the ice-nucleation protein InaZ Zee, Chih-Te; Glynn, Calina; Gallagher-Jones, Marcus IUCrJ, Vol. 6, Issue 2 https://doi.org/10.1107/s2052252518017621	journal	January 2019
Amyloid assembly and disassembly Chuang, Edward; Hori, Acacia M.; Hesketh, Christina D. Journal of Cell Science, Vol. 131, Issue 8 https://doi.org/10.1242/jcs.189928	journal	April 2018
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