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Elife. 2017 Jan 3;6. pii: e19273. doi: 10.7554/eLife.19273.

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

Author information

1
Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
2
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
3
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States.
4
UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States.
5
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
6
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
7
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States.
8
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
9
Brain Research Institute (BRI), University of California, Los Angeles, Los Angeles, United States.
10
Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

Abstract

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.

KEYWORDS:

MicroED; Type-II Diabetes; amyloid fibril; biochemistry; biophysics; cytotoxicity; human; islet amyloid polypeptide; structural biology

PMID:
28045370
PMCID:
PMC5207774
DOI:
10.7554/eLife.19273
[Indexed for MEDLINE]
Free PMC Article

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