Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States; UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States
Jose A Rodriguez
Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States
Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States
Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States
Francis E Reyes
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
Dan Shi
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
Brent L Nannenga
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
Marie E Oskarsson
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Stephan Philipp
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States
Sarah Griner
Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States
Lin Jiang
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Brain Research Institute (BRI), University of California, Los Angeles, Los Angeles, United States
Charles G Glabe
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States; Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
Gunilla T Westermark
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Tamir Gonen
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
David S Eisenberg
Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States; Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States; UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States
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.
