title: Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.
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.
authors.affiliation: 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.
authors.forename: Pascal
authors.identifier: 0000-0002-9582-658X
authors.initials: P
authors.lastname: Krotee
authors.affiliation: 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.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Rodriguez
authors.affiliation: 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.
authors.forename: Michael R
authors.identifier: 0000-0003-0874-9043
authors.initials: MR
authors.lastname: Sawaya
authors.affiliation: 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.
authors.forename: Duilio
authors.identifier: 0000-0002-3877-6803
authors.initials: D
authors.lastname: Cascio
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Francis E
authors.initials: FE
authors.lastname: Reyes
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Johan
authors.identifier: 0000-0002-8936-0912
authors.initials: J
authors.lastname: Hattne
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Nannenga
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Oskarsson
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States.
authors.forename: Stephan
authors.initials: S
authors.lastname: Philipp
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Griner
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Gunilla T
authors.initials: GT
authors.lastname: Westermark
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
authors.forename: Tamir
authors.initials: T
authors.lastname: Gonen
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Eisenberg
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020285:Cryoelectron Microscopy; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000633:toxicity*; D000072757:Protein Conformation, beta-Strand
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide
keywords: MicroED; Type-II Diabetes; amyloid fibril; biochemistry; biophysics; cytotoxicity; human; islet amyloid polypeptide; structural biology