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Atomic structures of fibrillar segments of hIAPP suggest tightly mated beta-sheets are important or cytotoxicity

Krotee, Pascal (author)
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.
Rodriguez, Jose A. (author)
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.
Sawaya, Michael R. (author)
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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Cascio, Duilio (author)
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.
Reyes, Francis E. (author)
Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA.
Shi, Dan (author)
Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA.
Hattne, Johan (author)
Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA.
Nannenga, Brent L. (author)
Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA.
Oskarsson, Marie E. (author)
Uppsala universitet,Institutionen för medicinsk cellbiologi
Philipp, Stephan (author)
Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA.
Griner, Sarah (author)
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.
Jiang, Lin (author)
Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA.;Univ Calif Los Angeles, BRI, Los Angeles, CA USA.
Glabe, Charles G. (author)
Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA.;King Abdulaziz Univ, Dept Biochem, Fac Sci, Jeddah, Saudi Arabia.;King Abdulaziz Univ, King Fahd Med Res Ctr, Expt Biochem Unit, Jeddah, Saudi Arabia.
Westermark, Gunilla T. (author)
Uppsala universitet,Institutionen för medicinsk cellbiologi
Gonen, Tamir (author)
Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA.
Eisenberg, David S. (author)
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.
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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. (creator_code:org_t)
2017
2017
English.
In: eLIFE. - 2050-084X. ; 6
Related links:
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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