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

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

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Article numbere19273
JournaleLife
Volume6
DOIs
StatePublished - Jan 3 2017

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity'. Together they form a unique fingerprint.

  • Cite this

    Krotee, P., Rodriguez, J. A., Sawaya, M. R., Cascio, D., Reyes, F. E., Shi, D., Hattne, J., Nannenga, B. L., Oskarsson, M. E., Philipp, S., Griner, S., Jiang, L., Glabe, C. G., Westermark, G. T., Gonen, T., & Eisenberg, D. S. (2017). Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity. eLife, 6, [e19273]. https://doi.org/10.7554/eLife.19273