Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils
- 15 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Structural & Molecular Biology
- Vol. 27 (7), 653-659
- https://doi.org/10.1038/s41594-020-0435-3
Abstract
Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM structure of recombinant full-length hIAPP fibrils. The fibril is composed of two symmetrically related protofilaments with ordered residues 14–37. Our hIAPP fibril structure (i) supports the previous hypothesis that residues 20–29 constitute the core of the hIAPP amyloid; (ii) suggests a molecular mechanism for the action of the hIAPP hereditary mutation S20G; (iii) explains why the six residue substitutions in rodent IAPP prevent aggregation; and (iv) suggests regions responsible for the observed hIAPP cross-seeding with β-amyloid. Furthermore, we performed structure-based inhibitor design to generate potential hIAPP aggregation inhibitors. Four of the designed peptides delay hIAPP aggregation in vitro, providing a starting point for the development of T2D therapeutics and proof of concept that the capping strategy can be used on full-length cryo-EM fibril structures.Keywords
Funding Information
- U.S. Department of Energy (DE-FC02-02ER63421, DE-FC02-02ER63421, DE-FC02-02ER63421)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (NIH AG 061847 NIH AG 054022, NIH AG 061847 NIH AG 054022, NIH AG 061847 NIH AG 054022)
- National Science Foundation Graduate Research Fellowship Program
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