Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 27, Issue 7, Pages 653-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41594-020-0435-3
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Funding
- NIH [1S10RR23057, IS10OD018111, AG 054022, AG061847]
- NSF [DBI-1338135]
- CNSI at UCLA
- DOE [DE-FC02-02ER63421]
- National Science Foundation Graduate Research Fellowship Program
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A cryo-EM structure of in vitro-formed fibrils of the human islet amyloid polypeptide (hIAPP) suggests both why the mutation S20G promotes aggregation and a potential basis for cross-seeding with beta-amyloid, and leads to the design of peptide inhibitors. 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 beta-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.
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