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Publication Abstract from PubMed

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.

Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils.,Cao Q, Boyer DR, Sawaya MR, Ge P, Eisenberg DS Nat Struct Mol Biol. 2020 Jun 15. pii: 10.1038/s41594-020-0435-3. doi:, 10.1038/s41594-020-0435-3. PMID:32541896^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.