Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils.

Abstract

Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone, but deposits as amyloid fibrils in more than 90% of Type-II Diabetes (T2D) patients. 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 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.