6VW2

Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils

Summary for 6VW2

• Entry DOI: 10.2210/pdb6vw2/pdb
• EMDB information: 21410
• Descriptor: Islet amyloid polypeptide (SUMO-tagged) (1 entity in total)
• Functional Keywords: hiapp, type ii diabetes, amyloid, protein fibril
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Total number of polymer chains: 10
• Total formula weight: 172742.73

Authors

Cao, Q.,Boyer, D.R.,Sawaya, M.R.,Eisenberg, D.S. (deposition date: 2020-02-18, release date: 2020-06-10, Last modification date: 2024-03-06)

Primary citation

Cao, Q.,Boyer, D.R.,Sawaya, M.R.,Ge, P.,Eisenberg, D.S.
Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils.
Nat.Struct.Mol.Biol., 27:653-659, 2020

PubMed 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.

PubMed: 32541896
DOI: 10.1038/s41594-020-0435-3

Experimental method

ELECTRON MICROSCOPY (3.4 Å)