title: Defining the molecular basis of amyloid inhibitors: human islet amyloid polypeptide-insulin interactions.
abstract: Human islet amyloid polypeptide (hIAPP or Amylin) is a 37 residue hormone that is cosecreted with insulin from the pancreatic islets. The aggregation of hIAPP plays a role in the progression of type 2 diabetes and contributes to the failure of islet cell grafts. Despite considerable effort, little is known about the mode of action of IAPP amyloid inhibitors, and this has limited rational drug design. Insulin is one of the most potent inhibitors of hIAPP fibril formation, but its inhibition mechanism is not understood. In this study, the aggregation of mixtures of hIAPP with insulin, as well as with the separate A and B chains of insulin, were characterized using ion mobility spectrometry-based mass spectrometry and atomic force microscopy. Insulin and the insulin B chain target the hIAPP monomer in its compact isoform and shift the equilibrium away from its extended isoform, an aggregation-prone conformation, and thus inhibit hIAPP from forming β-sheets and subsequently amyloid fibrils. All-atom molecular modeling supports these conclusions.
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Susa
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.forename: Summer L
authors.initials: SL
authors.lastname: Bernstein
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dupuis
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Raleigh
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D015195:Drug Design; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000494:pharmacology*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008958:Models, Molecular; D066329:Protein Aggregates / Q000187:drug effects*; D017433:Protein Structure, Secondary / Q000187:drug effects
chemical_list: D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D066329:Protein Aggregates