title: The amyloid formation mechanism in human IAPP: dimers have β-strand monomer-monomer interfaces.
abstract: Early oligomerization of human IAPP (hIAPP) is responsible for β-cell death in the pancreas and is increasingly considered a primary pathological process linked to Type II Diabetes (T2D). Yet, the assembly mechanism remains poorly understood, largely due to the inability of conventional techniques to probe distributions or detailed structures of early oligomeric species. Here, we describe the first experimental data on the isolated and unmodified dimers of human (hIAPP) and nonamyloidogenic rat IAPP (rIAPP). The experiments reveal that the human IAPP dimers are more extended than those formed by rat IAPP and likely descend from extended monomers. Independent all-atom molecular dynamics simulations show that rIAPP forms compact helix and coil rich dimers, whereas hIAPP forms β-strand rich dimers that are generally more extended. Also, the simulations reveal that the monomer-monomer interfaces of the hIAPP dimers are dominated by β-strands and that β-strands can recruit coil or helix structured regions during the dimerization process. Our β-rich interface contrasts with an N-terminal helix-to-helix interface proposed in the literature but is consistent with existing experimental data on the self-interaction pattern of hIAPP, mutation effects, and inhibition effects of the N-methylation in the mutation region.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dupuis
authors.forename: Chun
authors.initials: C
authors.lastname: Wu
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000818:Animals; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D051381:Rats; D013499:Surface Properties
chemical_list: D058228:Islet Amyloid Polypeptide