title: Human Islet Amyloid Polypeptide N-Terminus Fragment Self-Assembly: Effect of Conserved Disulfide Bond on Aggregation Propensity.
abstract: Amyloid formation by human islet amyloid polypeptide (hIAPP) has long been implicated in the pathogeny of type 2 diabetes mellitus (T2DM) and failure of islet transplants, but the mechanism of IAPP self-assembly is still unclear. Numerous fragments of hIAPP are capable of self-association into oligomeric aggregates, both amyloid and non-amyloid in structure. The N-terminal region of IAPP contains a conserved disulfide bond between cysteines at position 2 and 7, which is important to hIAPP's in vivo function and may play a role in in vitro aggregation. The importance of the disulfide bond in this region was probed using a combination of ion mobility-based mass spectrometry experiments, molecular dynamics simulations, and high-resolution atomic force microscopy imaging on the wildtype 1-8 hIAPP fragment, a reduced fragment with no disulfide bond, and a fragment with both cysteines at positions 2 and 7 mutated to serine. The results indicate the wildtype fragment aggregates by a different pathway than either comparison peptide and that the intact disulfide bond may be protective against aggregation due to a reduction of inter-peptide hydrogen bonding. Graphical Abstract ᅟ.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Alexandre I
authors.initials: AI
authors.lastname: Ilitchev
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Maxwell J
authors.initials: MJ
authors.lastname: Giammona
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Thanh D
authors.initials: TD
authors.lastname: Do
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400, USA.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Wong
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Buratto
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400, USA.|Research Department of Structural and Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Raleigh
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106, USA. bowers@chem.ucsb.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid; D003924:Diabetes Mellitus, Type 2; D004220:Disulfides / Q000737:chemistry*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D056004:Molecular Dynamics Simulation
chemical_list: D000682:Amyloid; D004220:Disulfides; D058228:Islet Amyloid Polypeptide
keywords: Amyloid; Atomic force microscopy; Diabetes; Electrospray ionization; IAPP; Ion mobility; Islet amyloid polypeptide; Peptide; Replica exchange molecular dynamics; T2DM; Type 2 diabetes mellitus; hIAPP; human Islet Amyloid Polypeptide