title: Promotion or Inhibition of Islet Amyloid Polypeptide Aggregation by Zinc Coordination Depends on Its Relative Concentration.
abstract: Zinc is reported to play a complex role in islet amyloid polypeptide (IAPP) aggregation, which is associated with β-cell death in type II diabetes (T2D). Depending on their relative concentrations in vitro, zinc could either promote or inhibit IAPP aggregation. Interestingly, genomewide association studies suggested both positive and negative correlations between T2D risks and activities of a β-cell-specific zinc transporter upon mutations, which determines zinc concentration in vivo. To decipher the effect of zinc coordination on IAPP aggregation, we performed atomistic discrete molecular dynamics simulations to systemically study aggregation propensities of zinc-coordinated IAPP oligomers with different molecular weights (MWs), whose populations are determined by zinc concentration. We find that at low zinc:IAPP stoichiometry, zinc coordination promotes aggregation by forming high-MW oligomers. The aggregation is inhibited when the stoichiometry increases and zinc binds individual peptides. Our computationally derived predictions are validated by the complementary thioflavin-T fluorescence assay measuring the dependence of IAPP aggregation on a wide range of zinc concentrations. Our combined computational and experimental study offers detailed mechanistic insight into the complex role of zinc on IAPP aggregation and T2D development.
authors.affiliation: Department of Physics and Astronomy, Clemson University , Clemson, South Carolina 29634, United States.
authors.forename: Praveen
authors.initials: P
authors.lastname: Nedumpully-Govindan
authors.affiliation: Department of Genetics and Biochemistry, Clemson University , Clemson, South Carolina 29634, United States.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Physics and Astronomy, Clemson University , Clemson, South Carolina 29634, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Andorfer
authors.affiliation: Department of Genetics and Biochemistry, Clemson University , Clemson, South Carolina 29634, United States.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Physics and Astronomy, Clemson University , Clemson, South Carolina 29634, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
mesh_terms: D000595:Amino Acid Sequence; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D008970:Molecular Weight; D015032:Zinc / Q000737:chemistry*
chemical_list: D058228:Islet Amyloid Polypeptide; D015032:Zinc