Molecular Basis of the Interaction Between Zinc and the Amyloidogenic Islet Amyloid Polypeptide

Abstract

Human islet amyloid polypeptide, hIAPP, is an amyloidogenic peptide hormone secreted primarily by pancreatic beta-cells in the islet of Langerhans. Human IAPP is cosecreted with insulin, and under normal the two proteins work to maintain glycemice control. The formation of hIAPP amyloid plaques near islet cells has been linked to the death of insulin-secreting beta-cells in humans and the progression of type II diabetes. One of the interesting questions surrounding this peptide is how the toxic and aggregation prone hIAPP peptide can be maintained in a safe state at the high concentrations that are found in the secretory granule where it is stored. Our studies have shown zinc, which is found at millimolar concentrations in the secretory granule, significantly inhibits hIAPP amyloid fibrillogenesis at concentrations similar to those found in the extracellular environment. We show here by ITC and PICUP cross-linking that zinc binds to a complex of several hIAPP peptides at micromolar concentrations similar to those found in the extracellular environment, and in the process, promotes the formation of small IAPP oligomers. Interestingly, this observed interaction is unique to the hIAPP as membrane disrupting peptides with similar sequences exhibit minimal interaction with zinc. By contrast, the fibrillar amyloid form of hIAPP has only low affinity for zinc. High-resolution NMR structures of hIAPP bound to zinc reveal changes in along residues that would be located along one face of the hIAPP alpha-helix proposed as an intermediate for amyloid formation. These changes occur on the hydrophilic side of the amphipathic alpha-helix, away from the proposed interface for amyloid nucleation on the hydrophobic side. Combined, these results suggest zinc promotes the formation of off-pathway oligomers while creating a thermodynamic barrier for the formation of amyloid fibers.