Human Islet Amyloid Polypeptide N-Terminus Fragment Self-Assembly: Effect of Conserved Disulfide Bond on Aggregation Propensity |
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| Authors: | Alexandre I. Ilitchev Maxwell J. Giammona Thanh D. Do Amy G. Wong Steven K. Buratto Joan-Emma Shea Daniel P. Raleigh Michael T. Bowers |
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| Affiliation: | 1.Department of Chemistry and Biochemistry,University of California,Santa Barbara,USA;2.Department of Chemistry,Stony Brook University,Stony Brook,USA;3.Research Department of Structural and Molecular Biology,University College London,London,UK |
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| 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. |
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