title: Cross-sequence interactions between human and rat islet amyloid polypeptides.
abstract: Human islet amyloid polypeptide (hIAPP) can assemble into toxic oligomers and fibrils, which are associated with cell degeneration and the pathogenesis of type 2 diabetes. Cross-interaction of hIAPP with rat IAPP (rIAPP)--a non-amyloidogenic peptide with high sequence similarity to hIAPP--might influence the aggregation and toxicity of hIAPP. However, the exact role of rIAPP in hIAPP aggregation and toxicity still remains unclear. In this work, we investigated the effect of cross-sequence interactions between full-length hIAPP(1-37) and rIAPP(1-37) on hybrid amyloid structures, aggregation kinetics, and cell toxicity using combined computational and experimental approaches. Experimental results indicate a contrasting role of rIAPP in hIAPP aggregation, in which rIAPP initially inhibits the early aggregation and nuclei formation of hIAPP, but hIAPP seeds can also recruit both hIAPP and rIAPP to form more hybrid fibrils, thus promoting amyloid fibrillation ultimately. The coincubation of hIAPP and rIAPP also decreases cell viability, presumably due to the formation of more toxic hybrid oligomers at the prolonged lag phase. Comparative MD simulations confirm that the cross-sequence interactions between hIAPP and rIAPP stabilize β-sheet structure and thus likely promote their fibrillization. This work provides valuable insights into a critical role of cross-amyloid interactions in protein aggregation.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Rundong
authors.initials: R
authors.lastname: Hu
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.forename: Kunal
authors.initials: K
authors.lastname: Patel
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Wang
authors.forename: Yung
authors.initials: Y
authors.lastname: Chang
authors.forename: Xiong
authors.initials: X
authors.lastname: Gong
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D058228:Islet Amyloid Polypeptide