title: Cross-Seeding Interaction between β-Amyloid and Human Islet Amyloid Polypeptide.
abstract: Alzheimer's disease (AD) and type 2 diabetes (T2D) are two common protein misfolding diseases. Increasing evidence suggests that these two diseases may be correlated with each other via cross-sequence interactions between β-amyloid peptide (Aβ) associated with AD and human islet amyloid polypeptide (hIAPP) associated with T2D. However, little is known about how these two peptides work and how they interact with each other to induce amyloidogenesis. In this work, we study the effect of cross-sequence interactions between Aβ and hIAPP peptides on hybrid amyloid structures, conformational changes, and aggregation kinetics using combined experimental and simulation approaches. Experimental results confirm that Aβ and hIAPP can interact with each other to aggregate into hybrid amyloid fibrils containing β-sheet-rich structures morphologically similar to pure Aβ and hIAPP. The cross-seeding of Aβ and hIAPP leads to the coexistence of both a retarded process at the initial nucleation stage and an accelerated process at the fibrillization stage, in conjunction with a conformational transition from random structures to α-helix to β-sheet. Further molecular dynamics simulations reveal that Aβ and hIAPP oligomers can efficiently cross-seed each other via the association of two highly similar U-shaped β-sheet structures; thus, conformational compatibility between Aβ and hIAPP aggregates appears to play a key role in determining barriers to cross-seeding. The cross-seeding effects in this work may provide new insights into the molecular mechanisms of interactions between AD and T2D.
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.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.|College of Chemical and Biological Engineering, Zhejiang University , Hangzhou, Zhejiang 310027, China.
authors.forename: Binbo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide
keywords: Aβ; amyloid aggregation; cross-seeding; hIAPP; protein misfolding