title: Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation.
abstract: Islet amyloid polypeptide (IAPP) is synthesized in pancreatic β-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid play a critical role in β-cell death in type 2 diabetic patients. Because Aβ-fibrils in Alzheimer disease activate the complement system, we have here investigated specific interactions between IAPP and complement factors. IAPP fibrils triggered limited activation of complement in vitro, involving both the classical and the alternative pathways. Direct binding assays confirmed that IAPP fibrils interact with globular head domains of complement initiator C1q. Furthermore, IAPP also bound complement inhibitors factor H and C4b-binding protein (C4BP). Recombinant C4BP mutants were used to show that complement control protein (CCP) domains 8 and 2 of the α-chain were responsible for the strong, hydrophobic binding of C4BP to IAPP. Immunostaining of pancreatic sections from type 2 diabetic patients revealed the presence of complement factors in the islets and varying degree of co-localization between IAPP fibrils and C1q, C3d, as well as C4BP and factor H but not membrane attack complex. Furthermore, C4BP enhanced formation of IAPP fibrils in vitro. We conclude that C4BP binds to IAPP thereby limiting complement activation and may be enhancing formation of IAPP fibrils from cytotoxic oligomers.
authors.affiliation: Department of Laboratory Medicine, Lund University, Wallenberg Laboratory, Skåne University Hospital, S-20502 Malmö, Sweden.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Sjölander
authors.forename: Gunilla T
authors.initials: GT
authors.lastname: Westermark
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D050716:Complement C4b-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D021381:Protein Transport; D051381:Rats
chemical_list: D000682:Amyloid; D050716:Complement C4b-Binding Protein; C521761:IAPP(20-29) peptide; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments