uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Islet Amyloid Polypeptide Triggers Limited Complement Activation and Binds Complement Inhibitor C4b-binding Protein, Which Enhances Fibril Formation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 14, 10824-10833 p.Article in journal (Refereed) Published
Abstract [en]

Islet amyloid polypeptide (IAPP) is synthesized in pancreatic beta-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid play a critical role in beta-cell death in type 2 diabetic patients. Because A beta-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 alpha-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.

Place, publisher, year, edition, pages
2012. Vol. 287, no 14, 10824-10833 p.
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-174578DOI: 10.1074/jbc.M111.244285ISI: 000302780100011OAI: oai:DiVA.org:uu-174578DiVA: diva2:529259
Available from: 2012-05-29 Created: 2012-05-22 Last updated: 2012-05-29Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Westermark, Gunilla T.
By organisation
Department of Medical Cell Biology
In the same journal
Journal of Biological Chemistry
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 240 hits
ReferencesLink to record
Permanent link

Direct link