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Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation.

Sjölander, Jonatan LU ; Westermark, Gunilla T; Renström, Erik LU and Blom, Anna LU (2012) In Journal of Biological Chemistry 287(14). p.10824-10833
Abstract
Islet amyloid polypeptide (IAPP) is synthesized in pancreatic β-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid plays a critical role in β-cell death in type 2 diabetic patients. Since Aβ-fibrils in Alzheimer's 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... (More)
Islet amyloid polypeptide (IAPP) is synthesized in pancreatic β-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid plays a critical role in β-cell death in type 2 diabetic patients. Since Aβ-fibrils in Alzheimer's 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 FH 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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
287
issue
14
pages
10824 - 10833
publisher
ASBMB
external identifiers
  • wos:000302780100011
  • pmid:22334700
  • scopus:84859514014
ISSN
1083-351X
DOI
10.1074/jbc.M111.244285
language
English
LU publication?
yes
id
7449bb3d-ba97-4f17-af6f-6d24ff278877 (old id 2366888)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22334700?dopt=Abstract
date added to LUP
2012-03-02 11:55:18
date last changed
2017-07-23 03:28:14
@article{7449bb3d-ba97-4f17-af6f-6d24ff278877,
  abstract     = {Islet amyloid polypeptide (IAPP) is synthesized in pancreatic β-cells and co-secreted with insulin. Aggregation and formation of IAPP-amyloid plays a critical role in β-cell death in type 2 diabetic patients. Since Aβ-fibrils in Alzheimer's 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 FH 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.},
  author       = {Sjölander, Jonatan and Westermark, Gunilla T and Renström, Erik and Blom, Anna},
  issn         = {1083-351X},
  language     = {eng},
  number       = {14},
  pages        = {10824--10833},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Islet amyloid polypeptide triggers limited complement activation and binds complement inhibitor C4b-binding protein, which enhances fibril formation.},
  url          = {http://dx.doi.org/10.1074/jbc.M111.244285},
  volume       = {287},
  year         = {2012},
}