Advanced

Structural and functional studies of complement inhibitor C4b-binding protein.

Blom, Anna LU (2002) In Biochemical Society Transactions 30(Pt 6). p.978-982
Abstract
C4b-binding protein (C4BP) is a potent inhibitor of the classical pathway of the complement system. This large plasma glycoprotein consists of seven identical a- chains and a unique b-chain held together by disulphide bridges. Both types of subunits are composed almost exclusively of complement control protein domains (CCPs). Using homology-based computer modelling and mutagenesis of recombinant proteins we have localized binding sites for several ligands of C4BP: complement factor C4b, heparin and vitamin K-dependent anticoagulant protein S (PS). We found that C4b requires CCP1–3 of the a-chain for binding. The interaction is ionic in nature and mediated by a cluster of positively charged amino acids present on the interface between CCP1... (More)
C4b-binding protein (C4BP) is a potent inhibitor of the classical pathway of the complement system. This large plasma glycoprotein consists of seven identical a- chains and a unique b-chain held together by disulphide bridges. Both types of subunits are composed almost exclusively of complement control protein domains (CCPs). Using homology-based computer modelling and mutagenesis of recombinant proteins we have localized binding sites for several ligands of C4BP: complement factor C4b, heparin and vitamin K-dependent anticoagulant protein S (PS). We found that C4b requires CCP1–3 of the a-chain for binding. The interaction is ionic in nature and mediated by a cluster of positively charged amino acids present on the interface between CCP1 and CCP2 of the a-chain. Loss of C4b-binding resulted in a loss of all inhibitory functions of C4BP within the classical pathway of complement. Binding of heparin required CCPs 1–3 of the a-chain, with CCP2 being the most important, as well as the cluster of positively charged amino acids involved in binding of C4b. The interaction between C4BP and PS is of very high affinity and conveyed by a cluster of surface exposed hydrophobic amino acids localized on CCP1 of the b-chain. Furthermore, C4BP is captured on the surface of several pathogens, which may contribute to their serum resistance and pathogenicity. We have localized interaction of C4BP with Neisseria gonorrhoeae, Bordetella pertussis, Streptococcus pyogenes and Escherichia coli to various regions of the a-chain. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Structure-Activity Relationship, Support, Animal, Binding Sites, Protein Binding, Protein Conformation, Biological, Complement Inactivators: chemistry, Complement Inactivators: physiology, Heparin: metabolism, Human, Ligands, Models, Non-U.S. Gov't
in
Biochemical Society Transactions
volume
30
issue
Pt 6
pages
978 - 982
publisher
Biochemical Society
external identifiers
  • wos:000179816600031
  • pmid:12440957
  • scopus:0036865204
ISSN
0300-5127
language
English
LU publication?
yes
id
6606e41c-1722-421b-970a-845599503091 (old id 114703)
alternative location
http://www.biochemsoctrans.org/bst/030/bst0300978.htm
date added to LUP
2007-07-24 11:34:03
date last changed
2017-01-29 03:25:57
@article{6606e41c-1722-421b-970a-845599503091,
  abstract     = {C4b-binding protein (C4BP) is a potent inhibitor of the classical pathway of the complement system. This large plasma glycoprotein consists of seven identical a- chains and a unique b-chain held together by disulphide bridges. Both types of subunits are composed almost exclusively of complement control protein domains (CCPs). Using homology-based computer modelling and mutagenesis of recombinant proteins we have localized binding sites for several ligands of C4BP: complement factor C4b, heparin and vitamin K-dependent anticoagulant protein S (PS). We found that C4b requires CCP1–3 of the a-chain for binding. The interaction is ionic in nature and mediated by a cluster of positively charged amino acids present on the interface between CCP1 and CCP2 of the a-chain. Loss of C4b-binding resulted in a loss of all inhibitory functions of C4BP within the classical pathway of complement. Binding of heparin required CCPs 1–3 of the a-chain, with CCP2 being the most important, as well as the cluster of positively charged amino acids involved in binding of C4b. The interaction between C4BP and PS is of very high affinity and conveyed by a cluster of surface exposed hydrophobic amino acids localized on CCP1 of the b-chain. Furthermore, C4BP is captured on the surface of several pathogens, which may contribute to their serum resistance and pathogenicity. We have localized interaction of C4BP with Neisseria gonorrhoeae, Bordetella pertussis, Streptococcus pyogenes and Escherichia coli to various regions of the a-chain.},
  author       = {Blom, Anna},
  issn         = {0300-5127},
  keyword      = {Structure-Activity Relationship,Support,Animal,Binding Sites,Protein Binding,Protein Conformation,Biological,Complement Inactivators: chemistry,Complement Inactivators: physiology,Heparin: metabolism,Human,Ligands,Models,Non-U.S. Gov't},
  language     = {eng},
  number       = {Pt 6},
  pages        = {978--982},
  publisher    = {Biochemical Society},
  series       = {Biochemical Society Transactions},
  title        = {Structural and functional studies of complement inhibitor C4b-binding protein.},
  volume       = {30},
  year         = {2002},
}