C4b-binding protein (C4BP) is a potent inhibitor of the classical pathway of the complement system. This large plasma glycoprotein consists of seven identical α-chains and a unique β-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 α-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 α-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 α-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 β-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 α-chain.
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November 2002
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Conference Article|
November 01 2002
Structural and functional studies of complement inhibitor C4b-binding protein
A. M. Blom
A. M. Blom
1
1Department of Clinical Chemistry, Lund University, The Wallenberg Laboratory, University Hospital Malmö, S-205 02 Malmö, Sweden
1E-mail anna.blom@klkemi.mas.lu.se
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Publisher: Portland Press Ltd
Received:
May 07 2002
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (6): 978–982.
Article history
Received:
May 07 2002
Citation
A. M. Blom; Structural and functional studies of complement inhibitor C4b-binding protein. Biochem Soc Trans 1 November 2002; 30 (6): 978–982. doi: https://doi.org/10.1042/bst0300978
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