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

In English

Författare

Summary, in English

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.

Publiceringsår

2002

Språk

Engelska

Sidor

978-982

Publikation/Tidskrift/Serie

Biochemical Society Transactions

Volym

30

Issue

Pt 6

Dokumenttyp

Artikel i tidskrift

Förlag

Biochemical Society

Ämne

  • Biochemistry and Molecular Biology

Nyckelord

  • 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

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 0300-5127