Mutations in alpha-chain of C4BP that selectively affect its factor I cofactor function
Författare
Summary, in English
C4b-binding protein (C4BP) inhibits all pathways of complement activation, acting as a cofactor to the serine protease factor I (FI) in the degradation of activated complement factors C4b and C3b. C4BP is a disulfide-linked polymer of seven alpha-chains and a unique beta-chain, the alpha- and beta-chains being composed of eight and three complement control protein (CCP) domains, respectively. In previous studies we have localized cofactor activity and binding of C4b to alpha-chain CCP1-3 of C4BP, whereas the binding of C3b required additionally CCP4. Likewise, introduced point mutations that decreased binding of C4b/C3b caused a decrease in cofactor activity. In the present study, we describe two mutants of C4BP, K126Q/K128Q and F144S/F149S, clustered on alpha-chain CCP3, which selectively lost their ability to act as cofactors in the cleavage of both C4b and C3b. Both mutants show the same binding affinity for C4b/C3b as measured by surface plasmon resonance and have the same inhibitory effect on formation and decay of the classical pathway C3-convertase as the wild type C4BP. It appears that C4b and C3b do not undergo the same conformational changes upon binding to the C4BP mutants as during the interaction with the wild type C4BP, which then results in the observed loss of the cofactor activity.
Avdelning/ar
Publiceringsår
2003
Språk
Engelska
Sidor
43437-43442
Publikation/Tidskrift/Serie
Journal of Biological Chemistry
Volym
278
Issue
44
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
American Society for Biochemistry and Molecular Biology
Ämne
- Medicinal Chemistry
- Other Basic Medicine
Aktiv
Published
Forskningsgrupp
- Protein Chemistry, Malmö
ISBN/ISSN/Övrigt
- ISSN: 1083-351X