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J. Biol. Chem., Vol. 278, Issue 44, 43437-43442, October 31, 2003

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Mutations in -Chain of C4BP That Selectively Affect Its Factor I Cofactor Function^*

Anna M. Blom, Bruno O. Villoutreix¶||, and Björn Dahlbäck

From the Lund University Department of Clinical Chemistry, University Hospital Malmö, The Wallenberg Laboratory, S-205 02 Malmö, Sweden and ^¶INSERM U428, Université Paris V, Paris 75006, France

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 -chains and a unique -chain, the - and -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 -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 -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.

Received for publication, June 23, 2003

^* This work was supported by the Swedish Research Council, the Österlunds Trust, Greta and Johan Kock's Trust, the Crafoord Trust, Clas Groschinsky's Trust, King Gustav V 80^th Anniversary Foundation, Thelma Zoega's Trust, Professor Nanna Svartz's Trust, Magnus Bergvall's Trust, the Hain Trust, and research grants from the University Hospital in Malmö and the Royal Physiographic Society in Lund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Grateful recipient of a grant on structural bioinformatics from the INSERM Institute.

To whom correspondence should be addressed: Lund University, Dept. of Clinical Chemistry, University Hospital Malmö, Entrance 46, The Wallenberg Laboratory, Floor 6, S-205 02 Malmö, Sweden. Tel.: 46-40-33-72-28; Fax: 46-40-33-70-44; E-mail: Anna.Blom{at}klkemi.mas.lu.se.

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