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J. Biol. Chem., Vol. 280, Issue 4, 2569-2578, January 28, 2005

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Molecular Dissection of Interactions between Components of the Alternative Pathway of Complement and Decay Accelerating Factor (CD55)^*

Claire L. Harris, Rachel J. M. Abbott¶||, Richard A. Smith**, B. Paul Morgan, and Susan M. Lea¶

From the Complement Biology Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, ^¶Department of Biochemistry, Laboratory of Molecular Biophysics, Oxford University, South Parks Road, Oxford OX1 3QU, and ^**Adprotech Ltd., Chesterford Research Park, Little Chesterford, Essex, CB10 1XL, United Kingdom

The complement regulatory protein decay accelerating factor (DAF; CD55), inhibits the alternative complement pathway by accelerating decay of the convertase enzymes formed by C3b and factor B. We show, using surface plasmon resonance, that in the absence of Mg²⁺, DAF binds C3b, factor B, and the Bb subunit with low affinity (K_D, 14 ± 0.1, 44 ± 10, and 20 ± 7 µM, respectively). In the presence of Mg²⁺, DAF bound Bb or the von Willebrand factor type A subunit of Bb with higher affinities (K_D, 1.3 ± 0.5 and 2.2 ± 0.1 µM, respectively). Interaction with the proenzyme C3bB was investigated by flowing factor B across a C3b-coated surface in the absence of factor D. The dissociation rate was dependent on the time of incubation, suggesting that a time-dependent conformational transition stabilized the C3b-factor B interaction. Activation by factor D (forming C3bBb) increased the complex half-life; however, the enzyme became susceptible to rapid decay by DAF, unlike the proenzyme, which was unaffected. A convertase assembled with cobra venom factor and Bb was decayed by DAF, albeit far less efficiently than C3bBb. DAF did not bind cobra venom factor, implying that Bb decay is accelerated, at least in part, through DAF binding of this subunit. It is likely that DAF binds the complex with higher affinity/avidity, promoting a conformational change in either or both subunits accelerating decay. Such analysis of component and regulator interactions will inform our understanding of inhibitory mechanisms and the ways in which regulatory proteins cooperate to control the complement cascade.

Received for publication, September 3, 2004 , and in revised form, November 5, 2004.

^* This work was supported by the Wellcome Trust (Grant 068823/Z). 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.

^|| Supported by a Medical Research Council studentship.

To whom correspondence should be addressed: Henry Wellcome Building, Heath Park, Cardiff, CF14 4XN, UK. Tel.: 44-29-20745254; Fax: 44-29-20744001; E-mail: harriscl{at}cardiff.ac.uk.

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