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J. Biol. Chem., Vol. 282, Issue 25, 18552-18562, June 22, 2007

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Structure-based Mapping of DAF Active Site Residues That Accelerate the Decay of C3 Convertases^*

Lisa Kuttner-Kondo, Dennis E. Hourcade, Vernon E. Anderson^¶, Nasima Muqim, Lynne Mitchell, Dinesh C. Soares^||, Paul N. Barlow^||, and M. Edward Medof¹

From the Institute of Pathology and ^¶Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, and the ^||Institute of Structural and Molecular Biology and School of Chemistry, University of Edinburgh, Edinburgh EH9 3JJ, Scotland, United Kingdom

Focused complement activation on foreign targets depends on regulatory proteins that decay the bimolecular C3 convertases. Although this process is central to complement control, how the convertases engage and disassemble is not established. The second and third complement control protein (CCP) modules of the cell surface regulator, decay-accelerating factor (DAF, CD55), comprise the simplest structure mediating this activity. Positioning the functional effects of 31 substitution mutants of DAF CCP2 to -4 on partial structures was previously reported. In light of the high resolution crystal structure of the DAF four-CCP functional region, we now reexamine the effects of these and 40 additional mutations. Moreover, we map six monoclonal antibody epitopes and overlap their effects with those of the amino acid substitutions. The data indicate that the interaction of DAF with the convertases is mediated predominantly by two patches 13Å apart, one centered around Arg⁶⁹ and Arg⁹⁶ on CCP2 and the other around Phe¹⁴⁸ and Leu¹⁷¹ on CCP3. These patches on the same face of the adjacent modules bracket an intermodular linker of critical length (16Å_). Although the key DAF residues in these patches are present or there are conservative substitutions in all other C3 convertase regulators that mediate decay acceleration and/or provide factor I-cofactor activity, the linker region is highly conserved only in the former. Intra-CCP regions also differ. Linker region comparisons suggest that the active CCPs of the decay accelerators are extended, whereas those of the cofactors are tilted. Intra-CCP comparisons suggest that the two classes of regulators bind different regions on their respective ligands.

Received for publication, December 20, 2006 , and in revised form, March 13, 2007.

^* This work was supported by National Institutes of Health Grants R01 AI23598 (to M. E. M.) and R01 AI05143 (to D. E. H.). 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.

¹ To whom correspondence should be addressed: Institute of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd., Rm. 301, Cleveland, OH 44106. Tel.: 216-368-5434; Fax: 216-368-0495; E-mail: mxm16{at}po.cwru.edu.

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