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J. Biol. Chem., Vol. 280, Issue 11, 10636-10645, March 18, 2005

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Functional Insights from the Structure of the Multifunctional C345C Domain of C5 of Complement^*

Janice Bramham, Chuong-Thu Thai, Dinesh C. Soares, Dusan Uhrín, Ronald T. Ogata, and Paul N. Barlow¶

From the Schools of Chemistry and Biological Sciences, University of Edinburgh, Edinburgh EH9 3JJ, Scotland, United Kingdom and Torrey Pines Institute for Molecular Studies, San Diego, California 92121-1122

The complement protein C5 initiates assembly of the membrane attack complex. This remarkable process results in lysis of target cells and is fundamental to mammalian defense against infection. The 150-amino acid residue domain at the C terminus of C5 (C5-C345C) is pivotal to C5 function. It interacts with enzymes that convert C5 to C5b, the first step in the assembly of the membrane attack complex; it also binds to the membrane attack complex components C6 and C7 with high affinity. Here a recombinant version of this C5-C345C domain is shown to adopt the oligosaccharide/oligonucleotide binding fold, with two helices packed against a five-stranded -barrel. The structure is compared with those from the netrin-like module family that have a similar fold. Residues critical to the interaction with C5-convertase cluster on a mobile, hydrophobic inter-strand loop that protrudes from the open face of the -barrel. The opposite, helix-dominated face of C5-C345C carries a pair of exposed hydrophobic side chains adjacent to a striking negatively charged patch, consistent with affinity for positively charged factor I modules in C6 and C7. Modeling of homologous domains from complement proteins C3 and C4, which do not participate in membrane attack complex assembly, suggests that this provisionally identified C6/C7-interacting face is indeed specific to C5.

Received for publication, November 22, 2004 , and in revised form, December 9, 2004.

The atomic coordinates (code 1XWE) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Medical Research Council of the UK, the Wellcome Trust, and National Institutes of Health Grant GM29831. 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.

^¶ To whom correspondence should be addressed: Schools of Chemistry and Biological Sciences, Joseph Black Chemistry Bldg., University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, UK. Tel.: 44-131-650-4727; Fax: 44-131-650-7055; E-mail: Paul.Barlow{at}ed.ac.uk.

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This article has been cited by other articles:

				M. M. Phelan, C.-T. Thai, D. C. Soares, R. T. Ogata, P. N. Barlow, and J. Bramham Solution Structure of Factor I-like Modules from Complement C7 Reveals a Pair of Follistatin Domains in Compact Pseudosymmetric Arrangement J. Biol. Chem., July 17, 2009; 284(29): 19637 - 19649. [Abstract] [Full Text] [PDF]