title: Functional insights from the structure of the multifunctional C345C domain of C5 of complement.
abstract: 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 beta-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 beta-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.
authors.affiliation: Schools of Chemistry and Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, UK.
authors.forename: Janice
authors.initials: J
authors.lastname: Bramham
authors.forename: Chuong-Thu
authors.initials: CT
authors.lastname: Thai
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Soares
authors.forename: Dusan
authors.initials: D
authors.lastname: Uhrín
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Ogata
authors.forename: Paul N
authors.initials: PN
authors.lastname: Barlow
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D003182:Complement C5 / Q000737:chemistry*; D003183:Complement C6 / Q000737:chemistry; D003184:Complement C7 / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D009844:Oligosaccharides / Q000737:chemistry; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013237:Stereoisomerism; D020349:Surface Plasmon Resonance; D013997:Time Factors
chemical_list: D003182:Complement C5; D003183:Complement C6; D003184:Complement C7; D009841:Oligonucleotides; D009844:Oligosaccharides; D011994:Recombinant Proteins