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

• Published in: The Journal of biological chemistry 2005-03, Vol.280 (11), p.10636-10645
• Main Authors: Bramham, Janice, Thai, Chuong-Thu, Soares, Dinesh C., Uhrín, Dusan, Ogata, Ronald T., Barlow, Paul N.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Cell Membrane - metabolism; Complement C5 - chemistry; Complement C6 - chemistry; Complement C7 - chemistry; Escherichia coli - metabolism; Genetic Vectors; Humans; Kinetics; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Oligonucleotides - chemistry; Oligosaccharides - chemistry; Point Mutation; Protein Binding; Protein Conformation; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Recombinant Proteins - chemistry; Sequence Homology, Amino Acid; Static Electricity; Stereoisomerism; Surface Plasmon Resonance; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M413126200

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 β-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 β-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.