title: Creating functional sophistication from simple protein building blocks, exemplified by factor H and the regulators of complement activation.
abstract: Complement control protein modules (CCPs) occur in numerous functionally diverse extracellular proteins. Also known as short consensus repeats (SCRs) or sushi domains each CCP contains approximately 60 amino acid residues, including four consensus cysteines participating in two disulfide bonds. Varying in length and sequence, CCPs adopt a β-sandwich type fold and have an overall prolate spheroidal shape with N- and C-termini lying close to opposite poles of the long axis. CCP-containing proteins are important as cytokine receptors and in neurotransmission, cell adhesion, blood clotting, extracellular matrix formation, haemoglobin metabolism and development, but CCPs are particularly well represented in the vertebrate complement system. For example, factor H (FH), a key soluble regulator of the alternative pathway of complement activation, is made up entirely from a chain of 20 CCPs joined by short linkers. Collectively, therefore, the 20 CCPs of FH must mediate all its functional capabilities. This is achieved via collaboration and division of labour among these modules. Structural studies have illuminated the dynamic architectures that allow FH and other CCP-rich proteins to perform their biological functions. These are largely the products of a highly varied set of intramolecular interactions between CCPs. The CCP can act as building block, spacer, highly versatile recognition site or dimerization mediator. Tandem CCPs may form composite binding sites or contribute to flexible, rigid or conformationally 'switchable' segments of the parent proteins.
authors.affiliation: School of Chemistry, The University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, U.K.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Makou
authors.affiliation: School of Chemistry, The University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, U.K.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Herbert
authors.affiliation: Schools of Chemistry and Biological Sciences, The University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh EH9 3FJ, U.K. Paul.Barlow@ed.ac.uk.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Barlow
mesh_terms: D000818:Animals; D001665:Binding Sites; D003166:Complement Activating Enzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003167:Complement Activation; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051056:Complement Inactivating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003169:Complement Inactivator Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D015202:Protein Engineering; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C493495:CFH protein, human; D051056:Complement Inactivating Agents; D003169:Complement Inactivator Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D017242:Complement Factor H; D003166:Complement Activating Enzymes
keywords: CCPs; SCRs; protein architecture; protein modules; sushi domains