title: New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3.
abstract: aHUS (atypical haemolytic uraemic syndrome), AMD (age-related macular degeneration) and other diseases are associated with defective AP (alternative pathway) regulation. CFH (complement factor H), CFI (complement factor I), MCP (membrane cofactor protein) and C3 exhibited the most disease-associated genetic alterations in the AP. Our interactive structural database for these was updated with a total of 324 genetic alterations. A consensus structure for the SCR (short complement regulator) domain showed that the majority (37%) of SCR mutations occurred at its hypervariable loop and its four conserved Cys residues. Mapping 113 missense mutations onto the CFH structure showed that over half occurred in the C-terminal domains SCR-15 to -20. In particular, SCR-20 with the highest total of affected residues is associated with binding to C3d and heparin-like oligosaccharides. No clustering of 49 missense mutations in CFI was seen. In MCP, SCR-3 was the most affected by 23 missense mutations. In C3, the neighbouring thioester and MG (macroglobulin) domains exhibited most of 47 missense mutations. The mutations in the regulators CFH, CFI and MCP involve loss-of-function, whereas those for C3 involve gain-of-function. This combined update emphasizes the importance of the complement AP in inflammatory disease, clarifies the functionally important regions in these proteins, and will facilitate diagnosis and therapy.
authors.affiliation: *Department of Structural and Molecular Biology, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: *Department of Structural and Molecular Biology, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Pavithra M
authors.initials: PM
authors.lastname: Rallapalli
authors.affiliation: *Department of Structural and Molecular Biology, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Osborne
authors.affiliation: *Department of Structural and Molecular Biology, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Perkins
mesh_terms: D003176:Complement C3 / Q000737:chemistry / Q000235:genetics; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics; D017244:Complement Factor I / Q000737:chemistry / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics; D030561:Databases, Nucleic Acid; D030562:Databases, Protein; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D051916:Membrane Cofactor Protein / Q000737:chemistry / Q000235:genetics; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary
chemical_list: C497857:CD46 protein, human; D003176:Complement C3; D051916:Membrane Cofactor Protein; D017242:Complement Factor H; C493611:CFI protein, human; D017244:Complement Factor I