title: Human factor H-related protein 2 (CFHR2) regulates complement activation.
abstract: Mutations and deletions within the human CFHR gene cluster on chromosome 1 are associated with diseases, such as dense deposit disease, CFHR nephropathy or age-related macular degeneration. Resulting mutant CFHR proteins can affect complement regulation. Here we identify human CFHR2 as a novel alternative pathway complement regulator that inhibits the C3 alternative pathway convertase and terminal pathway assembly. CFHR2 is composed of four short consensus repeat domains (SCRs). Two CFHR2 molecules form a dimer through their N-terminal SCRs, and each of the two C-terminal ends can bind C3b. C3b bound CFHR2 still allows C3 convertase formation but the CFHR2 bound convertases do not cleave the substrate C3. Interestingly CFHR2 hardly competes off factor H from C3b. Thus CFHR2 likely acts in concert with factor H, as CFHR2 inhibits convertases while simultaneously allowing factor H assisted degradation by factor I.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
authors.forename: Hannes U
authors.initials: HU
authors.lastname: Eberhardt
authors.forename: Denise
authors.initials: D
authors.lastname: Buhlmann
authors.forename: Peter
authors.initials: P
authors.lastname: Hortschansky
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Sascha
authors.initials: S
authors.lastname: Böhm
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Kemper
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartmann
authors.forename: Teresia
authors.initials: T
authors.lastname: Hallström
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
mesh_terms: D003176:Complement C3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050577:Complement C3-C5 Convertases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017244:Complement Factor I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000502:physiology*; D006801:Humans; D055503:Protein Multimerization / Q000502:physiology; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D020449:Repetitive Sequences, Amino Acid
chemical_list: C517621:CFHR1 protein, human; C586681:CFHR2 protein, human; D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H; D050577:Complement C3-C5 Convertases; D017244:Complement Factor I