title: Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein.
abstract: Factor H-related protein 5 (FHR-5) is a recently discovered member of the factor H (fH)-related protein family. FHR proteins are structurally similar to the complement regulator fH, but their biological functions remain poorly defined. FHR-5 is synthesized in the liver and consists of 9 short consensus repeats (SCRs), which display various degrees of homology to those of fH and the other FHR proteins. FHR-5 colocalizes with complement deposits in vivo and binds C3b in vitro, suggesting a role in complement regulation or localization. The current study examined whether rFHR-5 exhibits properties similar to those of fH, including heparin binding, CRP binding, cofactor activity for the factor I-mediated degradation of C3b and decay acceleration of the C3 convertase. rFHR-5 bound heparin-BSA and heparin-agarose and a defined series of truncations expressed in Pichia pastoris localized the heparin-binding region to within SCRs 5-7. rFHR-5 bound CRP, and this binding was also localized to SCRs 5-7. FHR-5 inhibited alternative pathway C3 convertase activity in a fluid phase assay; however, dissociation of the convertase was not observed in a solid phase assay. rFHR-5 displayed factor I-dependent cofactor activity for C3b cleavage, although it was apparently less effective than fH. In addition, we demonstrate association of FHR-5 with high density lipid lipoprotein complexes in human plasma. These results demonstrate that FHR-5 shares properties of heparin and CRP binding and lipoprotein association with one or more of the other FHRs but is unique among this family of proteins in possessing independent complement-regulatory activity.
authors.affiliation: Department of Nephrology, Immunology Research Centre, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia. Jennifer.MCRAE@svhm.org.au
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McRae
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Duthy
authors.forename: Kim M
authors.initials: KM
authors.lastname: Griggs
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ormsby
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: Brett A
authors.initials: BA
authors.lastname: Cromer
authors.forename: William J
authors.initials: WJ
authors.lastname: McKinstry
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Murphy
authors.forename: David L
authors.initials: DL
authors.lastname: Gordon
mesh_terms: D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002097:C-Reactive Protein / Q000378:metabolism*; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism / Q000502:physiology*; D003169:Complement Inactivator Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003165:Complement System Proteins; D016384:Consensus Sequence; D005340:Fibrinogen / Q000502:physiology; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics; D010843:Pichia / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020449:Repetitive Sequences, Amino Acid
chemical_list: D001798:Blood Proteins; C493495:CFH protein, human; C432223:CFHR5 protein, human; D003169:Complement Inactivator Proteins; D008075:Lipoproteins, HDL; D010446:Peptide Fragments; D011994:Recombinant Proteins; D003179:Complement C3b; D017242:Complement Factor H; D005340:Fibrinogen; D006493:Heparin; D003165:Complement System Proteins; D002097:C-Reactive Protein; D050577:Complement C3-C5 Convertases