Regulation of complement activation by C-reactive protein: targeting the complement inhibitory activity of factor H by an interaction with short consensus repeat domains 7 and 8-11.
C-reactive protein (CRP) is a major acute phase protein whose functions are not totally clear. In this study, we examined the interaction of CRP with factor H (FH), a key regulator of the alternative pathway (AP) of complement. Using the surface plasmon resonance technique and a panel of recombinantly expressed FH constructs, we observed that CRP binds to two closely located regions on short consensus repeat (SCR) domains 7 and 8-11 of FH. Also FH-like protein 1 (FHL-1), an alternatively spliced product of the FH gene, bound to CRP with its most C-terminal domain (SCR 7). The binding reactions were calcium-dependent and partially inhibited by heparin. In accordance with the finding that CRP binding sites on FH were distinct from the C3b binding sites, CRP preserved the ability of FH to promote factor I-mediated cleavage of C3b. We propose that the function of CRP is to target functionally active FH and FHL-1 to injured self tissues. Thereby, CRP could restrict excessive complement attack in tissues while allowing a temporarily enhanced AP activity against invading microbes in blood.
Jarva
H
H
Department of Bacteriology, Haartman Institute, University of Helsinki, Finland. hanna.jarva@helsinki.fi
Jokiranta
T S
TS
Hellwage
J
J
Zipfel
P F
PF
Meri
S
S
D001665:Binding Sites / Q000187:drug effects / Q000276:immunology; D002097:C-Reactive Protein / Q000378:metabolism / Q000502:physiology*; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D003180:Complement C3b Inactivator Proteins / Q000502:physiology; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016384:Consensus Sequence / Q000276:immunology; D006493:Heparin / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D010449:Peptide Mapping; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D020449:Repetitive Sequences, Amino Acid / Q000276:immunology; D020349:Surface Plasmon Resonance
C493495:CFH protein, human; D003180:Complement C3b Inactivator Proteins; D006495:Heparin, Low-Molecular-Weight; D010446:Peptide Fragments; D017242:Complement Factor H; D006493:Heparin; D002097:C-Reactive Protein