The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells.
Recently, a polymorphism in the complement regulator factor H (FH) gene has been associated with age-related macular degeneration. When histidine instead of tyrosine is present at position 384 in the seventh complement control protein (CCP) domain of FH, the risk for age-related macular degeneration is increased. It was recently shown that these allotypic variants of FH, in the context of a recombinant construct corresponding to CCPs 6-8, recognize polyanionic structures differently, which may lead to altered regulation of the alternative pathway of complement. We show now that His-384, corresponding to the risk allele, binds C-reactive protein (CRP) poorly compared with the Tyr-384 form. We also found that C1q and phosphorylcholine do not compete with FH for binding to C-reactive protein. The interaction with extracellular matrix protein fibromodulin, which we now show to be mediated, at least in part, by CCP6-8 of FH, occurs via the polypeptide of fibromodulin and not through its glycosaminoglycan modifications. The Tyr-384 variant of FH bound fibromodulin better than the His-384 form. Furthermore, we find that CCP6-8 is able to interact with DNA and necrotic cells, but in contrast the His-384 allotype binds these ligands more strongly than the Tyr-384 variant. The variations in binding affinity of the two alleles indicate that complement activation and local inflammation in response to different targets will differ between His/His and Tyr/Tyr homozygotes.
Sjöberg
Andreas P
AP
Department of Laboratory Medicine, University Hospital Malmö, Lund University, S-205 02 Malmo, Sweden.
Trouw
Leendert A
LA
Clark
Simon J
SJ
Sjölander
Jonatan
J
Heinegård
Dick
D
Sim
Robert B
RB
Day
Anthony J
AJ
Blom
Anna M
AM
D017398:Alternative Splicing; D002097:C-Reactive Protein / Q000378:metabolism*; D002460:Cell Line; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D000071235:Fibromodulin; D006639:Histidine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009336:Necrosis; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D011509:Proteoglycans; D000071235:Fibromodulin; D014443:Tyrosine; D006639:Histidine; D017242:Complement Factor H; D002097:C-Reactive Protein; D004247:DNA