Biochemical analysis of a common human polymorphism associated with age-related macular degeneration.
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. A large number of human genetic studies have associated a common variant (Y402H) of complement factor H (CFH) with a highly significant increase in AMD risk. CFH is a modular protein with 20 homologous short consensus repeats (SCRs). The Y402H variant is located in SCR7 of both CFH and factor H-like protein 1 (FHL-1), a splice variant of CFH (containing SCR1-7) with unique biochemical properties. Because SCR7 is known to bind to heparin, C-reactive protein (CRP), and M protein from Streptococcus pyogenes, it has been hypothesized that the AMD-associated polymorphism may affect interactions with these CFH ligands. In this study, we tested this hypothesis in the context of full-length CFH (SCR1-20) and FHL-1. We systematically analyzed the interactions of the Y402 and H402 variants of CFH and FHL-1 with heparin, CRP, and several bacterial ligands: M6 protein of Streptococcus pyogenes, PspC of Streptococcus pneumoniea, and BbCRASP-1 of Borrelia burgdorferi. In comparing the Y and H variants of CFH and FHL-1, we found no significant difference in their protein secretion, cofactor activity, or interactions with heparin, BbCRASP-1, or PspC, but a significant difference in binding to CRP and M6 protein. This study reveals the fundamental properties of a common polymorphism of CFH and lays the groundwork for elucidating the role of CFH in AMD pathogenesis.
Yu
Jiamei
J
Department of Physiology and Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Wiita
Patrick
P
Kawaguchi
Riki
R
Honda
Jane
J
Jorgensen
Adam
A
Zhang
Kang
K
Fischetti
Vincent A
VA
Sun
Hui
H
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D002460:Cell Line; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008268:Macular Degeneration / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide
D001426:Bacterial Proteins; C493495:CFH protein, human; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D008024:Ligands; D017242:Complement Factor H; D006493:Heparin; D002097:C-Reactive Protein