Biochemical Analysis of a Common Human Polymorphism Associated with Age-Related Macular Degeneration

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• 作者：Jiamei Yu ; Patrick Wiita ; Riki Kawaguchi ; Jane Honda ; Adam Jorgensen ; Kang Zhang ; Vincent A. Fischetti ; Hui Sun
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：July 17, 2007
• 年：2007
• 卷：46
• 期：28
• 页码：8451 - 8461
• 全文大小：901K
• 年卷期：v.46,no.28(July 17, 2007)
• ISSN：1520-4995

文摘

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness indeveloped 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 proteinwith 20 homologous short consensus repeats (SCRs). The Y402H variant is located in SCR7 of bothCFH and factor H-like protein 1 (FHL-1), a splice variant of CFH (containing SCR1-7) with uniquebiochemical properties. Because SCR7 is known to bind to heparin, C-reactive protein (CRP), and Mprotein from Streptococcus pyogenes, it has been hypothesized that the AMD-associated polymorphismmay affect interactions with these CFH ligands. In this study, we tested this hypothesis in the context offull-length CFH (SCR1-20) and FHL-1. We systematically analyzed the interactions of the Y402 andH402 variants of CFH and FHL-1 with heparin, CRP, and several bacterial ligands: M6 protein ofStreptococcus 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 proteinsecretion, cofactor activity, or interactions with heparin, BbCRASP-1, or PspC, but a significant differencein binding to CRP and M6 protein. This study reveals the fundamental properties of a commonpolymorphism of CFH and lays the groundwork for elucidating the role of CFH in AMD pathogenesis.