Yu Jiamei, Wiita Patrick, Kawaguchi Riki, Honda Jane, Jorgensen Adam, Zhang Kang, Fischetti Vincent A, Sun Hui
Department of Physiology and Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Biochemistry. 2007 Jul 17;46(28):8451-61. doi: 10.1021/bi700459a. Epub 2007 Jun 20.
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.
年龄相关性黄斑变性（AMD）是发达国家不可逆性失明的主要原因。大量人类遗传学研究已将补体因子H（CFH）的一个常见变体（Y402H）与AMD风险的显著增加联系起来。CFH是一种模块化蛋白，具有20个同源的短共有重复序列（SCR）。Y402H变体位于CFH和补体因子H样蛋白1（FHL-1，CFH的一种剪接变体，包含SCR1-7，具有独特的生化特性）的SCR7中。由于已知SCR7可与肝素、C反应蛋白（CRP）以及化脓性链球菌的M蛋白结合，因此有人推测与AMD相关的多态性可能会影响与这些CFH配体的相互作用。在本研究中，我们在全长CFH（SCR1-20）和FHL-1的背景下对这一假设进行了验证。我们系统地分析了CFH和FHL-1的Y402和H402变体与肝素、CRP以及几种细菌配体（化脓性链球菌的M6蛋白、肺炎链球菌的PspC和伯氏疏螺旋体的BbCRASP-1）之间的相互作用。在比较CFH和FHL-1的Y和H变体时，我们发现它们在蛋白质分泌、辅因子活性或与肝素、BbCRASP-1或PspC的相互作用方面没有显著差异，但在与CRP和M6蛋白的结合方面存在显著差异。本研究揭示了CFH常见多态性的基本特性，并为阐明CFH在AMD发病机制中的作用奠定了基础。
