Structure Shows That a Glycosaminoglycan and Protein Recognition Site in Factor H Is Perturbed by Age-related Macular Degeneration-linked Single Nucleotide Polymorphism

Department of Chemistry and Biochemistry, University of Texas at Tyler, Tyler, Texas, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2007; 282(26):18960-8. DOI: 10.1074/jbc.M609636200
Source: PubMed


A common single nucleotide polymorphism in the factor H gene predisposes to age-related macular degeneration. Factor H blocks the alternative pathway of complement on self-surfaces bearing specific polyanions, including the glycosaminoglycan chains of proteoglycans. Factor H also binds C-reactive protein, potentially contributing to noninflammatory apoptotic processes. The at risk sequence contains His (rather than Tyr) at position 402 (384 in the mature protein), in the seventh of the 20 complement control protein (CCP) modules (CCP7) of factor H. We expressed both His(402) and Tyr(402) variants of CCP7, CCP7,8, and CCP6-8. We determined structures of His(402) and Tyr(402) CCP7 and showed them to be nearly identical. The side chains of His/Tyr(402) have similar, solvent-exposed orientations far from interfaces with CCP6 and -8. Tyr(402) CCP7 bound significantly more tightly than His(402) CCP7 to a heparin affinity column as well as to defined-length sulfated heparin oligosaccharides employed in gel mobility shift assays. This observation is consistent with the position of the 402 side chain on the edge of one of two glycosaminoglycan-binding surface patches on CCP7 that we inferred on the basis of chemical shift perturbation studies with a sulfated heparin tetrasaccharide. According to surface plasmon resonance measurements, Tyr(402) CCP6-8 binds significantly more tightly than His(402) CCP6-8 to immobilized C-reactive protein. The data support a causal link between H402Y and age-related macular degeneration in which variation at position 402 modulates the response of factor H to age-related changes in the glycosaminoglycan composition and apoptotic activity of the macula.

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Available from: Bärbel Blaum, Jan 15, 2016
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    • "Around 30% of people of European descent carry at least one copy of the 402H risk allele (Sofat et al., 2012). Structurally, the Y402H polymorphism occurs in the seventh of FH's twenty complement control protein (CCP) domains (Fig. 2B) and does not alter the overall conformation of the protein (Herbert et al., 2007). Y402H, however, alters the binding of FH to a number of ligands (see Clark et al., 2010a and references within), most notably C-reactive protein (Sjöberg et al., 2007), Streptococcus M protein (Haapasalo et al., 2008) and sulfated polyanions (Clark et al., 2006), such as the glycosaminoglycan (GAG) chains of proteoglycans. "
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    • "The direction of SNP effects on plasma CFH is shown for their minor alleles, and the same alleles are consistently associated with opposite effects on plasma CFHR1 concentration (Fig. 5A). In contrast, CFH SNPs that alter the sequence and potentially the function of the protein [rs1061170 encoding Y402H (20–22,35,36) and rs800292 encoding I62V (28,35,37)] have effects on plasma CFH that appear uncorrelated with their effects on AMD risk (Fig. 5). For example, the above two non-synonymous CFH SNPs are associated with either no effect or a marginally lower plasma CFH, whereas both show a substantially increased AMD risk. "
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    • "The C-terminal SCRs in all CFHR proteins that correspond to SCR19 in factor H are highly conserved, while the most C-terminal SCRs which correspond to SCR20 in factor H (Fig. 2) are more diverse. SCR20 of factor H harbors an important heparin binding site (Herbert et al., 2007; Lehtinen et al., 2009), suggesting that the CFHRs may recognize and bind to different cell surfaces. The specific features of each CFHR protein are presented and discussed separately. "
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