Structural basis for complement factor H-linked age-related macular degeneration

Nearly 50 million people worldwide suffer from age- related macular degeneration ( AMD), which causes severe loss of central vision. A single- nucleotide polymorphism in the gene for the complement regulator factor H ( FH), which causes a Tyr- to- His substitution at position 402, is linked to similar to 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans ( GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease- associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan- binding site occupies the center of an extended interaction groove on the regulator ' s surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure- based site- directed mutagenesis, nuclear magnetic resonance - monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG - FH complex.