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 ∼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.

• Publication year

  2007

• Venue

  Journal of Experimental Medicine

• Publication date

  2007-10-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20071069PMID 17893204PMCID 2118454
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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