Related Experiment Video
Updated: Jul 11, 2026
Enrichment of Bruch's Membrane from Human Donor Eyes
Published on: November 15, 2015
Structural basis for complement factor H linked age-related macular degeneration
Beverly E Prosser1, Steven Johnson, Pietro Roversi
1Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, England, UK.
Insights
Age-related macular degeneration (AMD) affects millions. A common genetic risk factor involves a change in factor H (FH), a complement regulator. This study reveals how this change impacts FH
Area of Science:
- Biochemistry
- Genetics
- Structural Biology
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss, affecting nearly 50 million people globally.
- A significant risk factor for AMD is a specific single-nucleotide polymorphism in the factor H (FH) gene, resulting in a Tyr402His substitution.
- Factor H regulates the complement system, and its localization to cell surfaces is mediated by glycosaminoglycans (GAGs).
Purpose of the Study:
- To elucidate the molecular mechanism by which the Tyr402His polymorphism in factor H contributes to AMD risk.
- To understand the structural basis of GAG binding to factor H and how the polymorphism affects this interaction.
Main Methods:
- X-ray crystallography was used to determine the structure of the FH region containing His402 in complex with a GAG analogue.
- Structure-based site-directed mutagenesis was performed to investigate the functional consequences of the polymorphism.
- Nuclear magnetic resonance (NMR) spectroscopy was employed to monitor binding interactions of FH variants with GAGs.
Main Results:
- The crystal structure revealed direct coordination of the GAG ligand by the polymorphic His402 residue.
- This interaction site is centrally located within an extended groove, suggesting multivalent GAG binding.
- Mutagenesis and NMR binding studies confirmed the differential interaction of His402 and Tyr402 variants with GAGs, providing a molecular basis for the genetic association with AMD.
Conclusions:
- The Tyr402His polymorphism in factor H directly influences GAG binding, offering a molecular explanation for its link to AMD.
- The identified GAG-binding site on FH is crucial for complement regulation and cell surface localization.
- These findings provide critical insights into AMD pathogenesis and potential therapeutic strategies targeting the complement system.
Abstract:
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 approximately 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.
