His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form
Open accessAbstract
A polymorphism in complement factor H has recently been associated with age-related macular degeneration (AMD), the leading cause of blindness in the elderly. A histidine rather than a tyrosine at residue position 384 in the mature protein increases the risk of AMD. Here, using a recombinant construct, we show that amino acid 384 is adjacent to a heparin-binding site in CCP7 of factor H and demonstrate that the allotypic variants differentially recognize heparin. This functional alteration may affect binding of factor H to polyanionic patterns on host surfaces, potentially influencing complement activation, immune complex clearance, and inflammation in the macula of AMD patients.
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The reduction in HSPGs may exacerbate the effect of the FH p.Y402H polymorphism because the variant protein binds less well to HSPGs than the wild-type protein.
“This may exacerbate the effect of the FH p.Y402H polymorphism (a major genetic risk factor for AMD) as it has been proposed that the variant protein binds less well to HSPGs than the wild-type protein [56,57].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [56]
Heparan sulphate proteoglycans (HSPGs), key binders of complement regulator Factor H (FH), are reduced with age and may lead to increased complement activation.
“However, heparan sulphate proteoglycans (HSPGs), key binders of the complement regulator Factor H (FH), have been shown to be reduced with age [55] and may lead to increased complement activation [56,57].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [56]
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Self-citation
- Authors
- Clark, S. J., Higman, V. A., Mulloy, B., Perkins, S. J., Lea, S. M., Sim, R. B., & Day, A. J.
- Affiliations
- University of Oxford (GB)
- National Institute for Biological Standards and Control (GB)
- University College London (GB)
- University of Manchester (GB)
- Corresponding author
- Sim, Robert B.
- Day, Anthony J.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 281
- Issue
- 34
- Pages
- 24713-24720
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2074549590
- Cited by
- 185
- References
- 46
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 10 · 2023: 1 · 2022: 4 · 2021: 13 · 2020: 8 · 2019: 4 · 2018: 8 · 2017: 8 · 2016: 11 · 2015: 11 · 2014: 11 · 2013: 12 · 2012: 10
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Explore Bristol Research (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Keywords
- complement factor H, age-related macular degeneration, heparin binding, complement regulation, complement activation, immune complex clearance, inflammation, macula
- MeSH terms
- Alleles, Binding Sites, Complement Activation, Heparin, Histidine, Humans, Macular Degeneration, Models, Molecular, Protein Binding, Recombinant Proteins, Structure-Activity Relationship, Complement Factor H, Amino Acid Substitution
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