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Structural basis for complement factor H linked age-related macular degeneration
- Source :
- Prosser, B E, Johnson, S, Roversi, P, Herbert, A P, Blaum, B S, Tyrrell, J, Jowitt, T A, Clark, S J, Tarelli, E, Uhrin, D, Barlow, P N, Sim, R B, Day, A J & Lea, S M 2007, ' Structural basis for complement factor H-linked age-related macular degeneration ', Journal of Experimental Medicine, vol. 204, no. 10, pp. 2277-2283 . https://doi.org/10.1084/jem.20071069, The Journal of Experimental Medicine
- Publication Year :
- 2016
-
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 ∼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.
- Subjects :
- Models, Molecular
Aging
Sucrose
Surface Properties
Immunology
Regulator
Gene Products, gag
Mineralogy
Biology
Crystallography, X-Ray
Ligands
Glycosaminoglycan
03 medical and health sciences
0302 clinical medicine
Polysaccharides
medicine
Immunology and Allergy
Binding site
Protein Structure, Quaternary
Gene
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Binding Sites
Ligand
Brief Definitive Report
Macular degeneration
medicine.disease
Molecular biology
Protein Structure, Tertiary
Amino acid
chemistry
Complement Factor H
Factor H
Mutation
Brief Definitive Reports
030215 immunology
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Prosser, B E, Johnson, S, Roversi, P, Herbert, A P, Blaum, B S, Tyrrell, J, Jowitt, T A, Clark, S J, Tarelli, E, Uhrin, D, Barlow, P N, Sim, R B, Day, A J & Lea, S M 2007, ' Structural basis for complement factor H-linked age-related macular degeneration ', Journal of Experimental Medicine, vol. 204, no. 10, pp. 2277-2283 . https://doi.org/10.1084/jem.20071069, The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....5267c86159199a97e595a34f858bffb4