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Beverly E. Prosser¹, Steven Johnson¹, Pietro Roversi¹, Andrew P. Herbert³, Bärbel S. Blaum³, Jess Tyrrell¹, Thomas A. Jowitt⁴, Simon J. Clark^2,4, Edward Tarelli⁵, Duan Uhrín³, Paul N. Barlow³, Robert B. Sim², Anthony J. Day^2,4, and Susan M. Lea¹

¹ Sir William Dunn School of Pathology and the ² Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, Oxford, OX1 3RE, England, UK
³ Joseph Black Chemistry Building, University of Edinburgh, Edinburgh, EH9 3JJ, Scotland, UK
⁴ Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester M13 9PT, England, UK
⁵ Medical Biomics Centre, St. George's University of London, London SW17 0RE, England, UK

CORRESPONDENCE Susan M. Lea: susan.lea{at}path.ox.ac.uk OR Anthony J. Day: anthony.day{at}manchester.ac.uk

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.

B.E. Prosser and S. Johnson contributed equally to this paper.

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This article has been cited by other articles:

• Schmidt, C. Q., Herbert, A. P., Kavanagh, D., Gandy, C., Fenton, C. J., Blaum, B. S., Lyon, M., Uhrin, D., Barlow, P. N. (2008). A New Map of Glycosaminoglycan and C3b Binding Sites on Factor H. J. Immunol. 181: 2610-2619 [Abstract] [Full Text]  

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