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J. Biol. Chem., Vol. 282, Issue 26, 18960-18968, June 29, 2007

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Structure Shows That a Glycosaminoglycan and Protein Recognition Site in Factor H Is Perturbed by Age-related Macular Degeneration-linked Single Nucleotide Polymorphism^*

Andrew P. Herbert, Jon A. Deakin, Christoph Q. Schmidt, Bärbel S. Blaum, Claire Egan, Viviana P. Ferreira^¶, Michael K. Pangburn^¶, Malcolm Lyon, Dusan Uhrín, and Paul N. Barlow¹

From the Edinburgh Biomolecular NMR Unit, School of Chemistry and School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, United Kingdom, Cancer Research UK Glyco-Oncology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, United Kingdom, and the ^¶Department of Biochemistry, University of Texas Health Science Center, Tyler, Texas 75703

A common single nucleotide polymorphism in the factor H gene predisposes to age-related macular degeneration. Factor H blocks the alternative pathway of complement on self-surfaces bearing specific polyanions, including the glycosaminoglycan chains of proteoglycans. Factor H also binds C-reactive protein, potentially contributing to noninflammatory apoptotic processes. The at risk sequence contains His (rather than Tyr) at position 402 (384 in the mature protein), in the seventh of the 20 complement control protein (CCP) modules (CCP7) of factor H. We expressed both His⁴⁰² and Tyr⁴⁰² variants of CCP7, CCP7,8, and CCP6-8. We determined structures of His⁴⁰² and Tyr⁴⁰² CCP7 and showed them to be nearly identical. The side chains of His/Tyr⁴⁰² have similar, solvent-exposed orientations far from interfaces with CCP6 and -8. Tyr⁴⁰² CCP7 bound significantly more tightly than His⁴⁰² CCP7 to a heparin affinity column as well as to defined-length sulfated heparin oligosaccharides employed in gel mobility shift assays. This observation is consistent with the position of the 402 side chain on the edge of one of two glycosaminoglycan-binding surface patches on CCP7 that we inferred on the basis of chemical shift perturbation studies with a sulfated heparin tetrasaccharide. According to surface plasmon resonance measurements, Tyr⁴⁰² CCP6-8 binds significantly more tightly than His⁴⁰² CCP6-8 to immobilized C-reactive protein. The data support a causal link between H402Y and age-related macular degeneration in which variation at position 402 modulates the response of factor H to age-related changes in the glycosaminoglycan composition and apoptotic activity of the macula.

Received for publication, October 12, 2006 , and in revised form, January 31, 2007.

^* This work was supported in part by National Institutes of Health Grant DK35081 (to M. K. P.), Cancer Research UK Programme Grant funding (to M. L.), and grants from the Wellcome Trust and Medical Research Council (United Kingdom) (to P. N. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Chemistry Bldg., University of Edinburgh, West Mains Rd., Edinburgh EH9 3JJ, Scotland, United Kingdom. Tel.: 44-131-650-4727; Fax: 44-131-650-7155; E-mail: Paul.Barlow{at}ed.ac.uk.

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