HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 34, 24713-24720, August 25, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/34/24713    most recent M605083200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clark, S. J. Articles by Day, A. J. Search for Related Content PubMed PubMed Citation Articles by Clark, S. J. Articles by Day, A. J. Social Bookmarking                      What's this?

His-384 Allotypic Variant of Factor H Associated with Age-related Macular Degeneration Has Different Heparin Binding Properties from the Non-disease-associated Form^*

Simon J. Clark¹, Victoria A. Higman, Barbara Mulloy, Stephen J. Perkins^¶, Susan M. Lea^||, Robert B. Sim², and Anthony J. Day^**3

From the Medical Research Council (MRC) Immunochemistry Unit and ^||Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, National Institute of Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, and the ^¶Department of Biochemistry and Molecular Biology, University College London, WC1E 6BT, and the ^**Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

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.

Received for publication, May 26, 2006

^* This work was supported by grants from the MRC. 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 a supplemental table and two supplemental figures.

¹ A recipient of an MRC Studentship (G78/7925).

² To whom correspondence may be addressed: Dr. Robert B. Sim, MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Tel.: 44-1865-275351; Fax: 44-1865-275729; E-mail: bob.sim{at}bioch.ox.ac.uk. ³ To whom correspondence may be addressed: Faculty of Life Sciences, The University of Manchester, Oxford Rd., Manchester M13 9PT, UK. Tel.: 44-1865-275349; Fax: 44-1865-275729; E-mail: anthony.day{at}manchester.ac.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. Rohrer, Q. Long, B. Coughlin, R. B. Wilson, Y. Huang, F. Qiao, P. H. Tang, K. Kunchithapautham, G. S. Gilkeson, and S. Tomlinson A Targeted Inhibitor of the Alternative Complement Pathway Reduces Angiogenesis in a Mouse Model of Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., July 1, 2009; 50(7): 3056 - 3064. [Abstract] [Full Text] [PDF]

				D. Orth, A. B. Khan, A. Naim, K. Grif, J. Brockmeyer, H. Karch, M. Joannidis, S. J. Clark, A. J. Day, S. Fidanzi, et al. Shiga Toxin Activates Complement and Binds Factor H: Evidence for an Active Role of Complement in Hemolytic Uremic Syndrome J. Immunol., May 15, 2009; 182(10): 6394 - 6400. [Abstract] [Full Text] [PDF]

				K. C.M.C. Koeijvoets, S. P. Mooijaart, G. M. Dallinga-Thie, J. C. Defesche, E. W. Steyerberg, R. G.J. Westendorp, J. J.P. Kastelein, P. M. van Hagen, and E. J.G. Sijbrands Complement factor H Y402H decreases cardiovascular disease risk in patients with familial hypercholesterolaemia Eur. Heart J., March 1, 2009; 30(5): 618 - 623. [Abstract] [Full Text] [PDF]

				S. Hakobyan, C. L. Harris, C. W. van den Berg, M. C. Fernandez-Alonso, E. G. de Jorge, S. R. de Cordoba, G. Rivas, P. Mangione, M. B. Pepys, and B. P. Morgan Complement Factor H Binds to Denatured Rather than to Native Pentameric C-reactive Protein J. Biol. Chem., November 7, 2008; 283(45): 30451 - 30460. [Abstract] [Full Text] [PDF]

				C. Q. Schmidt, A. P. Herbert, D. Kavanagh, C. Gandy, C. J. Fenton, B. S. Blaum, M. Lyon, D. Uhrin, and P. N. Barlow A New Map of Glycosaminoglycan and C3b Binding Sites on Factor H J. Immunol., August 15, 2008; 181(4): 2610 - 2619. [Abstract] [Full Text] [PDF]

				R. J. Ormsby, S. Ranganathan, J. C. Tong, K. M. Griggs, D. P. Dimasi, A. W. Hewitt, K. P. Burdon, J. E. Craig, J. Hoh, and D. L. Gordon Functional and Structural Implications of the Complement Factor H Y402H Polymorphism Associated with Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., May 1, 2008; 49(5): 1763 - 1770. [Abstract] [Full Text] [PDF]

				P. J. Coffey, C. Gias, C. J. McDermott, P. Lundh, M. C. Pickering, C. Sethi, A. Bird, F. W. Fitzke, A. Maass, L. L. Chen, et al. Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction PNAS, October 16, 2007; 104(42): 16651 - 16656. [Abstract] [Full Text] [PDF]

				B. E. Prosser, S. Johnson, P. Roversi, A. P. Herbert, B. S. Blaum, J. Tyrrell, T. A. Jowitt, S. J. Clark, E. Tarelli, D. Uhrin, et al. Structural basis for complement factor H linked age-related macular degeneration J. Exp. Med., October 1, 2007; 204(10): 2277 - 2283. [Abstract] [Full Text] [PDF]

				A. P. Herbert, J. A. Deakin, C. Q. Schmidt, B. S. Blaum, C. Egan, V. P. Ferreira, M. K. Pangburn, M. Lyon, D. Uhrin, and P. N. Barlow Structure Shows That a Glycosaminoglycan and Protein Recognition Site in Factor H Is Perturbed by Age-related Macular Degeneration-linked Single Nucleotide Polymorphism J. Biol. Chem., June 29, 2007; 282(26): 18960 - 18968. [Abstract] [Full Text] [PDF]

				A. P. Sjoberg, L. A. Trouw, S. J. Clark, J. Sjolander, D. Heinegard, R. B. Sim, A. J. Day, and A. M. Blom The Factor H Variant Associated with Age-related Macular Degeneration (His-384) and the Non-disease-associated Form Bind Differentially to C-reactive Protein, Fibromodulin, DNA, and Necrotic Cells J. Biol. Chem., April 13, 2007; 282(15): 10894 - 10900. [Abstract] [Full Text] [PDF]

				P. T. Johnson, K. E. Betts, M. J. Radeke, G. S. Hageman, D. H. Anderson, and L. V. Johnson Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid PNAS, November 14, 2006; 103(46): 17456 - 17461. [Abstract] [Full Text] [PDF]