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Simon J. Clark, Liam Ridge, Andrew P. Herbert, Svetlana Hakobyan, Barbara Mulloy, Reinhard Wurzner, Paul Morgan, Dusan Uhrin, Paul N. Bishop, Anthony J. Day; The Disease-associated Glycosaminoglycan-binding (Y402H) Region Of Complement Factor H Mediates Host Recognition Of Human Bruch’S Membrane And Choroid: Implications Of Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2712.
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Factor H (CFH) binds to host surfaces via its interaction with the glycosaminoglycans (GAGs) heparan sulfate (HS) and dermatan sulfate (DS) and thus suppresses local complement activation, thereby preventing tissue damage. The CFH protein is comprised of 20 contiguous CCP domains, where it binds GAGs via its CCPs6-8 and CCPs19-20 regions. The Y402H polymorphism in CCP7, associated with AMD, alters CFH binding to HS/DS in Bruch’s membrane/choroid, whereas polymorphisms in CCP19-20 are associated with renal disease (i.e. atypical haemolytic uraemic syndrome). Here we directly compare the GAG-binding properties of these two regions of CFH and determine their relative contributions to the interaction of CFH with sites within the macula and kidney.
The heparin-binding properties of the CCPs6-8 region were compared with recombinant CCPs19-20 and the full-length protein (flCFH) by using affinity chromatography and solid phase binding assays. The competitive effects of CCP6-8 and CCP19-20 proteins on the binding of fluorescently-labelled flCFH to human macula and kidney tissues were also investigated.
Our studies demonstrate that the CCP6-8 region has a higher apparent affinity for heparin than CCP19-20 and their sulfate specificities are somewhat different. Interestingly, the CCP6-8 region makes more of a contribution to CFH’s binding to human macula tissues (i.e. the Bruch’s membrane and choroid) than CCP19-20, whereas the converse is seen for human kidney.
These data indicate that the CCP6-8 and CCP19-20 regions of CFH have distinct GAG-binding specificities where the former is ‘tuned’ to interact with GAGs in the macula. Furthermore, it provides an explanation as to why the Y402H polymorphism in CCP7 is associated with AMD, whereas polymorphisms in CCP19-20 are associated with renal disease. On the basis of these findings, tissue specific modulation of complement activity might represent a feasible strategy for the treatment of AMD.
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