His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form.
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.
Clark
Simon J
SJ
Medical Research Council (MRC) Immunochemistry Unit and Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, United Kingdom.
Higman
Victoria A
VA
Mulloy
Barbara
B
Perkins
Stephen J
SJ
Lea
Susan M
SM
Sim
Robert B
RB
Day
Anthony J
AJ
D000483:Alleles; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D003167:Complement Activation; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006639:Histidine; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D011994:Recombinant Proteins; D006639:Histidine; D017242:Complement Factor H; D006493:Heparin