Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions.
Complement factor H (CFH) regulates complement activation in host tissues through its recognition of polyanions, which mediate CFH binding to host cell surfaces and extracellular matrix, promoting the deactivation of deposited C3b. These polyanions include heparan sulfate (HS), a glycosaminoglycan with a highly diverse range of structures, for which two regions of CFH (CCP6-8 and CCP19-20) have been implicated in HS binding. Mutations/polymorphisms within these glycosaminoglycan-binding sites have been associated with age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome. In this study, we demonstrate that CFH has tissue-specific binding properties mediated through its two HS-binding regions. Our data show that the CCP6-8 region of CFH binds more strongly to heparin (a highly sulfated form of HS) than CCP19-20, and that their sulfate specificities are different. Furthermore, the HS binding site in CCP6-8, which is affected by the AMD-associated Y402H polymorphism, plays the principal role in host tissue recognition in the human eye, whereas the CCP19-20 region makes the major contribution to the binding of CFH in the human kidney. This helps provide a biochemical explanation for the genetic basis of tissue-specific diseases such as AMD and atypical hemolytic uremic syndrome, and leads to a better understanding of the pathogenic mechanisms for these diseases of complement dysregulation.
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Simon J
SJ
Clark
Liam A
LA
Ridge
Andrew P
AP
Herbert
Svetlana
S
Hakobyan
Barbara
B
Mulloy
Rachel
R
Lennon
Reinhard
R
Würzner
B Paul
BP
Morgan
Dusan
D
Uhrín
Paul N
PN
Bishop
Anthony J
AJ
Day
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D065766:Atypical Hemolytic Uremic Syndrome; D001344:Autopsy; D001665:Binding Sites; D003167:Complement Activation / Q000235:genetics; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D005123:Eye / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009928:Organ Specificity; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D017242:Complement Factor H; D006497:Heparan Sulfate; D011994:Recombinant Proteins