Human complement factor H-related protein 4 binds and recruits native pentameric C-reactive protein to necrotic cells.
Human complement factor H-related protein 4 (CFHR4) is a plasma glycoprotein which appears in two isoforms. CFHR4 is a member of the factor H protein family, and shares structural similarity and sequence homology with the other CFHR proteins and with the complement regulator factor H. Given the structural and sequence similarity, we hypothesized that similar to factor H, CFHR4 binds to C-reactive protein (CRP). We have recombinantly expressed the two CFHR4 isoforms and analyzed their binding to both native and denatured, monomeric CRP. Here, we show that both CFHR4 isoforms bind in the presence of calcium to native pentameric CRP, but not to modified CRP. This is in contrast to factor H, which binds to modified CRP independent of calcium. Comparison of the two CFHR4 isoforms and a recombinant CFHR4 fragment for CRP binding indicates that the first domain of CFHR4 is relevant for this interaction. Interaction of the native proteins was demonstrated by co-precipitation of CFHR4 and CRP from serum of sepsis patients with elevated CRP levels. CFHR4 bound to necrotic cells and was localized in necrotic tumor tissue as demonstrated by immunohistological analyses. In addition, CFHR4 facilitated binding of native CRP to the surface of necrotic cells. Altogether these data identify CFHR4 as a novel ligand for native CRP, and suggest a role for CFHR4 in opsonization of necrotic cells.
Mihlan
Michael
M
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.
Hebecker
Mario
M
Dahse
Hans-Martin
HM
Hälbich
Steffi
S
Huber-Lang
Markus
M
Dahse
Regine
R
Zipfel
Peter F
PF
Józsi
Mihály
M
D001053:Apolipoproteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002021:Buffers; D002097:C-Reactive Protein / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D009336:Necrosis / Q000378:metabolism*; D009994:Osmolar Concentration; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism
D001053:Apolipoproteins; D002021:Buffers; C105092:CFHR4 protein, human; D020033:Protein Isoforms; D011994:Recombinant Proteins; D002097:C-Reactive Protein; D002118:Calcium