Membrane cofactor protein (MCP; CD46). Isoforms differ in protection against the classical pathway of complement.
Membrane cofactor protein (MCP; CD46) is a widely distributed C3b/C4b-binding glycoprotein that inhibits complement activation on host cells. MCP is expressed primarily as four isoforms that arise by alternative splicing of a single gene. The differences reside in the domains for O-glycosylation and cytoplasmic tails. Tissue-specific expression of isoforms and the differential processing of precursors mediated by the cytoplasmic tails suggest that isoform variations are biologically significant. The goal of these experiments was to characterize the complement inhibitory profile of the four commonly expressed isoforms. The MCP isoforms (BC) with a larger O-glycosylation domain bound C4b more efficiently than the C isoforms, which are smaller and less glycosylated in this region. Additionally, cytoprotection assays of individual clones of transfected isoforms bearing equivalent copy numbers demonstrated that the BC isoforms also provided enhanced protection in a classical pathway-mediated system and cleaved cell-bound C4b more efficiently than the C isoforms. Taken together, these data demonstrate that BC isoforms preferentially protect against the classical pathway of complement. Such findings indicate a physiologic role for isoform variation and have therapeutic implications for use of MCP isoforms as complement inhibitors in such areas as xenotransplantation.
Liszewski
M K
MK
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Atkinson
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D015935:Complement C4b / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003171:Complement Pathway, Classical; D006224:Cricetinae; D006801:Humans; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D014162:Transfection
D015703:Antigens, CD; C497857:CD46 protein, human; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D015935:Complement C4b