Inhibition of the lytic activity of perforin (cytolysin) and of late complement components by proteoglycans.
The complement components (C6, C7, C8 and C9) implicated in the lysis of target cells and the pore-forming, lytic protein from cytotoxic T-lymphocytes and NK-cells, perforin, contain an amino acid sequence which is highly homologous to a repeat unit identified in the LDL-receptor (Tschopp et al., 1986, Nature, 322, 831-834). The domain of the LDL-receptor, which is thought to interact with a positively charged segment of its ligands apoprotein B and E, is rich in cysteine residues and contains a cluster of negative charges. We show that the negatively charged molecules suramin and glycosaminoglycans, the positively charged peptides protamine and polylysine, all of which are known to abolish binding of LDL to its receptor (Goldstein et al., 1985, A. Rev. cell. Biol., 1, 1-39) inhibit the lytic activities of C6, C7, C8, C9 and perforin. Moreover, these negatively charged molecules are potent inhibitors of cytolytic T-lymphocyte-mediated lysis of target cells, suggesting a functionally crucial role for perforin in cell-mediated cytolysis. We propose that the negatively charged, cysteine-rich domain of these complement proteins and perforin interacts with an as yet unidentified positively charged segment of its ligand in a manner analogous to the LDL-LDL receptor interaction. Homologous cysteine-rich domains in functionally unrelated proteins may therefore be functionally conserved as ideal rigid interaction domains with the conserved cysteine residues as framework. Specificity of the domain for its ligand would be conferred by the non-conserved amino acid residues.
D002460:Cell Line; D003186:Complement C9 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D006461:Hemolysis / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011509:Proteoglycans / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D003186:Complement C9; D003169:Complement Inactivator Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D011509:Proteoglycans; D054353:Perforin