The role of the thioester bond in C3 and C4 in the determination of the conformational and functional states of the molecule.
The numerous ligand binding properties expressed by the activated forms of C3 (C3b) and C4 (C4b) are best explained as arising from proteolytic-cleavage-induced conformational changes. The studies described above provide direct physical evidence for such conformational transitions in both complement proteins. Significantly, however, a virtually identical conformational end state was also produced by direct nucleophilic scission of the internal thioester bond in C3 and C4 in the absence of any proteolysis. Clearly, it is the integrity of this thiolactone structure that is the determining factor in maintaining the native conformation in C3 and C4. Recent studies suggest a similar conformational role for the thioester in alpha 2-macroglobulin. Proteolytic activation in all three thioester-containing molecules renders this structure more susceptible to nucleophilic or solvolytic attack. Whether this effect is mediated by a peptide-cleavage-induced increase in the electrophilicity of the reactive carbonyl, or simply by increasing the accessibility of the solvent to this structure, is as yet unknown. In the case of C3 and C4, removal of the activation peptide also has a profound effect on the kinetics of the conformational change initiated by the loss of the thioester. This kinetic constraint has made it possible to correlate the acquisition of ligand binding properties with the spectroscopically detectable conformational changes.
D002942:Circular Dichroism; D003176:Complement C3 / Q000378:metabolism*; D003179:Complement C3b / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism*; D015935:Complement C4b; D004952:Esters; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D010446:Peptide Fragments / Q000032:analysis; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014357:Trypsin; D000511:alpha-Macroglobulins / Q000378:metabolism*
D003176:Complement C3; D003181:Complement C4; D004952:Esters; D046911:Macromolecular Substances; D010446:Peptide Fragments; D013438:Sulfhydryl Compounds; D000511:alpha-Macroglobulins; D003179:Complement C3b; D015935:Complement C4b; D014357:Trypsin