Compstatin, a peptide inhibitor of complement, exhibits species-specific binding to complement component C3.
Although activation of complement protein C3 is essential for the generation of normal inflammatory responses against pathogens, its unregulated activation during various pathological conditions leads to host cell damage. Previously we have identified a 13-residue cyclic peptide, Compstatin, that inhibits C3 activation. In this study, we have examined the species-specificity of Compstatin. Bimolecular interaction analysis using a real-time surface plasmon resonance-based assay showed that Compstatin exhibits exclusive specificity for primate C3s and does not bind either to C3s from lower mammalian species or to two structural homologs of C3, human C4 and C5. Furthermore, it showed that although the kinetics of binding of Compstatin to non-human primate C3s were distinctly different from those to human C3, like human C3 its mechanism of binding to non-human primate C3 was biphasic and did not follow a simple 1:1 interaction, suggesting that this binding mechanism could be important for its inhibitory activity. Analysis of Ala substitution analogs of Compstatin for their inhibitory activities against mouse and rat complement suggested that the lack of binding of Compstatin to mouse and rat C3s was not a result of sterically hindered access to the binding pocket due to individual bulky side chains or the presence of charge on the Compstatin molecule. These results suggest that Compstatin's exclusive specificity for primate C3s could be exploited for the development of species-specific complement inhibitors.
Sahu
Arvind
A
National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, India.
Morikis
Dimitrios
D
Lambris
John D
JD
D019943:Amino Acid Substitution; D000818:Animals; D003179:Complement C3b / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D051379:Mice; D009154:Mutation; D010456:Peptides, Cyclic / Q000378:metabolism*; D011323:Primates; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity; D013552:Swine
D010456:Peptides, Cyclic; C111828:compstatin; D003179:Complement C3b