Alternate pathways exist to activate this family of kinases. Classically, the lipid second messenger, diacylglycerol, has been invoked. The tumor-promoting phorbol esters mimic the action of DAG. Both bind an identical site in the zinc-finger domain. In the nonclassical pathway, mild oxidation of thiol groups of cysteines independently leads to kinase activity. We believe that a unifying concept could explain the 2 activation modes. The key is the removal of the auto-inhibitory regulatory domain from the catalytic domain to allow unfettered access of ATP, substrate, and cofactors.
Much of this allosteric movement revolves around the zinc-finger domain that functions as a reversible hinge. We are especially interested in the redox mode of PKC activation, since retinoids have emerged as important cofactors that facilitate the oxidative activation of PKC isoforms (see images).
Current studies center on 2 biochemical events for which we have firm evidence: 1) oxidation of select thiol groups; and 2) relocation of zinc ions within the protein when no longer thiol-chelated. These studies are to be complemented by structure biology to discern the nature of the retinol binding site; to define the allosteric change within the zinc-finger domain induced by redox modifications; and to test the hypothesis that lipid second messengers may cause equivalent allosteric changes, albeit based on a different physical intervention with the zinc tetraheder.
