Rational Design of a Novel Allosteric Peptide that Selectively Inhibits One of δPKC Function

摘要

Protein kinase C (PKC) is a family of 11 lipid-dependent isozymes that plays a critical role in signal transduction and in a variety of diseases. Upon activation each isozyme can phosphorylate different substrates by localizing to various sub-cellular sites. Here, we describe a rational design of peptide inhibitors that will regulate just one substrate, Separation-of-Function (SOF) regulators. The first such SOF peptide is an allosteric inhibitor of 8PKC phosphorylation of one substrate, the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK). We previously reported that 8PKC activation increases cardiac damage after heart attack (cardiac ischemia) through the phosphorylation and activation of PDK, which in turn, phosphorylates and inactivates pyruvate dehydrogenase (PDH) [1]. This 5PKC effect results in a decline in ATP regeneration at the period after the ischemic event [2]. We previously reported that the C2 domain of 8PKC is critical for protein-protein interactions and therefore focus our study on that domain [3]. Since there are over 60 proteins with a C2 domain, our approach is likely relevant to a number of nonnal and disease-associated signaling events.