Protein Kinase C (PKC)ζ pseudosubstrate inhibitor peptide promiscuously binds PKC family isoforms and disrupts conventional PKC targeting and translocation

Abstract

PKM ζ is generated via an alternative transcriptional start site in the atypical protein kinaseC(PKC) ζ isoform, which removes N-terminal regulatory elements, including the inhibitory pseudosubstrate domain, consequently rendering the kinase constitutively active. Persistent PKM ζ activity has been proposed as a molecular mechanism for the long-term maintenance of synaptic plasticity underlying some forms of memory. Many studies supporting a role for PKM ζ in synaptic plasticity andmemory have relied on the PKC ζ pseudosubstrate-derived ζ -inhibitory peptide (ZIP). However, recent studies have demonstrated that ZIP-induced impairments to synaptic plasticity andmemory occur even in the absence of PKC ζ, suggesting that ZIP exerts its actions via additional cellular targets. In this study, we demonstrated that ZIP interacts with conventional and novel PKC, in addition to atypical PKC isoforms. Moreover, when brain abundance of each PKC isoform and affinity for ZIP are taken into account, the signaling capacity of ZIP-responsive pools of conventional and novel PKCs may match or exceed that for atypical PKCs. Pseudosubstrate-derived peptides, like ZIP, are thought to exert their cellular action primarily by inhibiting PKC catalytic activity; however, the ZIP-sensitive catalytic core of PKC is known to participate in the enzyme's subcellular targeting, suggesting an additional mode of ZIP action. Indeed, we have demonstrated that ZIP potently disrupts PKCa interaction with the PKC-targeting protein A-kinase anchoring protein (AKAP) 79 and interferes with ionomycin-induced translocation of conventional PKC to the plasma membrane. Thus, ZIP exhibits broadspectrum action toward the PKC family of enzymes, and this action may contribute to its unique ability to impair memory.