title: A new mechanism of action of a C2 domain-derived novel PKC inhibitor peptide.
abstract: Novel protein kinase Cs (nPKCs) contain an N-terminal C2 domain that cannot bind to calcium. We have previously shown that the Aplysia novel PKC Apl II's C2 domain inhibits binding of diacylglycerol (DAG) to the C1 domain and that this inhibition is removed by phosphatidic acid (PA) binding to the C1b domain. Another model for C2 domain regulation of nPKCs suggests that the C2 domain binds to receptors for activated C kinase (RACKs) to assist in kinase translocation and activation. In the present study, we examined how a pharmacological peptide derived from RACK-binding site in the vertebrate novel PKCɛ regulates translocation of PKC Apl II from the cytosol to the plasma membrane. We found that a C2 domain-derived inhibitor peptide inhibited PKC Apl II translocation. This inhibition was removed by R273H mutation in the C1b domain and by phosphatidic acid, which can both remove C2-domain mediated inhibition suggesting that the peptide can regulate C1-C2 domain interactions.
authors: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, BT 110, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
authors: Carole A
authors: CA
authors: Farah
authors: Wayne S
authors: WS
authors: Sossin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001048:Aplysia; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D016384:Consensus Sequence; D003593:Cytoplasm / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D015195:Drug Design; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D010712:Phosphatidic Acids / Q000494:pharmacology; D017354:Point Mutation; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D016415:Sequence Alignment; D018411:Spodoptera
chemical_list: D004075:Diglycerides; D007527:Isoenzymes; D010446:Peptide Fragments; D010712:Phosphatidic Acids; C121046:Apl II protein kinase C; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D002118:Calcium