Intrapeptide regulation of protein kinase C.
Protein kinase C is allosterically activated by diacylglycerol and phosphatidylserine. The enzyme is also activated by surprisingly dissimilar compounds such as short chained phosphatidylcholines and protamine sulfate. Here we show that conventional and nonconventional activators of protein kinase C beta II produce the same structural alteration. They expose Arg19 of the autoinhibitory pseudosubstrate domain to proteolysis. Molecular modeling of protein kinase C beta II's catalytic domain, based on the structure of the cAMP-dependent kinase's catalytic domain, indicates that Arg19 is shielded by a cluster of acidic residues when the pseudosubstrate occupies the substrate-binding site. Our biochemical data and structural modeling indicate a common mechanism of intrapeptide regulation of protein kinase C by all activators that involves release of the pseudosubstrate from the active site.
Orr
J W
JW
Department of Chemistry, Indiana University, Bloomington 47405.
Newton
A C
AC
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001120:Arginine; D001665:Binding Sites; D002118:Calcium; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism; D010713:Phosphatidylcholines / Q000494:pharmacology; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D009842:Oligopeptides; D010713:Phosphatidylcholines; C038470:1,2-heptanoylphosphatidylcholine; D001120:Arginine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium