Substrate inhibition subunits, domains

The consensus sequence for phosphorylation of proteins by protein kinase A is RRXSX. The RII subunit contains such a sequence in the autoinhibitory domain and is therefore subject to phosphorylation by the C subunit in the holoenzyme, but without release of inhibition. Inhibition of the C subunit by the R subunit is based on binding of the autoinhibitory sequence of R at the substrate-binding site and at parts of the active center of the C subunit. 

Many protein kinases are maintained in an inhibited state by an autoinhibitory domain within the protein or as a separate inhibitory subunit (Kemp et al., 1994). Activation thus involves exposure of the catalytic site so that the protein substrate may bind and be phosphorylated. A number of autoinhibitory sequences have structural similarities to the consensus phosphorylation site in the respective protein kinase substrates. Thus, the enzyme s active site may be ster-ically blocked by the autoinhibitory domain via a pseudosubstrate mechanism, where residues in the catalytic core bind to residues in the autoinhibitory region or substrate. 

The increase in oxidizable substrates (e.g., glucose and G-6-P) enhances ATP production, thereby inhibiting an ATP-sensitive K channel. This decrease in K conductance causes to rise, opening a voltage-sensitive Ccf channel Ccft then acts as the insulin secretagogue. The ATP-sensitive K channel in /3 cells is an octamer composed of four Kir 6.2 and four SURl subunits. Both subunits contain nucleotide-binding domains Kir 6.2 appears to mediate the inhibitory response to ATP SURl binds ADP, the channel activator diazoxide, and the channel inhibitors (and promoters of insulin secretion) sulfonylureas and meglitinide. 

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