Although the human genome is predicted to encode over 2,000 protein kinases, each is highly specific. The protein kinase active site represents an extended network of conserved residues that are poised to selectively transfer Ihe y-phosphate from ATP to specific protein substrates, and cAMP-dependent protein kinase (cAPK) serves as a structural template for the entire protein kinase family. Correct physiological function for any protein kinase requires: ( 1 ) catalytic specificity; (2) precise regulation; and (3) correct subcellular localization. Endogenous inhibition of cAPK is typically achieved by two classes of inhibitor proteins, the small heat staWe" protein kinase inhibitors (PKI's) and the regulatory (R) subunits. These inhibitor proteins share many common features: ( 1 ) they are peptide mimetics; (2) they are heat stable; (3) in their unbound state they show significant regions of disorder; (4) they are modular proteins; and (5) in addition to inhibition of C, they contribute directly to subcellular localization. PKI, in addition to its inhibitor site, harbors a nuclear export signal (NES) capable of actively exporting the C:PKI complex out of the nucleus. The R subunits. in addition to an inhibitor site followed by two tandem cAMP binding domains, have at their N-terminus a structurally distinct domain that not only maintains the protein as a ditner but also serves as a docking site for anchoring cAPK to various subcellular loci. This helical D/D domain is very stable and represents a unique structural motif. We have recently identified dual specific A Kinase Anchoring Proteins that bind to both ihc type I and II R subunits of PKA. D-AKAP1 binds to the outer mitochondrial membrane via a 30 residue targeting motif at its N-terminus, while D-AKAP2 has RGS domain. (Supported by grants from the NIH).
|Original language||English (US)|
|State||Published - 1998|
ASJC Scopus subject areas
- Molecular Biology