ExplorEnz: EC 2.7.11.11

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2.7.11.11

Accepted name:

cAMP-dependent protein kinase

Reaction:

ATP + a [protein]-(L-serine/L-threonine) = ADP + a [protein]-(L-serine/L-threonine) phosphate

Glossary:

3′,5′-cyclic-AMP = cAMP

Other name(s):

PKA; protein kinase A; PKA catalytic (C) subunit; A kinase; ATP:protein phosphotransferase (cAMP-dependent)

Systematic name:

ATP:protein Ser^/Thr-phosphotransferase (3′,5′-cAMP-dependent)

Comments:

This eukaryotic enzyme recognizes the sequence -Arg-Arg-X-Ser*/Thr*-Hpo, where * indicates the phosphorylated residue and Hpo indicates a hydrophobic residue.The inactive holoenzyme is a heterotetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. Each R subunit occludes the active site of a C subunit and contains two binding sites for 3′,5′-cyclic-AMP (cAMP). Binding of cAMP activates the enzyme by causing conformational changes that release two free monomeric C subunits from a dimer of the R subunits, i.e. R2C2 + 4 cAMP = R2(cAMP)4 + 2 C. Activity requires phosphorylation of a conserved Thr in the activation loop (T-loop) sequence (Thr¹⁹⁸ in human Cα; Thr²²⁴ in budding yeast Tpk2), installed by auto-phosphorylation or by the 3-phosphoinositide-dependent protein kinase-1 (PDPK1). Certain R2C2 combinations can be localized to particular subcellular regions by their association with diverse species of 'A Kinase-Anchoring Proteins' (AKAPs). The enzyme has been characterized from many organisms. Humans have three C units (Cα, Cβ, and Cγ) encoded by the paralogous genes PRKACA, PRKACB and PRKACG, respectively, and four R subunits (R1α, RIβ, RIIα and RIIβ), encoded by PKRAR1A, PKRAR1B, PKRAR2A and PKRAR2B, respectively. Yeast (Saccharomyces cerevisiae) has three C subunits (Tpk1, Tpk2, and Tpk3) encoded by the paralogous genes TPK1, TPK2 and TPK3, respectively, and a single R subunit (Bcy1) encoded by the BCY1 gene. Some validated substrates of the enzyme include cAMP-response element-binding protein (CREB), phosphorylase kinase α subunit (PHKA), and tyrosine 3-monooxygenase (TH) in mammals; Adr1, Whi3, Nej1, and Pyk1 in yeast.

Links to other databases:

BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 142008-29-5

References:

1.	Krebs, E.G. The Albert Lasker Medical Awards. Role of the cyclic AMP-dependent protein kinase in signal transduction. JAMA 262 (1989) 1815–1818. [DOI] [PMID: 2550680]
2.	Technikova-Dobrova, Z., Sardanelli, A.M., Speranza, F., Scacco, S., Signorile, A., Lorusso, V. and Papa, S. Cyclic adenosine monophosphate-dependent phosphorylation of mammalian mitochondrial proteins: enzyme and substrate characterization and functional role. Biochemistry 40 (2001) 13941–13947. [DOI] [PMID: 11705384]
3.	Smith, F.D., Samelson, B.K. and Scott, J.D. Discovery of cellular substrates for protein kinase A using a peptide array screening protocol. Biochem. J. 438 (2011) 103–110. [DOI] [PMID: 21644927]
4.	Broach, J.R. Nutritional control of growth and development in yeast. Genetics 192 (2012) 73–105. [DOI] [PMID: 22964838]
5.	Embogama, D.M. and Pflum, M.K. K-BILDS: a kinase substrate discovery tool. Chembiochem 18 (2017) 136–141. [DOI] [PMID: 27860220]
6.	Taylor, S.S., Wu, J., Bruystens, J.GH., Del Rio, J.C., Lu, T.W., Kornev, A.P. and Ten Eyck, L.F. From structure to the dynamic regulation of a molecular switch: A journey over 3 decades. J. Biol. Chem. 296:100746 (2021). [DOI] [PMID: 33957122]
7.	Ramms, D.J., Raimondi, F., Arang, N., Herberg, F.W., Taylor, S.S. and Gutkind, J.S. Gαs-protein kinase A (PKA) pathway signalopathies: the emerging genetic landscape and therapeutic potential of human diseases driven by aberrant Gαs-PKA signaling. Pharmacol Rev 73 (2021) 155–197. [DOI] [PMID: 34663687]

[EC 2.7.11.11 created 2005 (EC 2.7.1.37 part-incorporated 2005), modified 2022]