cGMP-dependent protein kinase

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protein kinase, cGMP-dependent, type I
CGMP-dependent.png
Crystallographic structure of the leucine zipper domain of human cGMP dependent protein kinase I beta.[1]
Identifiers
SymbolPRKG1
Alt. symbolsPRKGR1B, PRKG1B
NCBI gene5592
HGNC9414
OMIM176894
RefSeqNM_006258
UniProtQ13976
Other data
LocusChr. 10 q11.2
protein kinase, cGMP-dependent, type II
Identifiers
SymbolPRKG2
NCBI gene5593
HGNC9416
OMIM601591
RefSeqNM_006259
UniProtQ13237
Other data
LocusChr. 4 q13.1-21.1

cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle relaxation, platelet function, sperm metabolism, cell division, and nucleic acid synthesis.

Genes and proteins[edit]

PKG are serine/threonine kinases that are present in a variety of eukaryotes ranging from the unicellular organism Paramecium to humans. Two PKG genes, coding for PKG type I (PKG-I) and type II (PKG-II), have been identified in mammals. The N-terminus of PKG-I is encoded by two alternatively spliced exons that specify for the PKG-Iα and PKG-Iβ isoforms. PKG-Iβ is activated at ~10-fold higher cGMP concentrations than PKG-Iα. The PKG-I and PKG-II are homodimers of two identical subunits (~75 kDa and ~85 kDa, respectively) and share common structural features.

Each subunit is composed of three functional domains:

  • (1) an N-terminal domain that mediates homodimerization, suppression of the kinase activity in the absence of cGMP, and interactions with other proteins including protein substrates
  • (2) a regulatory domain that contains two non-identical cGMP-binding sites
  • (3) a kinase domain that catalyzes the phosphate transfer from ATP to the hydroxyl group of a serine/threonine side chain of the target protein

Binding of cGMP to the regulatory domain induces a conformational change which stops the inhibition of the catalytic core by the N-terminus and allows the phosphorylation of substrate proteins. Whereas PKG-I is predominantly localized in the cytoplasm, PKG-II is anchored to the plasma membrane by N-terminal myristoylation.

Tissue distribution[edit]

In general, PKG-I and PKG-II are expressed in different cell types.

Specifically, in smooth muscle tissue, PKG promotes the opening of calcium-activated potassium channels, leading to cell hyperpolarization and relaxation, and blocks agonist activity of phospholipase C, reducing liberation of stored calcium ions by inositol triphosphate.

Role in cancer[edit]

Cancerous colon cells stop producing PKG, which apparently limits beta-catenin thus allowing the VEGF enzyme to solicit angiogenesis.[2]

Behavioral genetics in Drosophila melanogaster[edit]

In Drosophila melanogaster the foraging (for) gene is a polymorphic trait that underlies differences in food-seeking behaviors. The for locus is made up of Rover (forR) and Sitter (forS) alleles, with the Rover allele being dominant. Rover individuals typically travel greater distances when foraging for food, while Sitter individuals travel less distance to forage for food. Both Rover and Sitter phenotypes are considered wild-type, as fruit fly populations typically exhibit a 70:30 Rover-to-Sitter ratio.[3] The Rover and Sitter alleles are located within the 24A3-5 region of the Drosophila melanogaster polytene chromosome, a region which contains the PKG d2g gene. PKG expression levels account for differences in forR and forS allele frequency and therefore behavior as Rover individuals show higher PKG expression than Sitter individuals, and the Sitter phenotype can be converted to Rover by over-expression of the dg2 gene.[4]

See also[edit]

References[edit]

  1. ^ PDB: 3NMD​; Casteel DE, Smith-Nguyen EV, Sankaran B, Roh SH, Pilz RB, Kim C (October 2010). "A crystal structure of the cyclic GMP-dependent protein kinase I{beta} dimerization/docking domain reveals molecular details of isoform-specific anchoring". The Journal of Biological Chemistry. 285 (43): 32684–8. doi:10.1074/jbc.C110.161430. PMC 2963381. PMID 20826808.
  2. ^ Kwon IK, Schoenlein PV, Delk J, Liu K, Thangaraju M, Dulin NO, et al. (April 2008). "Expression of cyclic guanosine monophosphate-dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis". Cancer. 112 (7): 1462–70. doi:10.1002/cncr.23334. PMID 18260092. S2CID 4763327.
  3. ^ Sokolowski MB (November 2001). "Drosophila: genetics meets behaviour". Nature Reviews. Genetics. 2 (11): 879–90. doi:10.1038/35098592. PMID 11715043. S2CID 13152094.
  4. ^ Osborne KA, Robichon A, Burgess E, Butland S, Shaw RA, Coulthard A, et al. (August 1997). "Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila". Science. 277 (5327): 834–6. doi:10.1126/science.277.5327.834. PMID 9242616.

External links[edit]