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
Symbol PRKG1
Alt. symbols PRKGR1B, PRKG1B
Entrez 5592
HUGO 9414
OMIM 176894
RefSeq NM_006258
UniProt Q13976
Other data
Locus Chr. 10 q11.2
protein kinase, cGMP-dependent, type II
Identifiers
Symbol PRKG2
Entrez 5593
HUGO 9416
OMIM 601591
RefSeq NM_006259
UniProt Q13237
Other data
Locus Chr. 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]

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". J. Biol. Chem. 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, Ganapathy V, Berger FG, Browning DD (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. 

External links[edit]