Pathways & interactions
Adenylyl cyclase class-4/guanylyl cyclase, conserved site (IPR018297)
Short name: A/G_cyclase_CS
Guanylate cyclases (EC:18.104.22.168) [PMID: 1680765, PMID: 1982420, PMID: 1356629, PMID: 1349465] catalyze the formation of cyclic GMP (cGMP) from GTP. cGMP acts as an intracellular messenger, activating cGMP-dependent kinases and regulating CGMP-sensitive ion channels. The role of cGMP as a second messenger in vascular smooth muscle relaxation and retinal photo-transduction is well established. Guanylate cyclase is found both in the soluble and particular fraction of eukaryotic cells. The soluble and plasma membrane-bound forms differ in structure, regulation and other properties.
Most currently known plasma membrane-bound forms are receptors for small polypeptides. The topology of such proteins is the following: they have a N-terminal extracellular domain which acts as the ligand binding region, then a transmembrane domain, followed by a large cytoplasmic C-terminal region that can be subdivided into two domains: a protein kinase-like domain that appears important for proper signalling and a cyclase catalytic domain. This topology is schematically represented below.
+-----------------------xxxxx----------------------+------------+ | Ligand-binding XXXXX Protein Kinase like | Cyclase | +-----------------------xxxxx----------------------+------------+ Extracellular Transmembrane Cytoplasmic
The known guanylate cyclase receptors are:
- The sea-urchins receptors for speract and resact, which are small peptides that stimulate sperm motility and metabolism.
- The receptors for natriuretic peptides (ANF). Two forms of ANF receptors with guanylate cyclase activity are currently known: GC-A (or ANP-A) which seems specific to atrial natriuretic peptide (ANP), and GC-B (or ANP-B) which seems to be stimulated more effectively by brain natriuretic peptide (BNP) than by ANP.
- The receptor for Escherichia coli heat-stable enterotoxin (GC-C). The endogenous ligand for this intestinal receptor seems to be a small peptide called guanylin.
- Retinal guanylate cyclase (retGC) which probably plays a specific functional role in the rods and/or cones of photoreceptors. It is not known if this protein acts as receptor, but its structure is similar to that of the other plasma membrane-bound GCs.
The soluble forms of guanylate cyclase are cytoplasmic heterodimers. The two subunits, alpha and beta are proteins of from 70 to 82 Kd which are highly related. Two forms of beta subunits are currently known: beta-1 which seems to be expressed in lung and brain, and beta-2 which is more abundant in kidney and liver.
The membrane and cytoplasmic forms of guanylate cyclase share a conserved domain which is probably important for the catalytic activity of the enzyme. Such a domain is also found twice in the different forms of membrane-bound adenylate cyclases (also known as class-III) [PMID: 8330684, PMID: 7863008] from mammals, slime mold or Drosophila.
- PS00452 (GUANYLATE_CYCLASE_1)