PROSITE documentation PDOC00425

Guanylate cyclase domain signature and profile

Guanylate cyclases (EC 4.6.1.2) [1,2,3,4] 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, α and β are proteins of from 70 to 82 Kd which are highly related. Two forms of β subunits are currently known: β-1 which seems to be expressed in lung and brain, and β-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) [5,6] from mammals, slime mold or Drosophila. We have derived a consensus pattern from the most conserved region in that domain. We also developed a profile which covers the domain.