Molecular aspects of sGC activation and stimulator function

Mammalian sGC is a heterodimer composed of α- and β-subunits. The C-terminus of each subunit contains a catalytic domain and the active site is composed of residues from both subunits. The catalytic domains also form a pseudosymmetric site that contains residues known to be involved in nucleotide binding, but lack the complete complement of amino acids required for catalysis. Sequence analysis shows that each subunit also contains well-defined PAS-like domain, and a predicted coiled-coil region. The N-termini of the α- and β-subunits are homologous to the H-NOX ( Heme- Nitric oxide/ OXygen) family of proteins. The N-terminus of β-subunit contains a ferrous heme cofactor that serves a receptor for NO. Additional studies point toward a more complicated role for NO and stimulators in the regulation of activity. Structural and biochemical results have broadened the current molecular view of the regulation of sGC and provide a framework to understand the action of sGC modulators of activity. Activity and structural studies involved with regulation will be discussed. NO also functions as a signaling molecule in Choanoflagellates. Choanoflagellates are a group of free-living unicellular and eukaryotes considered to be the closest living relatives of the animals. The evolutionary history of NO signaling is proving to be informative on function.