Abstract
Cyclic GMP is produced by enzymes called guanylyl cyclases, of which the membrane-associated forms contain an intracellular pseudokinase domain that allosterically regulates the C-terminal guanylyl cyclase domain. Ligand binding to the extracellular domain of these single transmembrane-spanning domain receptors elicits an increase in cGMP levels in the cell. The pseudokinase domain (or kinase-homology domain) in these receptors appears to be critical for ligand-mediated activation. While the pseudokinase domain does not possess kinase activity, biochemical evidence indicates that the domain can bind ATP and thereby allosterically regulate the catalytic activity of these receptors. The pseudokinase domain also appears to be the site of interaction of regulatory proteins, as seen in the retinal guanylyl cyclases that are involved in visual signal transduction. In the absence of structural information on the pseudokinase-guanylyl cyclase domain organization of any member of this family of receptors, biochemical evidence has provided clues to the physical interaction of the pseudokinase and guanylyl cyclase domain. An α-helical linker region between the pseudokinase domain and the guanylyl cyclase domain regulates the basal activity of these receptors in the absence of a stimulatory ligand and is important for stabilizing the structure of the pseudokinase domain that can bind ATP. Here, we present an overview of salient features of ATP-mediated regulation of receptor guanylyl cyclases and describe biochemical approaches that allow a clearer understanding of the intricate interplay between the pseudokinase domain and catalytic domain in these proteins.