Delineating a new class of membrane-bound guanylate cyclases

Membrane-bound guanylate cyclases (GCs)possessing intrinsic GC activity constitute a family of catalytically active membrane-associated proteins that play crucial roles in a myriad of signal transduction processes. Currently known membrane-bound GCs are catalytically monofunctional with a domain architecture that consists of an extracellular ligand-binding domain and an intracellular portion that is composed of an inactive kinase homology domain and a functional GC catalytic center. A novel class of GC-linked receptor kinases was unearthed using homology-guided bioinformatic data mining tools designed from annotated amino acid residues in the GC catalytic centers of lower eukaryotes. The GC catalytic center in this new class of membrane-bound GCs is encapsulated within an active kinase domain, thereby conferring a dual catalytic function to this class of proteins. This is contrary to currently known classical membrane-bound GCs, which are monofunctional. There are currently four members of this novel class of membrane-bound GCs which have been demonstrated to possess intrinsic GC and kinase activity. Although there is a paucity of information as to how the dual catalysis in bifunctional membrane-bound GCs is physiologically regulated, their mechanism of action maybe markedly distinct from that of classical membrane bound GCs.