Allosteric regulatory step and configuration of the ATP-binding pocket in atrial natriuretic factor receptor guanylate cyclase transduction mechanism

The atrial natriuretic factor (ANF) signal transduction mechanism consists of the transformation of the signal information into the production of cycl ic GMP. The binding of ANF to its receptor, which is also a guanylate cycla se, generates the signal. This cyclase has been termed atrial natriuretic f actor receptor guanylate cyclase, ANF-RGC. ANF-RGC is a single transmembran e-spanning protein. The ANF receptor domain resides in the extracellular re gion of the protein, and the catalytic domain is located in the intracellul ar region at the C-terminus of the protein. Thus, the signal is relayed pro gressively from the receptor domain to the catalytic domain, where it is co nverted into the formation of cyclic GMP. The first transduction step is th e direct binding of ATP with ANF-RGC. This causes allosteric regulation of the enzyme and primes it for the activation of its catalytic moiety. The pa rtial structural motif of the ATP binding domain in ANF-RGC has been elucid ated, and it has been named ATP regulatory module (ARM). In this presentati on, we provide a brief review of the ATP-regulated transduction mechanism a nd the ARM model. The model depicts a configuration of the ATP-binding pock et that has been experimentally validated, and the model shows that the ATP -dependent transduction process is a two- (or more) step event. The first s tep involves the binding of ATP with its ARM. This partially activates the cyclase and prepares it for the subsequent steps, which are consistent with its being phosphorylated and attaining the fully activated state.