Three dimensional atomic model and experimental validation for the ATP-regulated module (ARM) of the atrial natriuretic factor receptor guanylate cyclase

Atrial natriuretic factor (ANF) receptor guanylate cyclase (ANF-RGC) is a s ingle chain transmembrane-spanning protein, containing both ANF binding and catalytic activities. ANF binding to the extracellular receptor domain act ivates the cytosolic catalytic domain, generating the second messenger cycl ic GMP. Obligatory in this activation process is an intervening transductio n step, which is regulated by the binding of ATP to the cyclase. The partia l structural motif of the ATP binding domain of the cyclase has been elucid ated and has been termed ATP Regulatory Module (ARM). The crystal structure s of the tyrosine kinase domains of the human insulin receptor and haematop oietic cell kinase were used to derive a homology-based model of the ARM do main of ANF-RGC. The model identifies the precise configuration of the ATP- binding pocket in the ARM domain, accurately represents its ATP-dependent f eatures, and shows that the ATP-dependent transduction phenomenon is a two- step mechanism. In the first step, ATP binds to its pocket and changes its configuration; in the second step, via an unknown protein kinase, it phosph orylates the cyclase for its full activation.