ATP MODULATION OF THE LIGAND-BINDING AND SIGNAL-TRANSDUCTION ACTIVITIES OF THE TYPE-C NATRIURETIC PEPTIDE RECEPTOR GUANYLATE-CYCLASE

The type C natriuretic peptide (CNP)-activated guanylate cyclase (CNP- RGC) is a single-chain transmembrane-spanning protein, containing both CNP binding and catalytic cyclase activities. Upon binding CNP to the extracellular receptor domain, the cytosolic catalytic domain of CNP- RGC is activated, generating the second messenger cyclic GMP. Obligato ry in this activation process is an intervening signal transduction st ep which is regulated by ATP binding to the cyclase. This bridges the events of ligand binding and cyclase activation. A defined sequence mo tif (Gly(499)-Xa-Xa-Xa-Gly(503)), termed ATP regulatory module (ARM), is critical for this step. The present study shows that ATP not only a mplifies the signal transduction step, it also concomitantly reduces t he ligand binding activity of CNP-RGC. Reduction in the ligand binding activity is a consequence of the transformation of the high affinity receptor-form to the low affinity receptor-form. A single ARM residue Gly(499) is critical in the mediation of both ATP effects, signal tran sduction and ligand binding activity of the receptor. Thus, this resid ue represents an ATP bimodal switch to turn the CNP signal on and off.