The glycine residue of ATP regulatory module in receptor guanylate cyclases that is essential in natriuretic factor signaling

Abstract

Atrial natriuretic factor (ANF) and C-type natriuretic peptide (CNP)-activated guanylate cyclases are single-chain transmembrane-spanning proteins, containing both ligand binding and catalytic activities. In both proteins, ligand binding to the extracellular receptor domain activates the cytosolic catalytic domain, generating the second messenger cyclic GMP. Obligatory in this activation process is an ATP-dependent step. ATP directly binds to a defined ATP-regulatory module (ARM) sequence motif in the cyclases and through ARM bridges the events of ligand binding and signal transduction. These ARM sequence motifs are respectively represented by Gly 503-Xa-Gly 505-Xa-Xa-Xa-Gly 509 and Gly 499-Xa-Xa-Xa-Gly 503 in the case of ANF receptor guanylate cyclase (ANF-RGC) and CNP receptor guanylate cyclase (CNP-RGC). Through genetic remodeling techniques, we now show that ARM-Gly 505 in ANF-RGC and the corresponding ARM-Gly 499 in CNP-RGC are critical for ANF and CNP signaling, and other ARM-Gly residues have minimal effect in the respective signaling processes.