SINGLE AMINO-ACID RESIDUE-LINKED SIGNALING SHIFTS IN THE TRANSDUCTION ACTIVITIES OF ATRIAL AND TYPE-C NATRIURETIC FACTOR-RECEPTOR GUANYLATE CYCLASES

The type A (ANF) and the type C (CNP) natriuretic factor activated guanylate cyclases, respectively termed as ANF-RGC and CNP-RGC, are single-chain transmembrane-spanning proteins, containing ligand binding and catalytic cyclase domains at two opposite ends of the protein. The binding activity resides at the N-terminal extracellular region and the catalytic cyclase activity at the carboxyl end. The ANF-RGC residue Leu-364, residing in the extracellular region, is critical for the ANF-binding activity; the CNP-RGC residue Glu-332 is critical for the CNP-binding activity. The counter part of CNP-RGC-Glu-332 residue is the ANF-RGC residue Gln-338 and of ANF-RGC-Leu-364 residue in CNP-RGC is the Valine-358. The present study shows a remarkable signal switching phenomenon associated with these residues. By changing the ANF-RGC residue Gln-338 to Glu, ANF-RGC switches from no to significant CNP signal transduction activity; similarly, a change from Valine-358 to Leu generates ANF signal transduction activity in CNP-RGC. These acquired signal transduction activities in the cyclases are in addition to their natural signal transduction activities. Thus, these new cyclases show both ANF and CNP signaling activities. (C) 1995 Academic Press, Inc.