title: ATP allosteric activation of atrial natriuretic factor receptor guanylate cyclase.
abstract: Atrial natriuretic factor receptor guanylate cyclase (ANF-RGC) is the receptor and the signal transducer of two natriuretic peptide hormones: atrial natriuretic factor and brain natriuretic peptide. It is a single transmembrane-spanning protein. It binds these hormones at its extracellular domain and activates its intracellular catalytic domain. This results in the accelerated production of cyclic GMP, a second messenger in controlling blood pressure, cardiac vasculature and fluid secretion. ATP is obligatory for the transduction of this hormonal signal. Two models of ATP action have been proposed. In Model 1, it is a direct allosteric transducer. It binds to the defined regulatory domain (ATP-regulated module) juxtaposed to the C-terminal side of the transmembrane domain of ANF-RGC, induces a cascade of temporal and spatial changes and activates the catalytic module residing at the C-terminus of the cyclase. In Model 2, before ATP can exhibit its allosteric effect, ANF-RGC must first be phosphorylated by an as yet unidentified protein kinase. This initial step is obligatory in atrial natriuretic factor signaling of ANF-RGC. Until now, none of these models has been directly validated because it has not been possible to segregate the allosteric and the phosphorylation effects of ATP in ANF-RGC activation. The present study accomplishes this aim through a novel probe, staurosporine. This unequivocally validates Model 1 and settles the over two-decade long debate on the role of ATP in ANF-RGC signaling. In addition, the present study demonstrates that the mechanisms of allosteric modification of ANF-RGC by staurosporine and adenylyl-imidodiphosphate, a nonhydrolyzable analog of ATP, are almost (or totally) identical.
authors.affiliation: Research Divisions of Biochemistry and Molecular Biology, Salus University, Elkins Park, PA 19027, USA. tduda@salus.edu
authors.forename: Teresa
authors.initials: T
authors.lastname: Duda
authors.forename: Prem
authors.initials: P
authors.lastname: Yadav
authors.forename: Rameshwar K
authors.initials: RK
authors.lastname: Sharma
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001665:Binding Sites; D004789:Enzyme Activation; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D000255:Adenosine Triphosphate; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A