title: Atrial natriuretic factor receptor guanylate cyclase signaling: new ATP-regulated transduction motif.
abstract: ANF-RGC membrane guanylate cyclase is the receptor for the hypotensive peptide hormones, atrial natriuretic factor (ANF) and type B natriuretic peptide (BNP). It is a single transmembrane spanning protein. Binding the hormone to the extracellular domain activates its intracellular catalytic domain. This results in accelerated production of cyclic GMP, a second messenger in controlling blood pressure, cardiac vasculature, and fluid secretion. ATP is the obligatory transducer of the ANF signal. It works through its ATP regulated module, ARM, which is juxtaposed to the C-terminal side of the transmembrane domain. Upon interaction, ATP induces a cascade of temporal and spatial changes in the ARM, which, finally, result in activation of the catalytic module. Although the exact nature and the details of these changes are not known, some of these have been stereographed in the simulated three-dimensional model of the ARM and validated biochemically. Through comprehensive techniques of steady state, time-resolved tryptophan fluorescence and Forster Resonance Energy Transfer (FRET), site-directed and deletion-mutagenesis, and reconstitution, the present study validates and explains the mechanism of the model-based predicted transduction role of the ARM's structural motif, (669)WTAPELL(675). This motif is critical in the ATP-dependent ANF signaling. Molecular modeling shows that ATP binding exposes the (669)WTAPELL(675) motif, the exposure, in turn, facilitates its interaction and activation of the catalytic module. These principles of the model have been experimentally validated. This knowledge brings us a step closer to our understanding of the mechanism by which the ATP-dependent spatial changes within the ARM cause ANF signaling of ANF-RGC.
authors.affiliation: Unit of Regulatory & Molecular Biology, Division 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: Shashank
authors.initials: S
authors.lastname: Bharill
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Wojtas
authors.forename: Prem
authors.initials: P
authors.lastname: Yadav
authors.forename: Ignacy
authors.initials: I
authors.lastname: Gryczynski
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Gryczynski
authors.forename: Rameshwar K
authors.initials: RK
authors.lastname: Sharma
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000502:physiology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D031541:Fluorescence Resonance Energy Transfer; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D045265:Natriuretic Peptides / Q000378:metabolism; D011487:Protein Conformation; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D045265:Natriuretic Peptides; D000255:Adenosine Triphosphate; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor