title: Allosteric modification, the primary ATP activation mechanism of atrial natriuretic factor receptor guanylate cyclase.
abstract: ANF-RGC is the prototype receptor membrane guanylate cyclase being both the receptor and the signal transducer of the most hypotensive hormones, ANF and BNP. It is a single transmembrane-spanning protein. After binding these hormones at the extracellular domain it at its intracellular domain signals activation of the C-terminal catalytic module and accelerates the production of its second messenger, cyclic GMP, which controls blood pressure, cardiac vasculature, and fluid secretion. ATP is obligatory for the posttransmembrane dynamic events leading to ANF-RGC activation. It functions through the ATP-regulated module, ARM (KHD) domain, of ANF-RGC. In the current over a decade held model "phosphorylation of the KHD is absolutely required for hormone-dependent activation of NPR-A" [Potter, L. R., and Hunter, T. (1998) Mol. Cell. Biol. 18, 2164-2172]. The presented study challenges this concept. It demonstrates that, instead, ATP allosteric modification of ARM is the primary signaling step of ANF-GC activation. In this two-step new dynamic model, ATP in the first step binds ARM. This triggers in it a chain of transduction events, which cause its allosteric modification. The modification partially activates (about 50%) ANF-RGC and, concomitantly, also prepares the ARM for the second successive step. In this second step, ARM is phosphorylated and ANF-RGC achieves additional (∼50%) full catalytic activation. The study defines a new paradigm of the ANF-RGC signaling mechanism.
authors.affiliation: Research Division of Biochemistry, The Unit of Regulatory and Molecular Biology, Salus University, 8360 Old York Road, Elkins Park, Pennsylvania 19027, United States. 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 / Q000378:metabolism / Q000494:pharmacology*; D000494:Allosteric Regulation / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002384:Catalysis; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017461:Receptors, Atrial Natriuretic Factor / Q000737:chemistry / Q000378:metabolism*; D054928:Validation Studies as Topic
chemical_list: D050505:Mutant Proteins; D000255:Adenosine Triphosphate; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor