Three dimensional atomic model and experimental validation for the ATP-regulated module (ARM) of the atrial natriuretic factor receptor guanylate cyclase |
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Authors: | Duda Teresa Yadav Prem Jankowska Anna Venkataraman Venkateswar Sharma Rameshwar K. |
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Affiliation: | (1) The Unit of Regulatory and Molecular Biology, Departments of Cell Biology, Ophthalmology, and Academic Computing Center, NJMS & SOM, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA;(2) Department of Radiobiology and Cell Biology, University of Medical Sciences, Swiecickiego, Poznan, Poland;(3) The Unit of Regulatory and Molecular Biology, Departments of Cell Biology, Ophthalmology, and Academic Computing Center, NJMS & SOM, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA |
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Abstract: | Atrial natriuretic factor (ANF) receptor guanylate cyclase (ANF-RGC) is a single chain transmembrane-spanning protein, containing both ANF binding and catalytic activities. ANF binding to the extracellular receptor domain activates the cytosolic catalytic domain, generating the second messenger cyclic GMP. Obligatory in this activation process is an intervening transduction step, which is regulated by the binding of ATP to the cyclase. The partial structural motif of the ATP binding domain of the cyclase has been elucidated and has been termed ATP Regulatory Module (ARM). The crystal structures of the tyrosine kinase domains of the human insulin receptor and haematopoietic cell kinase were used to derive a homology-based model of the ARM domain of ANF-RGC. The model identifies the precise configuration of the ATP-binding pocket in the ARM domain, accurately represents its ATP-dependent features, and shows that the ATP-dependent transduction phenomenon is a two-step mechanism. In the first step, ATP binds to its pocket and changes its configuration; in the second step, via an unknown protein kinase, it phosphorylates the cyclase for its full activation. |
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Keywords: | ANF-RGC ATP ARM allosteric regulation phosphorylation three-dimensional model |
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