Allosteric Communication of the Dimerization and the Catalytic Domain in Photoreceptor Guanylate Cyclase.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Chemical Society.
    • Subject Terms:
    • Abstract:
      Phototransduction in vertebrate photoreceptor cells is controlled by Ca 2+ -dependent feedback loops involving the membrane-bound guanylate cyclase GC-E that synthesizes the second messenger guanosine-3',5'-cyclic monophosphate. Intracellular Ca 2+ -sensor proteins named guanylate cyclase-activating proteins (GCAPs) regulate the activity of GC-E by switching from a Ca 2+ -bound inhibiting state to a Ca 2+ -free/Mg 2+ -bound activating state. The gene GUCY2D encodes for human GC-E, and mutations in GUCY2D are often associated with an imbalance of Ca 2+ and cGMP homeostasis causing retinal disorders. Here, we investigate the Ca 2+ -dependent inhibition of the constitutively active GC-E mutant V902L. The inhibition is not mediated by GCAP variants but by Ca 2+ replacing Mg 2+ in the catalytic center. Distant from the cyclase catalytic domain is an α-helical domain containing a highly conserved helix-turn-helix motif. Mutating the critical amino acid position 804 from leucine to proline left the principal activation mechanism intact but resulted in a lower level of catalytic efficiency. Our experimental analysis of amino acid positions in two distant GC-E domains implied an allosteric communication pathway connecting the α-helical and the cyclase catalytic domains. A computational connectivity analysis unveiled critical differences between wildtype GC-E and the mutant V902L in the allosteric network of critical amino acid positions.
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    • Accession Number:
      EC 4.6.1.2 (Guanylate Cyclase)
      SY7Q814VUP (Calcium)
      0 (Guanylate Cyclase-Activating Proteins)
      I38ZP9992A (Magnesium)
      0 (Receptors, Cell Surface)
    • Publication Date:
      Date Created: 20240823 Date Completed: 20240903 Latest Revision: 20241015
    • Publication Date:
      20241016
    • Accession Number:
      PMC11375764
    • Accession Number:
      10.1021/acs.biochem.4c00170
    • Accession Number:
      39175413