Quaternary Structure Controls Ligand Dynamics in Soluble Guanylate Cyclase

Abstract : Soluble guanylate cyclase (sGC) is the mammalian endogenous nitric oxide (NO) receptor. The mechanisms of activation and deactivation of this heterodimeric enzyme are unknown. For deciphering them, functional domains can be overexpressed. We have probed the dynamics of the diatomic ligands NO and CO within the isolated heme domain β1(190) of human sGC by piconanosecond absorption spectroscopy. After photo-excitation of nitrosylated sGC, only NO geminate rebinding occurs in 7.5 ps. In β1(190), both photo-dissociation of 5c-NO and photo-oxidation occur, contrary to sGC, followed by NO rebinding (7 ps) and back-reduction (230 ps and 2 ns). In full-length sGC, CO geminate rebinding to the heme does not occur. In contrast, CO geminately rebinds to β1(190) with fast multiphasic process (35, 171, and 18 ns). We measured the bimolecular association rates kon = 0.075 ± 0.01 × 106 M−1*s−1 for sGC and 0.83 ± 0.1 × 106 M−1*s−1 for β1(190). These different dynamics reflect conformational changes and less proximal constraints in the isolated heme domain with respect to the dimeric native sGC. We concluded that the α-subunit and the β1(191-619) domain exert structural strains on the heme domain. These strains are likely involved in the transmission of the energy and relaxation toward the activated state after Fe2+-His bond breaking. This also reveals the heme domain plasticity modulated by the associated domains and subunit.
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Byung-Kuk Yoo, Isabelle Lamarre, Jean-Louis Martin, Michel Negrerie. Quaternary Structure Controls Ligand Dynamics in Soluble Guanylate Cyclase. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2012, 287, pp.6851-6859. ⟨10.1074/jbc.M111.299297⟩. ⟨hal-00018765⟩



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