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Structural Basis of Neuronal Nitric-Oxide Synthase Interaction with Dystrophin Repeats 16 and 17

Abstract : Duchenne muscular dystrophy is a lethal genetic defect that is associated with the absence of dystrophin protein. Lack of dystrophin protein completely abolishes muscular nitric oxide synthase (NOS) function as a regulator of blood flow during muscle contraction. In normal muscles, nNOS function is ensured by its localization at the sarcolemma through an interaction of its PDZ domain with dystrophin spectrin-like repeats R16 and R17. Early studies suggested that repeat R17 is the primary site of interaction but ignored the involved nNOS residues, and the R17 binding site has not been described at an atomic level. In this study, we characterized the specific amino acids involved in the binding site of nNOS-PDZ with dystrophin R16-17 using combined experimental biochemical and structural in silico approaches. First, 32 alanine-scan mutagenesis variants of dystrophin R16-17 indicated the regions where mutagenesis modified the affinity of the dystrophin interaction with the nNOS-PDZ. Second, using small angle X-ray scattering-based models of dystrophin R16-17 and molecular docking methods, we generated atomic models of the dystrophin R16-17: nNOS-PDZ complex that correlated well with the alanine-scanning-identified regions of dystrophin. The structural regions constituting the dystrophin interaction surface involve the A/B loop and the N-terminal end of helix B of repeat R16 and the N-terminal end of helix A' and a small fraction of helix B' and a large part of the helix C' of repeat R17. The interaction surface of nNOS-PDZ involves its main β-sheet and its specific C-terminal β-finger.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01214011
Contributor : Laurent Jonchère <>
Submitted on : Friday, October 9, 2015 - 3:44:43 PM
Last modification on : Monday, March 2, 2020 - 10:24:41 AM

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Anne-Elisabeth Molza, Khushdeep Mangat, Elisabeth Le Rumeur, Jean-François Hubert, Nick Menhart, et al.. Structural Basis of Neuronal Nitric-Oxide Synthase Interaction with Dystrophin Repeats 16 and 17. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2015, 290 (49), pp.29531-29541. ⟨10.1074/jbc.M115.680660⟩. ⟨hal-01214011⟩

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