Molecular clues about the dystrophin-neuronal nitric oxide synthase interaction: a theoretical approach.
Dystrophin is a large skeletal muscle protein located at the internal face of the plasma membrane and interacting with membrane phospholipids and a number of cytosolic proteins. Binding of neuronal nitric oxide synthase (nNOS) to dystrophin appears to be crucial for exercise-induced increases in blood supply in muscle cells. By contrast, utrophin, the developmental homologous protein of dystrophin, does not display nNOS interaction. Recent in vitro and in vivo experiments showed that the dystrophin region involved in nNOS binding is located in spectrin-like repeats R16 and R17 of its filamentous central domain. Using homology modeling and atomistic molecular dynamics simulation, we compared the structural organization and surface potentials of dystrophin, utrophin, and chimeric fragments, thus revisiting the dystrophin-nNOS binding region. Our simulation results are in good agreement with experimental data. They provide a three-dimensional representation of the repeats and give insight into the molecular organization of the regions involved in dystrophin-nNOS interaction. This study also further elucidates the physical properties crucial for this interaction, particularly the presence of a large hydrophobic patch. These results will be helpful to improving our understanding of the phenotypic features of patients bearing mutations in the nNOS-binding region of dystrophin.
Université de Rennes1 , 35700 Rennes, France.
Emmanuel
E
Giudice
Anne-Elisabeth
AE
Molza
Yoann
Y
Laurin
Aurélie
A
Nicolas
Elisabeth
E
Le Rumeur
Olivier
O
Delalande
D020816:Amino Acid Motifs; D016189:Dystrophin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D052248:Nitric Oxide Synthase Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary
D016189:Dystrophin; D052248:Nitric Oxide Synthase Type I