Molecular Clues about the Dystrophin鈥揘euronal Nitric Oxide Synthase Interaction: A Theoretical Approach

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• 作者：Emmanuel Giudice ; Anne-Elisabeth Molza ; Yoann Laurin ; Aur茅lie Nicolas ; Elisabeth Le Rumeur ; Olivier Delalande
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：November 5, 2013
• 年：2013
• 卷：52
• 期：44
• 页码：7777-7784
• 全文大小：733K
• 年卷期：v.52,no.44(November 5, 2013)
• ISSN：1520-4995

文摘

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鈥搉NOS 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鈥搉NOS 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.