Structural basis of the interactions between tyrosine kinase c-Src and the Hepatitis C virus proteins NS5A and NS5B, and their influence on liver damage and regeneration (A11)

在感染丙型肝炎病毒的细胞中，对调节细胞生长和分化很重要的酪氨酸激酶c-Src被丙型肝炎病毒蛋白NS5A和-B招募到病毒复制机制中。NS5A固有的无序性和酪氨酸磷酸化似乎是NS5A/B/c-Src复合体形成的关键。我们的结果表明，NS5A与c-Src存在典型的SH2-和SH3-以及非典型的SH3-结合，但没有NS5B/c-Src的直接相互作用。我们现在的重点是在纳米盘中建立复杂的重构及其结构分析。特定的复合体形成抑制物将有助于理解NS5A和-B如何影响正常的c-Src功能。

In HCV infected cells tyrosine kinase c-Src, which is important for regulation of cell growth and differentiation, is recruited into the viral replication machinery by the HCV proteins NS5A and -B. The intrinsically disordered character and tyrosine-phosphorylation of NS5A seems to be crucial for NS5A/B/ c-Src complex formation. Our results demonstrate canonical SH2- and SH3- as well as non-canonical SH3-binding of NS5A with c-Src, but no direct NS5B/ c-Src interaction. Our focus now lies on the establishment of complex reconstitution in nanodiscs and its structural analysis. Specific inhibitors of complex formation will help to understand how NS5A and -B influence normal c-Src functions.