Regulation of the Src-family kinase Lck by posttranslational modifications and TCR/Lck interactions (B19)

酪氨酸激酶Lck磷酸化T细胞受体(TCR)的基于酪氨酸的免疫受体信号基序(ITAM)，因此对T细胞的激活至关重要。LCK酶活性受翻译后修饰和LCK构象动力学的调节。第二个资助期的结果和Schamel小组(Freiburg)的数据支持TCR启动的新模型，在该模型中，配体诱导的TCR开放诱导Lck从头激活，从而促进ITAM的磷酸化。利用新的生化、显微镜、细胞和小鼠模型，B19将评估TCR和Lck如何合作启动信号以及新的翻译后修饰如何调节Lck的活性。

The tyrosine kinase Lck phosphorylates the immunoreceptor tyrosine based signaling motifs (ITAMS) of the T cell receptor (TCR) and, hence, is crucial for T cell activation. Lck enzymatic activity is regulated by post-translational modifications and Lck conformational dynamics. Results of the 2nd funding period and data from the Schamel group (Freiburg) support a new model for the initiation of TCR triggering in which ligand-induced "TCR-opening" induces de novo activation of Lck, thereby facilitating ITAM phosphorylation. Using novel biochemical, microscopy, cellular and mouse models B19 will assess the mechanistic aspects of how the TCR and Lck cooperate for signal initiation and how new post-translational modifications regulate Lck’s activity.