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Abl N-terminal cap stabilization of SH3 domain dynamics.

机译：SH3域动力学的ABL N末端帽稳定。

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摘要

Crystal structures and other biochemical data indicate that the N-terminal cap (NCap) region of the Abelson tyrosine kinase (c-Abl) is important for maintaining the downregulated conformation of the kinase domain. The exact contributions that the NCap makes in stabilizing the various intramolecular interactions within c-Abl are less clear. While the NCap appears to be important for locking the SH3 and SH2 domains to the back of the kinase domain, there may be other more subtle elements of regulation. Hydrogen exchange (HX) and mass spectrometry (MS) were used to determine if the NCap contributes to intramolecular interactions involving the Abl SH3 domain. Under physiological conditions, the Abl SH3 domain underwent partial unfolding and its unfolding half-life was slowed during binding to the SH2 kinase linker, providing a unique assay for testing NCap-induced stabilization of the SH3 domain in various constructs. The results showed that the NCap stabilizes the dynamics of the SH3 domain in certain constructs but does not increase the relative affinity of the SH3 domain for the native SH2 kinase linker. The stabilization effect was absent in constructs of just the NCap and SH3 but was obvious when the SH2 domain and the SH2 kinase linker were present. These results suggest that interactions between the NCap and the SH3 domain can contribute to c-Abl stabilization in constructs that contain at least the SH2 domain, an effect that may partially compensate for the absence of the negative regulatory C-terminal tail found in the related Src family of kinases.
机译：晶体结构和其他生物化学数据表明Abelson酪氨酸激酶（C-ABL）的n末端帽（NCAP）区域对于保持激酶结​​构域的下调构象是重要的。 NCAP在C-ABL内稳定各种分子内相互作用的确切贡献较小。虽然NCAP对于将SH3和SH2结构域锁定到激酶结构域的后部，但可能存在其他更微妙的调节元件。氢交换（HX）和质谱（MS）用于确定NCAP是否有助于涉及ABL SH3结构域的分子内相互作用。在生理条件下，在与SH2激酶接头结合期间，在与SH2激酶接头的结合期间，逐渐变慢偏离部分展开的ABL SH3结构域并在各种构建体中检测NCAP诱导的SH3结构域的稳定化的独特测定。结果表明，NCAP在某些构建体中稳定了SH3结构域的动态，但不会增加天然SH2激酶接头的SH3结构域的相对亲和力。仅在NCAP和SH3的构建体中不存在稳定效果，但是当存在SH2结构域和SH2激酶接头时显而易见。这些结果表明，NCAP和SH3结构域之间的相互作用可以有助于含有至少SH2结构域的构建体中的C-ABL稳定化，该效果可以部分地补偿存在于相关的阴性调节C末端尾部的缺失SRC系列的激酶。

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