Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK.
Curr Opin Struct Biol. 2009 Dec;19(6):643-9. doi: 10.1016/j.sbi.2009.10.001. Epub 2009 Nov 18.
The Src homology 2 (SH2) domain is a sequence-specific phosphotyrosine-binding module present in many signaling molecules. In cytoplasmic tyrosine kinases, the SH2 domain is located N-terminally to the catalytic kinase domain (SH1) where it mediates cellular localization, substrate recruitment, and regulation of kinase activity. Initially, structural studies established a role of the SH2 domain stabilizing the inactive state of Src family members. However, biochemical characterization showed that the presence of the SH2 domain is frequently required for catalytic activity, suggesting a crucial function stabilizing the active state of many nonreceptor tyrosine kinases. Recently, the structure of the SH2-kinase domain of Fes revealed that the SH2 domain stabilizes the active kinase conformation by direct interactions with the regulatory helix alphaC. Stabilizing interactions between the SH2 and the kinase domains have also been observed in the structures of active Csk and Abl. Interestingly, mutations in the SH2 domain found in human disease can be explained by SH2 domain destabilization or incorrect positioning of the SH2. Here we summarize our understanding of mechanisms that lead to tyrosine kinase activation by direct interactions mediated by the SH2 domain and discuss how mutations in the SH2 domain trigger kinase inactivation.
Src 同源结构域 2（SH2）是一种存在于许多信号分子中的序列特异性磷酸酪氨酸结合模块。在细胞质酪氨酸激酶中，SH2 结构域位于催化激酶结构域（SH1）的 N 端，它介导细胞定位、底物募集和激酶活性的调节。最初，结构研究确立了 SH2 结构域稳定 Src 家族成员无活性状态的作用。然而，生化特征表明，SH2 结构域的存在通常是催化活性所必需的，这表明它对于稳定许多非受体酪氨酸激酶的活性状态具有至关重要的功能。最近，Fes 的 SH2-激酶结构域的结构揭示了 SH2 结构域通过与调节螺旋 alphaC 的直接相互作用稳定激酶的活性构象。在活性 Csk 和 Abl 的结构中也观察到了 SH2 和激酶结构域之间的稳定相互作用。有趣的是，在人类疾病中发现的 SH2 结构域中的突变可以通过 SH2 结构域的不稳定或 SH2 的不正确定位来解释。在这里，我们总结了我们对通过 SH2 结构域介导的直接相互作用导致酪氨酸激酶激活的机制的理解，并讨论了 SH2 结构域中的突变如何引发激酶失活。
