Tandem SH2 binding sites mediate the RasGAP-RhoGAP interaction: A conformational mechanism for SH3 domain regulation
Tandem SH2 binding sites mediate the RasGAP-RhoGAP interaction: A conformational mechanism for SH3 domain regulation
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DOI：
10.1093/emboj/16.3.473
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发表时间：
1997-02-03
期刊：
影响因子：
11.4
通讯作者：
Settleman, J
中科院分区：
文献类型：
--
作者：
Hu, KQ;Settleman, J
许多细胞信号蛋白含有 SH3（Src 同源 3）结构域，可通过特定的含脯氨酸肽介导蛋白质相互作用。 SH2 结构域与含酪氨酸肽的相互作用是通过 SH2 结合位点的磷酸化促进的，而 SH3 相互作用的调节机制尚不清楚。p120 RasGAP（GTP 酶激活蛋白）包含一个 SH3 结构域，两侧有两个 SH2 结构域，在表达活化酪氨酸激酶的细胞中与 p190 RhoGAP 形成丰富的 SH2 介导的复合物。我们在 p190 中鉴定出两个紧密相连的含酪氨酸肽，它们在 p190 磷酸化后同时与 RasGAP SH2 结构域结合。这种相互作用预计将使两个 SH2 结构域更加接近。因此，RasGAP 经历构象变化，导致其 SH3 结构域的靶结合表面的可及性增加 100 倍。这些结果表明，在多种细胞信号蛋白中发现的 SH2 和 SH3 结构域的串联排列可以提供通过酪氨酸磷酸化调节 SH3 依赖性相互作用的构象机制。此外，p190 在 RasGAP 信号复合物中的作用似乎是通过通过促进与 RasGAP 的额外蛋白质相互作用。它的SH3域。
Many cellular signaling proteins contain SH3 (Src homology 3) domains that mediate protein interactions via specific proline-containing peptides. Unlike SH2 domains, whose interactions with tyrosine-containing peptides are promoted by phosphorylation of the SH2 binding site, the regulatory mechanism for SH3 interactions is unclear p120 RasGAP (GTPase-activating protein), which contains an SH3 domain flanked by two SH2 domains, forms an abundant SH2-mediated complex with p190 RhoGAP in cells expressing activated tyrosine kinases. We have identified two closely linked tyrosine-containing peptides in p190 that bind simultaneously to the RasGAP SH2 domains upon p190 phosphorylation. This interaction is expected to bring the two SH2 domains into close proximity. Consequently, RasGAP undergoes a conformational change that results in a 100-fold increase in the accessibility of the target binding surface of its SH3 domain, These results indicate that the tandem arrangement of SH2 and SH3 domains found in a variety of cellular signaling proteins can provide a conformational mechanism for regulating SH3-dependent interactions through tyrosine phosphorylation, In addition, it appears that the role of p190 in the RasGAP signaling complex is to promote additional protein interactions with RasGAP via its SH3 domain.