Gold Matthew G, Barford David, Komander David
Section of Structural Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Curr Opin Struct Biol. 2006 Dec;16(6):693-701. doi: 10.1016/j.sbi.2006.10.006. Epub 2006 Nov 2.
The regulation of the activity of kinases and phosphatases is an essential aspect of intracellular signal transduction. Recently determined structures of AGC protein kinases, including isoforms of PKB, PKC, GRK and ROCK, indicate that occupancy of a hydrophobic pocket in the kinase N-lobe by a segment of the protein immediately C terminal to the kinase domain provides a mechanism for regulating kinase activity. In addition, crystal structures of Aurora-A and Aurora-B, which are closely related to AGC family kinases, in complex with their activators, TPX2 and INCENP, respectively, show how allosteric kinase activation is achieved by the binding of the activator protein to an equivalent hydrophobic pocket. Hence, regulation of kinase activity by analogous interactions is a shared regulatory mechanism of these kinases. Two crystal structures have explained the molecular basis of PKA anchoring through its regulatory subunits by members of the AKAP family of scaffold proteins. AKAPs can also interact directly with protein kinase and phosphatase catalytic domains. The crystal structure of the PP1 catalytic subunit in complex with the targeting subunit MYPT1 indicates that there is also scope for intimate phosphatase regulation by scaffold proteins.
激酶和磷酸酶活性的调节是细胞内信号转导的一个重要方面。最近确定的AGC蛋白激酶的结构，包括蛋白激酶B（PKB）、蛋白激酶C（PKC）、G蛋白偶联受体激酶（GRK）和Rho相关卷曲螺旋形成蛋白激酶（ROCK）的亚型，表明激酶结构域紧邻的C末端的一段蛋白占据激酶N叶中的一个疏水口袋，为调节激酶活性提供了一种机制。此外，与AGC家族激酶密切相关的Aurora-A和Aurora-B分别与它们的激活剂TPX2和着丝粒蛋白（INCENP）形成复合物的晶体结构，展示了激活剂蛋白与等效疏水口袋结合是如何实现变构激酶激活的。因此，通过类似相互作用调节激酶活性是这些激酶共有的调节机制。两个晶体结构解释了支架蛋白AKAP家族成员通过其调节亚基对蛋白激酶A（PKA）进行锚定的分子基础。AKAPs还可以直接与蛋白激酶和磷酸酶催化结构域相互作用。蛋白磷酸酶1（PP1）催化亚基与靶向亚基肌球蛋白磷酸酶靶向亚基1（MYPT1）形成复合物的晶体结构表明，支架蛋白也有对磷酸酶进行精细调节的空间。
