C2 结构域在蛋白激酶 C 信号转导中的作用。

The role of C2 domains in PKC signaling.

机构信息

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, BT 105, 3801 University Street, Montreal, QC H3A 2B4, Canada.

出版信息

Adv Exp Med Biol. 2012;740:663-83. doi: 10.1007/978-94-007-2888-2_29.

DOI:10.1007/978-94-007-2888-2_29

PMID:22453964

Abstract

More than two decades ago, the discovery of the first C2 domain in conventional Protein Kinase Cs (cPKCs) and of its role as a calcium-binding motif began to shed light on the activation mechanism of this family of Serine/Threonine kinases which are involved in several critical signal transduction pathways. In this chapter, we review the current knowledge of the structure and the function of the different C2 domains in PKCs. The C2 domain of cPKCs is a calcium sensor and its calcium-dependent binding to phospholipids is crucial for kinase activation. While the functional role of the cPKC C2 domain is better understood, phylogenetic analysis revealed that the novel C2 domain is more ancient and related to the C2 domain in the fungal PKC family, while the cPKC C2 domain is first associated with PKC in metazoans. The C2 domain of novel PKCs (nPKCs) does not contain a calcium-binding motif but still plays a critical role in nPKCs activation by regulating C1-C2 domain interactions and consequently C2 domain-mediated inhibition in both the nPKCs of the epsilon family and the nPKCs of the delta family. Moreover, the C2 domain of the nPKCs of the delta family was shown to recognize phosphotyrosines in a novel mode different from the ones observed for the Src Homology 2 (SH2) and the phosphotyrosine binding domains (PTB). By binding to phosphotyrosines, the C2 domain regulates the activation of this subclass of PKCs. The C2 domain was also shown to be involved in protein-protein interactions and binding to the receptor for activated C-kinase (RACKs) thus contributing to the subcellular localization of PKCs. In summary, the C2 domain is a critical player that can sense the activated signaling pathway in response to external stimuli to specifically regulate the different conventional and novel PKC isoforms.

摘要

二十多年前，人们首次在传统蛋白激酶 C（cPKC）中发现了 C2 结构域，并发现其作为钙结合基序，这为人们深入研究丝氨酸/苏氨酸激酶家族的激活机制提供了重要线索，该家族激酶参与了许多重要的信号转导途径。在本章中，我们将回顾目前关于 PKC 不同 C2 结构域的结构和功能的相关知识。cPKC 的 C2 结构域是一个钙传感器，其钙依赖性与磷脂结合对于激酶的激活至关重要。尽管 cPKC C2 结构域的功能作用已经得到较好的理解，但系统发育分析表明，新型 C2 结构域更为古老，与真菌 PKC 家族的 C2 结构域相关，而 cPKC C2 结构域最初与后生动物中的 PKC 相关联。新型 PKC（nPKC）的 C2 结构域不含钙结合基序，但仍通过调节 C1-C2 结构域相互作用以及随后调节 nPKC 家族 epsilon 和 delta 亚家族的 C2 结构域介导抑制作用，在 nPKC 的激活中发挥关键作用。此外，还发现新型 PKC 家族 delta 亚家族的 C2 结构域以一种不同于Src Homology 2（SH2）和磷酸酪氨酸结合结构域（PTB）的新型模式识别磷酸酪氨酸。通过与磷酸酪氨酸结合，C2 结构域调节了这一类 PKC 的激活。C2 结构域还参与了蛋白-蛋白相互作用以及与激活的 C 激酶受体（RACK）的结合，从而有助于 PKC 的亚细胞定位。综上所述，C2 结构域是一个关键的调节因子，可以感知外部刺激激活的信号通路，以特异性地调节不同的传统和新型 PKC 同工型。