Structural anatomy of Protein Kinase C C1 domain interactions with diacylglycerol and other agonists.
Structural anatomy of Protein Kinase C C1 domain interactions with diacylglycerol and other agonists.
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DOI：
10.1038/s41467-022-30389-2
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发表时间：
2022-05-16
影响因子：
16.6
通讯作者：
Igumenova, Tatyana I.
中科院分区：
文献类型：
--
作者：
Katti, Sachin S.;Krieger, Inna, V;Ann, Jihyae;Lee, Jeewoo;Sacchettini, James C.;Igumenova, Tatyana I.
二酰基甘油（DAG）是一种多功能脂质，其1,2-sn立体异构体在控制重要细胞过程的信号转导途径中充当第二信使，并作为下游信号脂质（如磷脂酸）的代谢前体。效应蛋白通过使用保守的同源1 （C1）结构域作为DAG传感模块，转运到膜中可用的DAG池中。然而，自蛋白激酶C （PKC）作为DAG效应体的第一个成员被发现以来的40年里，C1结构域如何在生物膜的复杂环境中识别和捕获DAG一直没有得到解决。在此，我们报告了C1结构域（来自PKCδ的C1B）与DAG和四种强效PKC激动剂复合物的高分辨率晶体结构，这些激动剂产生不同的生物学读数并具有强烈的治疗兴趣。这些结构信息详细介绍了C1结构域对DAG立体特异性识别的机制，脂质结合位点的功能特性，以及识别和捕获DAG和外源性激动剂所需的关键残基的身份。此外，五个C1结构域复合物的结构为设计调节DAG效应蛋白活性的药物提供了高分辨率的指导。蛋白激酶Cs （PKCs）在调节细胞生长、分化、凋亡和运动的细胞内磷酸肌苷信号通路中定义了一个中心的dag感知节点。PKC C1结构域配合物与DAG和4激动剂的结构揭示了配体识别和捕获的分子基础。
Diacylglycerol (DAG) is a versatile lipid whose 1,2-sn-stereoisomer serves both as second messenger in signal transduction pathways that control vital cellular processes, and as metabolic precursor for downstream signaling lipids such as phosphatidic acid. Effector proteins translocate to available DAG pools in the membranes by using conserved homology 1 (C1) domains as DAG-sensing modules. Yet, how C1 domains recognize and capture DAG in the complex environment of a biological membrane has remained unresolved for the 40 years since the discovery of Protein Kinase C (PKC) as the first member of the DAG effector cohort. Herein, we report the high-resolution crystal structures of a C1 domain (C1B from PKCδ) complexed to DAG and to each of four potent PKC agonists that produce different biological readouts and that command intense therapeutic interest. This structural information details the mechanisms of stereospecific recognition of DAG by the C1 domains, the functional properties of the lipid-binding site, and the identities of the key residues required for the recognition and capture of DAG and exogenous agonists. Moreover, the structures of the five C1 domain complexes provide the high-resolution guides for the design of agents that modulate the activities of DAG effector proteins. Protein kinase Cs (PKCs) define a central DAG-sensing node in intracellular phosphoinositide signaling pathways that regulate cell growth, differentiation, apoptosis, and motility. The structures of PKC C1 domain complexes with DAG and 4 agonists reveal the molecular basis of ligand recognition and capture.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
13.8
作者：
Hanke, C. William;Albrecht, Lorne;Spelman, Lynda
通讯作者：
Spelman, Lynda
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
--
作者：
Antal, Corina E.;Violin, Jonathan D.;Newton, Alexandra C.
通讯作者：
Newton, Alexandra C.
影响因子：
2
作者：
Hatzakis, Emmanuel;Agiomyrgianaki, Alexia;Dais, Photis
通讯作者：
Dais, Photis