法国欧洲分子生物学实验室Matthew W. Bowler，Erika Pellegrini和瑞士日内瓦大学Francesco Luigi Gervasio共同合作，近期取得重要工作进展。他们研究发现，MKK6-p38α复合物的结构决定了MAPK的特异性和激活基础。相关研究成果2023年9月15日在线发表于《科学》杂志上

据介绍，有丝分裂原激活蛋白激酶（MAPK，一种特异于丝氨酸和苏氨酸的蛋白激酶，参与调节细胞的多种功能）。p38α是炎症和免疫反应信号传导的核心成分，因此是重要的药物靶点。由于捕获瞬时和动态异激酶复合物存在挑战，人们对MAPK激酶（MAP2K）双磷酸化激活其的分子机制还知之甚少。

研究人员采用多学科方法生成p38α与MAP2K、MKK6组成复合物的结构模型，来了解其激活机制。并将冷冻电镜与分子动力学模拟、氢-氘交换质谱和细胞实验相结合。研究人员发现了动态、多步骤的磷酸化机制，识别了催化相关的相互作用，并表明MAP2K无序氨基末端决定了通路特异性。

总之，这一工作捕捉到了细胞信号传导的基本步骤：一种磷酸化下游靶激酶的激酶。

附：英文全文

Title: Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Author: Pauline Juyoux, Ioannis Galdadas, Dorothea Gobbo, Jill von Velsen, Martin Pelosse, Mark Tully, Oscar Vadas, Francesco Luigi Gervasio, Erika Pellegrini, Matthew W. Bowler

Issue&Volume: 2023-09-15

Abstract: The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double phosphorylation from MAPK kinases (MAP2Ks), because of the challenge of trapping a transient and dynamic heterokinase complex. We applied a multidisciplinary approach to generate a structural model of p38α in complex with its MAP2K, MKK6, and to understand the activation mechanism. Integrating cryo–electron microscopy with molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and experiments in cells, we demonstrate a dynamic, multistep phosphorylation mechanism, identify catalytically relevant interactions, and show that MAP2K-disordered amino termini determine pathway specificity. Our work captures a fundamental step of cell signaling: a kinase phosphorylating its downstream target kinase.

DOI: add7859

Source: https://www.science.org/doi/10.1126/science.add7859