德国奥斯纳布吕克大学Jacob Piehler、英国约克大学Ian S. Hitchcock和芬兰赫尔辛基大学Ilpo Vattulainen研究组合作揭示致癌突变导致同型二聚体细胞因子受体激活和失调的机制。相关论文发表在2020年2月7日出版的《科学》杂志上。

他们通过单分子荧光显微镜定量了活细胞质膜中三个原型I类细胞因子受体的二聚化。各个受体亚基的时空相关性显示配体诱导的二聚化，并揭示相关的Janus激酶2（JAK2）通过其假激酶结构域二聚化。致癌受体和过度活跃的JAK2突变体促进了不依赖配体的二聚化，突出了受体二聚体的形成，并作为负责信号激活的开关。基于对二聚化相关的相互作用进行精细的能量分析的原子建模和分子动力学模拟，为同源二聚体I类细胞因子受体激活及其单个突变失调提供了机制蓝图。

据了解，假定同源二聚体I类细胞因子受体以预先形成的二聚体形式存在，并被配体诱导的构象变化激活。

附：英文原文

Title: Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

Author: Stephan Wilmes, Maximillian Hafer, Joni Vuorio, Julie A. Tucker, Hauke Winkelmann, Sara Lchte, Tess A. Stanly, Katiuska D. Pulgar Prieto, Chetan Poojari, Vivek Sharma, Christian P. Richter, Rainer Kurre, Stevan R. Hubbard, K. Christopher Garcia, Ignacio Moraga, Ilpo Vattulainen, Ian S. Hitchcock, Jacob Piehler

Issue&Volume: 2020/02/07

Abstract: Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.

DOI: 10.1126/science.aaw3242

Source: https://science.sciencemag.org/content/367/6478/643