TRIB1 假激酶通过切换分子内开关来调节 COP1 核输出。
The pseudokinase TRIB1 toggles an intramolecular switch to regulate COP1 nuclear export.
机构信息
Cardiovascular Research Institute, University of California-San Francisco, San Francisco, CA, USA.
Cardiovascular Research Institute, University of California-San Francisco, San Francisco, CA, USA
出版信息
EMBO J. 2019 Feb 15;38(4). doi: 10.15252/embj.201899708. Epub 2019 Jan 28.
COP1 is a highly conserved ubiquitin ligase that regulates diverse cellular processes in plants and metazoans. Tribbles pseudokinases, which only exist in metazoans, act as scaffolds that interact with COP1 and its substrates to facilitate ubiquitination. Here, we report that, in addition to this scaffolding role, TRIB1 promotes nuclear localization of COP1 by disrupting an intramolecular interaction between the WD40 domain and a previously uncharacterized regulatory site within COP1. This site, which we have termed the pseudosubstrate latch (PSL), resembles the consensus COP1-binding motif present in known COP1 substrates. Our findings support a model in which binding of the PSL to the WD40 domain stabilizes a conformation of COP1 that is conducive to CRM1-mediated nuclear export, and TRIB1 displaces this intramolecular interaction to induce nuclear retention of COP1. Coevolution of Tribbles and the PSL in metazoans further underscores the importance of this role of Tribbles in regulating COP1 function.
COP1 是一种高度保守的泛素连接酶，它在植物和后生动物中调节多种细胞过程。仅存在于后生动物中的 Tribbles 假激酶作为支架，与 COP1 及其底物相互作用，促进泛素化。在这里，我们报告说，TRIB1 除了这种支架作用外，还通过破坏 WD40 结构域和 COP1 内先前未表征的调节位点之间的分子内相互作用，促进 COP1 的核定位。我们将这个位点称为假底物锁（PSL），它类似于已知 COP1 底物中存在的 COP1 结合基序的共识。我们的研究结果支持这样一种模型，即 PSL 与 WD40 结构域的结合稳定了 COP1 的构象，有利于 CRM1 介导的核输出，而 TRIB1 取代这种分子内相互作用，从而诱导 COP1 的核保留。Tribbles 和 PSL 在后生动物中的共同进化进一步强调了 Tribbles 在调节 COP1 功能方面的重要性。
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