The pseudokinase TRIB1 toggles an intramolecular switch to regulate COP1 nuclear export.,The EMBO Journal

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The pseudokinase TRIB1 toggles an intramolecular switch to regulate COP1 nuclear export.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-01-28 , DOI: 10.15252/embj.201899708
Jennifer E Kung ₁ , Natalia Jura _{2,

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Affiliation

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.

中文翻译：

假激酶 TRIB1 通过切换分子内开关来调节 COP1 核输出。

COP1 是一种高度保守的泛素连接酶，可调节植物和后生动物的多种细胞过程。 Tribbles 假激酶仅存在于后生动物中，充当与 COP1 及其底物相互作用的支架，以促进泛素化。在这里，我们报告说，除了这种支架作用之外，TRIB1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来促进COP1的核定位。这个位点，我们称之为假底物闩锁（PSL），类似于已知 COP1 底物中存在的共有 COP1 结合基序。我们的研究结果支持一个模型，其中 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 取代了这种分子内相互作用以诱导 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 功能中的重要性。

更新日期：2019-02-15

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