The pseudokinase TRIB 1 toggles an intramolecular switch to regulate COP 1 nuclear export

Abstract

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. ![][1] COP1 is a highly conserved E3 ubiquitin ligase that shuttles between the nucleus and cytoplasm. In plants, COP1 localization is controlled by light, while in metazoans, the pseudokinase TRIB1 promotes COP1 nuclear localization by competing with an intramolecular site that regulates CRM1‐mediated nuclear export of COP1. The EMBO Journal (2019) e99708 [1]: /embed/graphic-1.gif