Eyers Patrick A, Keeshan Karen, Kannan Natarajan
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK.
Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 0YN, UK.
Trends Cell Biol. 2017 Apr;27(4):284-298. doi: 10.1016/j.tcb.2016.11.002. Epub 2016 Nov 28.
The Tribbles (TRIB) pseudokinases control multiple aspects of eukaryotic cell biology and evolved unique features distinguishing them from all other protein kinases. The atypical pseudokinase domain retains a regulated binding platform for substrates, which are ubiquitinated by context-specific E3 ligases. This plastic configuration has also been exploited as a scaffold to support the modulation of canonical MAPK and AKT modules. In this review, we discuss the evolution of TRIBs and their roles in vertebrate cell biology. TRIB2 is the most ancestral member of the family, whereas the emergence of TRIB3 homologs in mammals supports additional biological roles, many of which are currently being dissected. Given their pleiotropic role in diseases, the unusual TRIB pseudokinase conformation provides a highly attractive opportunity for drug design.
Tribbles（TRIB）伪激酶控制真核细胞生物学的多个方面，并进化出了使其有别于所有其他蛋白激酶的独特特征。非典型伪激酶结构域保留了一个用于底物的受调控结合平台，这些底物会被特定环境下的E3连接酶泛素化。这种可塑性结构也被用作支架来支持对经典丝裂原活化蛋白激酶（MAPK）和蛋白激酶B（AKT）模块的调控。在这篇综述中，我们讨论了TRIBs的进化及其在脊椎动物细胞生物学中的作用。TRIB2是该家族中最原始的成员，而哺乳动物中TRIB3同源物的出现支持了更多的生物学功能，其中许多功能目前正在研究中。鉴于它们在疾病中的多效性作用，不同寻常的TRIB伪激酶构象为药物设计提供了极具吸引力的机会。
