Durzynska Izabela, Xu Xiang, Adelmant Guillaume, Ficarro Scott B, Marto Jarrod A, Sliz Piotrek, Uljon Sacha, Blacklow Stephen C
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Structure. 2017 Feb 7;25(2):287-294. doi: 10.1016/j.str.2016.12.008. Epub 2017 Jan 12.
Serine/threonine kinase 40 (STK40) was originally identified as a distant homolog of Tribbles-family proteins. Despite accumulating data attesting to the importance of STK40 in a variety of different physiologic processes, little is known about its biological activity or mechanism of action. Here, we show that STK40 interacts with Constitutive Photomorphogenic Protein 1 (COP1), relying primarily on a C-terminal sequence analogous to the motif found in Tribbles proteins. In order to further elucidate structure-function relationships in STK40, we determined the crystal structure of the STK40 kinase homology domain at 2.5 Å resolution. The structure, together with ATP-binding assay results, show that STK40 is a pseudokinase, in which substitutions of conserved residues within the kinase domain prevent ATP binding. Although the structure of the kinase homology domain diverges from the analogous region of Trib1, the results reported here suggest functional parallels between STK40 and Tribbles-family proteins as COP1 adaptors.
丝氨酸/苏氨酸激酶40（STK40）最初被鉴定为Tribbles家族蛋白的远亲同源物。尽管越来越多的数据证明STK40在各种不同生理过程中具有重要性，但其生物学活性或作用机制仍知之甚少。在此，我们表明STK40与组成型光形态建成蛋白1（COP1）相互作用，主要依赖于类似于Tribbles蛋白中发现的基序的C末端序列。为了进一步阐明STK40中的结构-功能关系，我们以2.5埃的分辨率确定了STK40激酶同源结构域的晶体结构。该结构与ATP结合试验结果表明，STK40是一种假激酶，其中激酶结构域内保守残基的取代阻止了ATP结合。尽管激酶同源结构域的结构与Trib1的类似区域不同，但本文报道的结果表明STK40与作为COP1衔接蛋白的Tribbles家族蛋白之间存在功能相似性。
