美国布兰代斯大学Dorothee Kern课题组揭示了丝氨酸-苏氨酸激酶变构激活的历史起源。这一研究成果于2020年2月21日发表在国际学术期刊《科学》上。

研究人员使用祖先序列重建的方法重现两个共定位蛋白Aurora A激酶及其变构激活剂TPX2（Xklp2的靶向蛋白）的祖先序列，以此来描绘变构激活的进化历程。激活环的自磷酸化是最古老的激活机制。它在最古老的激酶中已得到充分的发展，并且在十亿年的进化中一直保持稳定。随着微管相关蛋白TPX2的出现，有效激酶与TPX2的结合得以发展，这可能是由于共定位提高了适应性。随后，TPX2介导的变构激酶调节逐渐得以发展。 意外的是，这种调节进化是由激酶编码的，而不是由共同进化主导的。

据介绍，很多细胞事件受变构作用的调节。因此，探究这一过程的发展具有根本意义。

附：英文原文

Title: Ancient origins of allosteric activation in a Ser-Thr kinase

Author: Adelajda Hadzipasic, Christopher Wilson, Vy Nguyen, Nadja Kern, Chansik Kim, Warintra Pitsawong, Janice Villali, Yuejiao Zheng, Dorothee Kern

Issue&Volume: 2020/02/21

Abstract: AbstractA myriad of cellular events are regulated by allostery; therefore, evolution of this process is of fundamental interest. Here, we use ancestral sequence reconstruction to resurrect ancestors of two colocalizing proteins, Aurora A kinase and its allosteric activator TPX2 (targeting protein for Xklp2), to experimentally characterize the evolutionary path of allosteric activation. Autophosphorylation of the activation loop is the most ancient activation mechanism; it is fully developed in the oldest kinase ancestor and has remained stable over 1 billion years of evolution. As the microtubule-associated protein TPX2 appeared, efficient kinase binding to TPX2 evolved, likely owing to increased fitness by virtue of colocalization. Subsequently, TPX2-mediated allosteric kinase regulation gradually evolved. Surprisingly, evolution of this regulation is encoded in the kinase and did not arise by a dominating mechanism of coevolution.

DOI: 10.1126/science.aay9959

Source: https://science.sciencemag.org/content/367/6480/912