Max F. Perutz Laboratories, Medical University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria.
Department of Biology, Indiana University, Bloomington, IN 47405, USA.
J Mol Biol. 2018 Oct 19;430(21):4209-4229. doi: 10.1016/j.jmb.2018.08.017. Epub 2018 Aug 24.
Lysine methyltransferases (KMTs) were initially associated with transcriptional control through their methylation of histones and other nuclear proteins, but have since been found to regulate many other cellular activities. The apical complex lysine (K) methyltransferase (AKMT) of the human parasite Toxoplasma gondii was recently shown to play a critical role in regulating cellular motility. Here we report a 2.1-Å resolution crystal structure of the conserved and functional C-terminal portion (aa289-709) of T. gondii AKMT. AKMT dimerizes via a unique intermolecular interface mediated by the C-terminal tetratricopeptide repeat-like domain together with a specific zinc-binding motif that is absent from all other KMTs. Disruption of AKMT dimerization impaired both its enzyme activity and parasite egress from infected host cells in vivo. Structural comparisons reveal that AKMT is related to the KMTs in the SMYD family, with, however, a number of distinct structural features in addition to the unusual dimerization interface. These features are conserved among the apicomplexan parasites and their free-living relatives, but not found in any known KMTs in animals. AKMT therefore is the founding member of a new subclass of KMT that has important implications for the evolution of the apicomplexans.
赖氨酸甲基转移酶（KMTs）最初通过组蛋白和其他核蛋白的甲基化与转录调控有关，但后来发现它们还调节许多其他细胞活动。最近，人类寄生虫弓形虫的顶端复合物赖氨酸（K）甲基转移酶（AKMT）被证明在调节细胞运动中起着关键作用。在这里，我们报告了弓形虫 AKMT 的保守和功能 C 端部分（aa289-709）的 2.1 Å分辨率晶体结构。AKMT 通过独特的分子间界面二聚化，该界面由 C 端四肽重复样结构域与特定的锌结合基序介导，而所有其他 KMT 都没有该基序。AKMT 二聚化的破坏既损害了其酶活性，又损害了寄生虫在体内从受感染的宿主细胞中逸出。结构比较表明，AKMT 与 SMYD 家族的 KMT 有关，但除了不寻常的二聚化界面外，还有许多独特的结构特征。这些特征在顶复门寄生虫及其自由生活的近亲中是保守的，但在任何已知的动物 KMT 中都没有发现。因此，AKMT 是一个新的 KMT 亚类的创始成员，这对顶复门的进化具有重要意义。
