On Aug 3rd, Prof. YAO Xuebiao's group published a paper on PNAS titled “Dynamic localization of kinase to kinetochores is essential for accurate spindle microtubule attachment”, in which they provide new understandings on the effect of Mps1 kinase activity in the spatiotemporal organization of kinetochore during mitosis. Cell is the basic unit of life activities, and cell division is the key to realize the self-replicating life activities. Precise mitosis is vital to individual development and multiplying of living organisms. During mitosis, the duplicated genome must be evenly distributed to two daughter cells, in this process the appropriate kinetochore -microtubule (MT) adhesion is required, and defect in this kinetochore -MT adhesion will lead to the inaccurate separation, which will finally lead to aneuploidy - a hallmark of cancer.
Before this study, Prof. YAO's group revealed the molecular dynamics of Kinase Mps1 during cell cycle by immunoelectronic microscope (Dou et al., 2003. Cell Research), and clarified the regulation mechanism of Mps1-Aurora B-Ndc80 signaling axis (Zhu et al., 2013. J. Biol. Chem.). In this study, they indicated that Kinase Mps1 includes an internal region for kinetochore localization (IRK) adjacent to the tetratricopeptide repeat domain. Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment. Importantly, the IRK region determines the kinetochore localization of inactive Mps1, and an accumulation of inactive Mps1 perturbs accurate chromosome alignment and mitotic progression. Mechanistically, the IRK region binds to the nuclear division cycle 80 complex (Ndc80C), and accumulation of inactive Mps1 at the kinetochores prevents a dynamic interaction between Ndc80C and spindle microtubules (MTs), resulting in an aberrant kinetochore attachment.
Figure: A model illustrating dynamic localization of Mps1 at the kinetochore before and after its activation. Image by Prof. YAO’s group.Thus, the results present a previously undefined mechanism by which Mps1 functions in chromosome alignment by orchestrating Ndc80C–MT interactions and highlight the importance of the precise spatiotemporal regulation of Mps1 kinase activity and kinetochore localization in accurate mitotic progression.At present, Prof. YAO's team is dissecting the physical foundation underlying the molecular conformation dynamics of Mps1 and unimolecular mechanisms in Mps1 regulation of spatiotemporal dynamics within different chromosomes or cell fate decision.The co-first authors are DOU Zhen (Associate Professor) and LIU Xing (Postdoctoral researcher) from Hefei National Laboratory for Physical Sciences at the Microscale (HFNL). This study is funded by National Natural Science Foundation, Chinese Academy of Sciences, Ministry of Science and Technology, Ministry of Education, Anhui Provincial Natural Science Foundation Grants, etc. Link to this paper: http://www.pnas.org/content/112/33/E4546.abstract
(HUANG Jun, School of Life Science)