@article{2860230e435944ea8480b70d10ee0e2a,
title = "Interactions between N-terminal Modules in MPS1 Enable Spindle Checkpoint Silencing",
abstract = "Faithful chromosome segregation relies on the ability of the spindle assembly checkpoint (SAC) to delay anaphase onset until chromosomes are attached to the mitotic spindle via their kinetochores. MPS1 kinase is recruited to kinetochores to initiate SAC signaling and is removed from kinetochores once stable microtubule attachments have been formed to allow normal mitotic progression. Here, we show that a helical fragment within the kinetochore-targeting N-terminal extension (NTE) module of MPS1 is required for interactions with kinetochores and forms intramolecular interactions with its adjacent tetratricopeptide repeat (TPR) domain. Bypassing this NTE-TPR interaction results in high MPS1 levels at kinetochores due to loss of regulatory input into MPS1 localization, inefficient MPS1 delocalization upon microtubule attachment, and SAC silencing defects. These results show that SAC responsiveness to attachments relies on regulated intramolecular interactions in MPS1 and highlight the sensitivity of mitosis to perturbations in the dynamics of the MPS1-NDC80-C interactions. Pachis et al. show that proper binding dynamics of the spindle checkpoint kinase MPS1 to kinetochores are ensured by regulated intramolecular interactions. Perturbing these interactions can lead to inefficient displacement of MPS1 upon microtubule attachment and defects in inactivating the spindle assembly checkpoint, which is necessary for timely chromosome segregation.",
author = "Pachis, {Spyridon T.} and Yoshitaka Hiruma and Tromer, {Eelco C.} and Anastassis Perrakis and Kops, {Geert J.P.L.}",
note = "Funding Information: We thank all Kops and Perrakis lab members for suggestions and discussions. We especially acknowledge Prof. Marcellus Ubbink for providing access to the NMR facility at the Leiden Institute of Chemistry (Leiden University) and for critically discussing initial NMR experiments and data, Wouter Touw for help with the TALOS software, and Marvin Tanenbaum and his group for help with FRAP experiments. This work is part of the Oncode Institute and was funded by grants from the Dutch Cancer Society ( KWF/HUBR-2012-5427 ) and from the Netherlands Organisation for Scientific Research ( NWO-Vici 865.12.004 ). E.C.T. is supported by a postdoctoral fellowship from the Herchel Smith Fund in Cambridge, UK. Funding Information: We thank all Kops and Perrakis lab members for suggestions and discussions. We especially acknowledge Prof. Marcellus Ubbink for providing access to the NMR facility at the Leiden Institute of Chemistry (Leiden University) and for critically discussing initial NMR experiments and data, Wouter Touw for help with the TALOS software, and Marvin Tanenbaum and his group for help with FRAP experiments. This work is part of the Oncode Institute and was funded by grants from the Dutch Cancer Society (KWF/HUBR-2012-5427) and from the Netherlands Organisation for Scientific Research (NWO-Vici 865.12.004). E.C.T. is supported by a postdoctoral fellowship from the Herchel Smith Fund in Cambridge, UK. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = feb,
day = "19",
doi = "10.1016/j.celrep.2019.01.017",
language = "English",
volume = "26",
pages = "2101--2112.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}