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The BUBR1 pseudokinase domain promotes efficient kinetochore PP2A-B56 recruitment to regulate spindle checkpoint silencing and chromosome alignment

View ORCID ProfileLuciano Gama Braga, View ORCID ProfileAngel F. Cisneros, Michelle Mathieu, Maxime Clerc, Pauline Garcia, Baptiste Lottin, Chantal Garand, Philippe Thebault, View ORCID ProfileChristian R Landry, View ORCID ProfileSabine Elowe
doi: https://doi.org/10.1101/733378
Luciano Gama Braga
Biologie cellulaire et moléculaire, Faculté de Médicine, Université LavalCentre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, CanadaPROTEO-regroupement québécois de recherche sur la fonction, l’ingénierie et les applications des protéines, Québec G1V 0A6, QC, Canada
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Angel F. Cisneros
PROTEO-regroupement québécois de recherche sur la fonction, l’ingénierie et les applications des protéines, Québec G1V 0A6, QC, CanadaInstitut de Biologie Intégrative et des Systèmes (IBIS) et Centre de Recherche en Données Massives de l’Université Laval, Université Laval, Québec, QC, CanadaDépartement de Biochimie, Microbiologie et Bio-informatique, Université Laval, G1V 0A6 Québec, Québec, Canada
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  • ORCID record for Angel F. Cisneros
Michelle Mathieu
Biologie cellulaire et moléculaire, Faculté de Médicine, Université LavalCentre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, Canada
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Maxime Clerc
Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, Canada
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Pauline Garcia
Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, Canada
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Baptiste Lottin
Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, Canada
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Chantal Garand
Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, Canada
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Philippe Thebault
Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, Canada
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Christian R Landry
PROTEO-regroupement québécois de recherche sur la fonction, l’ingénierie et les applications des protéines, Québec G1V 0A6, QC, CanadaInstitut de Biologie Intégrative et des Systèmes (IBIS) et Centre de Recherche en Données Massives de l’Université Laval, Université Laval, Québec, QC, CanadaDépartement de Biochimie, Microbiologie et Bio-informatique, Université Laval, G1V 0A6 Québec, Québec, CanadaDépartement de biologie, Université Laval, G1V 0A6 Québec, Québec, Canada
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Sabine Elowe
Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Axe de réproduction, santé de la mère et de l’enfant, Québec G1V 4G2, QC, CanadaPROTEO-regroupement québécois de recherche sur la fonction, l’ingénierie et les applications des protéines, Québec G1V 0A6, QC, CanadaDépartement de Pédiatire, Faculté de Médicine, Université Laval et le Centre de recherche sur le cancer de l’Université Laval, Québec G1R 2J6, QC, Canada
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  • ORCID record for Sabine Elowe
  • For correspondence: Sabine.elowe@crchuq.ulaval.ca
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ABSTRACT

The balance of phospho-signalling at outer-kinetochores during mitosis is critical for the accurate attachments between kinetochores and the mitotic spindle and timely exit from mitosis. In humans, a major player in determining this balance is the PP2A-B56 phosphatase which is recruited to the Kinase Attachment Regulatory Domain (KARD) of the Spindle Assembly Checkpoint protein Budding Uninhibited by Benzimidazole 1-related 1 (BUBR1) in a phospho-dependent manner. This event unleashes a rapid, switch-like phosphatase relay that reverses phosphorylation at the kinetochore, extinguishing the checkpoint and promoting anaphase entry. Here, we conclusively demonstrate that the pseudokinase domain of human BUBR1 lacks phosphotransfer activity and that it was maintained in vertebrates because it allosterically promotes KARD phosphorylation. Mutation or removal of this domain results in decreased PP2A-B56 recruitment to the outer kinetochore, attenuated checkpoint silencing and errors in chromosome alignment as a result of imbalance in Aurora B activity. We demonstrate that the functions of the BUBR1 pseudokinase and the BUB1 kinase domains are intertwined, providing an explanation for retention of the pseudokinase domain in certain eukaryotes.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 13, 2019.
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The BUBR1 pseudokinase domain promotes efficient kinetochore PP2A-B56 recruitment to regulate spindle checkpoint silencing and chromosome alignment
Luciano Gama Braga, Angel F. Cisneros, Michelle Mathieu, Maxime Clerc, Pauline Garcia, Baptiste Lottin, Chantal Garand, Philippe Thebault, Christian R Landry, Sabine Elowe
bioRxiv 733378; doi: https://doi.org/10.1101/733378
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The BUBR1 pseudokinase domain promotes efficient kinetochore PP2A-B56 recruitment to regulate spindle checkpoint silencing and chromosome alignment
Luciano Gama Braga, Angel F. Cisneros, Michelle Mathieu, Maxime Clerc, Pauline Garcia, Baptiste Lottin, Chantal Garand, Philippe Thebault, Christian R Landry, Sabine Elowe
bioRxiv 733378; doi: https://doi.org/10.1101/733378

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