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Bub1 positions Mad1 close to KNL1 MELT repeats to promote checkpoint signalling

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  • Gang Zhang

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Thomas Kruse

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Blanca López-Méndez

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Kathrine Beck Sylvestersen

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Dimitriya H. Garvanska

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Simone Schopper

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Michael Lund Nielsen

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Jakob Nilsson

    (The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

Abstract

Proper segregation of chromosomes depends on a functional spindle assembly checkpoint (SAC) and requires kinetochore localization of the Bub1 and Mad1/Mad2 checkpoint proteins. Several aspects of Mad1/Mad2 kinetochore recruitment in human cells are unclear and in particular the underlying direct interactions. Here we show that conserved domain 1 (CD1) in human Bub1 binds directly to Mad1 and a phosphorylation site exists in CD1 that stimulates Mad1 binding and SAC signalling. Importantly, fusion of minimal kinetochore-targeting Bub1 fragments to Mad1 bypasses the need for CD1, revealing that the main function of Bub1 is to position Mad1 close to KNL1 MELT repeats. Furthermore, we identify residues in Mad1 that are critical for Mad1 functionality, but not Bub1 binding, arguing for a direct role of Mad1 in the checkpoint. This work dissects functionally relevant molecular interactions required for spindle assembly checkpoint signalling at kinetochores in human cells.

Suggested Citation

  • Gang Zhang & Thomas Kruse & Blanca López-Méndez & Kathrine Beck Sylvestersen & Dimitriya H. Garvanska & Simone Schopper & Michael Lund Nielsen & Jakob Nilsson, 2017. "Bub1 positions Mad1 close to KNL1 MELT repeats to promote checkpoint signalling," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15822
    DOI: 10.1038/ncomms15822
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    Cited by:

    1. Elyse S. Fischer & Conny W. H. Yu & Johannes F. Hevler & Stephen H. McLaughlin & Sarah L. Maslen & Albert J. R. Heck & Stefan M. V. Freund & David Barford, 2022. "Juxtaposition of Bub1 and Cdc20 on phosphorylated Mad1 during catalytic mitotic checkpoint complex assembly," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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