Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling

Author:

Primorac Ivana1,Weir John R1,Chiroli Elena2,Gross Fridolin2,Hoffmann Ingrid1,van Gerwen Suzan1,Ciliberto Andrea2,Musacchio Andrea13

Affiliation:

1. Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany

2. IFOM—The FIRC Institute of Molecular Oncology, Milan, Italy

3. Centre for Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen, Germany

Abstract

Regulation of macromolecular interactions by phosphorylation is crucial in signaling networks. In the spindle assembly checkpoint (SAC), which enables errorless chromosome segregation, phosphorylation promotes recruitment of SAC proteins to tensionless kinetochores. The SAC kinase Mps1 phosphorylates multiple Met-Glu-Leu-Thr (MELT) motifs on the kinetochore subunit Spc105/Knl1. The phosphorylated MELT motifs (MELTP) then promote recruitment of downstream signaling components. How MELTP motifs are recognized is unclear. In this study, we report that Bub3, a 7-bladed β-propeller, is the MELTP reader. It contains an exceptionally well-conserved interface that docks the MELTP sequence on the side of the β-propeller in a previously unknown binding mode. Mutations targeting the Bub3 interface prevent kinetochore recruitment of the SAC kinase Bub1. Crucially, they also cause a checkpoint defect, showing that recognition of phosphorylated targets by Bub3 is required for checkpoint signaling. Our data provide the first detailed mechanistic insight into how phosphorylation promotes recruitment of checkpoint proteins to kinetochores.

Funder

European Research Council

Seventh Framework Programme of the European Commission

Italian Association for Cancer Research (AIRC)

Umberto Veronesi Foundation

European Commission

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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