Auto-inhibition of Mif2/CENP-C ensures centromere-dependent kinetochore assembly in budding yeast.

The EMBO Journal
Kerstin KillingerStefan Westermann

Abstract

Kinetochores are chromatin-bound multi-protein complexes that allow high-fidelity chromosome segregation during mitosis and meiosis. Kinetochore assembly is exclusively initiated at chromatin containing Cse4/CENP-A nucleosomes. The molecular mechanisms ensuring that subcomplexes assemble efficiently into kinetochores only at centromeres, but not anywhere else, are incompletely understood. Here, we combine biochemical and genetic experiments to demonstrate that auto-inhibition of the conserved kinetochore subunit Mif2/CENP-C contributes to preventing unscheduled kinetochore assembly in budding yeast cells. We show that wild-type Mif2 is attenuated in its ability to bind a key downstream component in the assembly pathway, the Mtw1 complex, and that addition of Cse4 nucleosomes overcomes this inhibition. By exchanging the N-terminus of Mif2 with its functional counterpart from Ame1/CENP-U, we have created a Mif2 mutant which bypasses the Cse4 requirement for Mtw1 binding in vitro, thereby shortcutting kinetochore assembly. Expression of this Mif2 mutant in cells leads to mis-localization of the Mtw1 complex and causes pronounced chromosome segregation defects. We propose that auto-inhibition of Mif2/CENP-C constitutes a key concep...Continue Reading

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Citations

Nov 18, 2020·Open Biology·G E Hamilton, T N Davis
May 7, 2021·Molecular Biology of the Cell·Ekaterina V TarasovetcEkaterina L Grishchuk
Jul 2, 2021·Science Advances·Kai WalsteinAndrea Musacchio

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Methods Mentioned

BETA
dissection
fluorescence microscopy
isothermal titration calorimetry
pulldown
gel filtration

Software Mentioned

Origin
ImageJ
GraphPad Prism
BLAST
Photoshop
Adobe
Windows
Spectra Manager
Jalview
Clustalx

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