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Elife. 2014 Jul 8;3:e02978. doi: 10.7554/eLife.02978.

The pseudo GTPase CENP-M drives human kinetochore assembly.

Author information

1
Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
2
Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
3
Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
4
Computational Biology and Bioinformatics Group, Institute of Biomedicine of Seville, Campus Hospital Universitario Virgen del Rocio, Seville, Spain.
5
Department of Biochemistry and Gene Center, Ludwig-Maximilians-Universität, München, Munich, Germany.
6
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
7
Structural Biology and Biocomputing Programme, Spanish National Cancer Centre-CNIO, Madrid, Spain.
8
Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, Essen, Germany andrea.musacchio@mpi-dortmund.mpg.de.

Abstract

Kinetochores, multi-subunit complexes that assemble at the interface with centromeres, bind spindle microtubules to ensure faithful delivery of chromosomes during cell division. The configuration and function of the kinetochore-centromere interface is poorly understood. We report that a protein at this interface, CENP-M, is structurally and evolutionarily related to small GTPases but is incapable of GTP-binding and conformational switching. We show that CENP-M is crucially required for the assembly and stability of a tetramer also comprising CENP-I, CENP-H, and CENP-K, the HIKM complex, which we extensively characterize through a combination of structural, biochemical, and cell biological approaches. A point mutant affecting the CENP-M/CENP-I interaction hampers kinetochore assembly and chromosome alignment and prevents kinetochore recruitment of the CENP-T/W complex, questioning a role of CENP-T/W as founder of an independent axis of kinetochore assembly. Our studies identify a single pathway having CENP-C as founder, and CENP-H/I/K/M and CENP-T/W as CENP-C-dependent followers.DOI: http://dx.doi.org/10.7554/eLife.02978.001.

KEYWORDS:

centromeres; kinetochores; mitosis

PMID:
25006165
PMCID:
PMC4080450
[Indexed for MEDLINE]
Free PMC Article
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