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Characterization of spindle checkpoint kinase Mps1 reveals domain with functional and structural similarities to tetratricopeptide repeat motifs of Bub1 and BubR1 checkpoint kinases.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Lee, Semin 
Thebault, Philippe 
Freschi, Luca 
Beaufils, Sylvie 
Blundell, Tom L 

Abstract

Kinetochore targeting of the mitotic kinases Bub1, BubR1, and Mps1 has been implicated in efficient execution of their functions in the spindle checkpoint, the self-monitoring system of the eukaryotic cell cycle that ensures chromosome segregation occurs with high fidelity. In all three kinases, kinetochore docking is mediated by the N-terminal region of the protein. Deletions within this region result in checkpoint failure and chromosome segregation defects. Here, we use an interdisciplinary approach that includes biophysical, biochemical, cell biological, and bioinformatics methods to study the N-terminal region of human Mps1. We report the identification of a tandem repeat of the tetratricopeptide repeat (TPR) motif in the N-terminal kinetochore binding region of Mps1, with close homology to the tandem TPR motif of Bub1 and BubR1. Phylogenetic analysis indicates that TPR Mps1 was acquired after the split between deutorostomes and protostomes, as it is distinguishable in chordates and echinoderms. Overexpression of TPR Mps1 resulted in decreased efficiency of both chromosome alignment and mitotic arrest, likely through displacement of endogenous Mps1 from the kinetochore and decreased Mps1 catalytic activity. Taken together, our multidisciplinary strategy provides new insights into the evolution, structural organization, and function of Mps1 N-terminal region.

Description

Keywords

Amino Acid Motifs, Animals, Cattle, Cell Cycle Proteins, Chromosomes, Human, Computational Biology, Enzyme Stability, Evolution, Molecular, HeLa Cells, Humans, Hydrogen-Ion Concentration, M Phase Cell Cycle Checkpoints, Mice, Models, Molecular, Protein Multimerization, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Protein Transport, Protein-Tyrosine Kinases, Rats

Journal Title

J Biol Chem

Conference Name

Journal ISSN

0021-9258
1083-351X

Volume Title

287

Publisher

Elsevier BV

Rights

All rights reserved