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J Biol Chem. 2015 Jan 23;290(4):2431-43. doi: 10.1074/jbc.M114.616490. Epub 2014 Dec 10.

The Cdc20-binding Phe box of the spindle checkpoint protein BubR1 maintains the mitotic checkpoint complex during mitosis.

Author information

  • 1From the Department of Pharmacology.
  • 2From the Department of Pharmacology, Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
  • 3Department of Biophysics, and.
  • 4From the Department of Pharmacology, xuelian.luo@utsouthwestern.edu.
  • 5From the Department of Pharmacology, Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 hongtao.yu@utsouthwestern.edu.

Abstract

The spindle checkpoint ensures accurate chromosome segregation by monitoring kinetochore-microtubule attachment. Unattached or tensionless kinetochores activate the checkpoint and enhance the production of the mitotic checkpoint complex (MCC) consisting of BubR1, Bub3, Mad2, and Cdc20. MCC is a critical checkpoint inhibitor of the anaphase-promoting complex/cyclosome, a ubiquitin ligase required for anaphase onset. The N-terminal region of BubR1 binds to both Cdc20 and Mad2, thus nucleating MCC formation. The middle region of human BubR1 (BubR1M) also interacts with Cdc20, but the nature and function of this interaction are not understood. Here we identify two critical motifs within BubR1M that contribute to Cdc20 binding and anaphase-promoting complex/cyclosome inhibition: a destruction box (D box) and a phenylalanine-containing motif termed the Phe box. A BubR1 mutant lacking these motifs is defective in MCC maintenance in mitotic human cells but is capable of supporting spindle-checkpoint function. Thus, the BubR1M-Cdc20 interaction indirectly contributes to MCC homeostasis. Its apparent dispensability in the spindle checkpoint might be due to functional duality or redundant, competing mechanisms.

KEYWORDS:

APC/C; Cell Cycle; Kinetochore; Mitosis; Mitotic Checkpoint Complex; Protein-Protein Interaction; Spindle Checkpoint; Ubiquitylation (Ubiquitination)

PMID:
25505175
PMCID:
PMC4303692
DOI:
10.1074/jbc.M114.616490
[PubMed - indexed for MEDLINE]
Free PMC Article
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