期刊
EMBO JOURNAL
卷 32, 期 2, 页码 303-314出版社
WILEY
DOI: 10.1038/emboj.2012.335
关键词
APC/C; Kif18A; Nek2A; spindle assembly checkpoint
资金
- Lundbeck Foundation
- Novo Nordisk Foundation
- Danish Cancer Society
- Danish Council for Independent Research
- Wellcome Trust [079643/Z/06/Z]
- Cancer Research UK [13678] Funding Source: researchfish
The Anaphase Promoting Complex/Cyclosome (APC/C) in complex with its co-activator Cdc20 is responsible for targeting proteins for ubiquitin-mediated degradation during mitosis. The activity of APC/C-Cdc20 is inhibited during prometaphase by the Spindle Assembly Checkpoint (SAC) yet certain substrates escape this inhibition. Nek2A degradation during prometaphase depends on direct binding of Nek2A to the APC/C via a C-terminal MR dipeptide but whether this motif alone is sufficient is not clear. Here, we identify Kif18A as a novel APC/C-Cdc20 substrate and show that Kif18A degradation depends on a C-terminal LR motif. However in contrast to Nek2A, Kif18A is not degraded until anaphase showing that additional mechanisms contribute to Nek2A degradation. We find that dimerization via the leucine zipper, in combination with the MR motif, is required for stable Nek2A binding to and ubiquitination by the APC/C. Nek2A and the mitotic checkpoint complex (MCC) have an overlap in APC/C subunit requirements for binding and we propose that Nek2A binds with high affinity to apo-APC/C and is degraded by the pool of Cdc20 that avoids inhibition by the SAC. The EMBO Journal (2013) 32, 303-314. doi:10.1038/emboj.2012.335; Published online 4 January 2013
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