Nature Cell Biology 8, 607 - 614 (2006)
Published online: 30 April 2006; | doi:10.1038/ncb1410
Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/CMichelle J. Hayes1, 4, Yuu Kimata2, 4, Samantha L. Wattam1, Catherine Lindon3, Guojie Mao1, Hiroyuki Yamano2
& Andrew M. Fry11
Department of Biochemistry, University of Leicester, Leicester, Leics LE1 7RH, UK. 2
Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, UK. 3
Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge CB2 1QR, UK. 4
These authors contributed equally to this work.
Correspondence should be addressed to Andrew M. Fry amf5@le.ac.uk cyclin Bsecurincyclin ANek2ACdc20Cdh1Apc10Doc1The temporal control of mitotic protein degradation remains incompletely understood. In particular, it is unclear why the mitotic checkpoint prevents the anaphase-promoting complex/cyclosome (APC/C)-mediated degradation of cyclin B and securin in early mitosis, but not cyclin A
1,
2,
3. Here, we show that another APC/C substrate, NIMA-related kinase 2A (Nek2A), is also destroyed in pro-metaphase in a checkpoint-independent manner and that this depends on an exposed carboxy-terminal methionine–arginine (MR) dipeptide tail. Truncation of the Nek2A C terminus delays its degradation until late mitosis, whereas Nek2A C-terminal peptides interfere with APC/C activity in an MR-dependent manner. Most importantly, we show that Nek2A binds directly to the APC/C, also in an MR-dependent manner, even in the absence of the adaptor protein Cdc20. As similar C-terminal dipeptide tails promote direct association of Cdc20, Cdh1 and Apc10–Doc1 with core APC/C subunits, we propose that this sequence also allows a substrate, Nek2A, to directly bind the APC/C. Thus, although Cdc20 is required for the degradation of Nek2A, it is not required for its recruitment and this renders its degradation insensitive to the mitotic checkpoint.
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