Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor

Genes and Development - Tập 20 Số 17 - Trang 2410-2420 - 2006
Julie J. Miller1, Matthew K. Summers2, David V. Hansen3, Maxence V. Nachury2, Norman L. Lehman2, Alex V. Loktev2, Peter K. Jackson4,2,5,3
1Program in Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA
2Department of Pathology
3Program in Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA
4Department of Microbiology and Immunology, Stanford University School of Medicine Stanford, California 94305 USA
5Genentech, Inc., San Francisco, California 94080, USA.

Tóm tắt

The periodic destruction of mitotic cyclins is triggered by the activation of the anaphase-promoting complex/cyclosome (APC/C) in mitosis. Although the ability of the APC/C to recognize destruction box (D-box) substrates oscillates throughout the cell cycle, the mechanism regulating APC/C binding to D-box substrates remains unclear. Here, we show that the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator, binds to the D-box receptor site on the APC/CCdh1, and competes with APC/C substrates for D-box binding. Emi1 itself contains a conserved C-terminal D-box, which provides APC/C-binding affinity, and a conserved zinc-binding region (ZBR), which antagonizes APC/C E3 ligase activity independent of tight APC binding. Mutation of the ZBR converts Emi1 into a D-box-dependent APC/C substrate. The identification of a direct Emi1–APC/C complex further explains how Emi1 functions as a stabilizing factor for cyclin accumulation and the need to destroy Emi1 for APC/C activation in mitosis. The combination of a degron/E3 recognition site and an anti-ligase function in Emi1 suggests a general model for how E3 substrates evolve to become pseudosubstrate inhibitors.

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Genes and Development

Tập 20 Số 17

2410-2420

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