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PMID: 16921029 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Genes & development ·Vol. 20 ·No. 17 ·2006-09-01 ·Pages 2410-20

Miller JJ, Summers MK, Hansen DV, Nachury MV, Lehman NL, Loktev A, Jackson PK

Abstract

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/C(Cdh1), 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.

MeSH Terms
Amino Acid Motifs Anaphase-Promoting Complex-Cyclosome Antigens, CD Binding, Competitive Cadherins/metabolism,physiology Cell Cycle Proteins/metabolism,physiology Cell Nucleus/enzymology,metabolism Conserved Sequence Enzyme Inhibitors/metabolism F-Box Proteins/metabolism,physiology HeLa Cells Humans Interphase/physiology Protein Binding Substrate Specificity Ubiquitin-Protein Ligase Complexes/antagonists & inhibitors,metabolism
Chemicals
Antigens, CD CDH1 protein, human Cadherins Cell Cycle Proteins Enzyme Inhibitors F-Box Proteins FBXO5 protein, human Ubiquitin-Protein Ligase Complexes Anaphase-Promoting Complex-Cyclosome
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Miller Julie J
Program in Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA.
Summers Matthew K
Hansen David V
Nachury Maxence V
Lehman Norman L
Loktev Alex
Jackson Peter K
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1454006
Published
2006-09-01
Epub
2006-00-18
Pages
2410-20
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC1560415
Subset
IM
Grants
NIGMS NIH HHS · R01 GM054811 · United States
NIGMS NIH HHS · T32 GM007365 · United States
NCI NIH HHS · T32 CA009151 · United States
NIGMS NIH HHS · R01 GM060439 · United States
NIGMS NIH HHS · GM07365 · United States
NINDS NIH HHS · K08 NS045077 · United States
NCI NIH HHS · CA09151 · United States
NIGMS NIH HHS · R01 GM54811 · United States
NIGMS NIH HHS · R01 GM60439 · United States
External Links
PubMed source DOI: 10.1101/gad.1454006 PMC Full Text View journal details
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