The anaphase promoting complex (APC) is a ubiquitin ligase that promotes the degradation of cell-cycle regulators by the 26S proteasome. Cdc20 and Cdh1 are WD40-containing APC co-activators that bind destruction boxes (DB) and KEN boxes within substrates to recruit them to the APC for ubiquitination. Acm1 is an APC(Cdh1) inhibitor that utilizes a DB and a KEN box to bind Cdh1 and prevent substrate binding, although Acm1 itself is not a substrate. We investigated what differentiates an APC substrate from an inhibitor. We identified the Acm1 A-motif that interacts with Cdh1 and together with the DB and KEN box is required for APC(Cdh1) inhibition. A genetic screen identified Cdh1 WD40 domain residues important for Acm1 A-motif interaction and inhibition that appears to reside near Cdh1 residues important for DB recognition. Specific lysine insertion mutations within Acm1 promoted its ubiquitination by APC(Cdh1) whereas lysine removal from the APC substrate Hsl1 converted it into a potent APC(Cdh1) inhibitor. These findings suggest that tight Cdh1 binding combined with the inaccessibility of ubiquitinatable lysines contributes to pseudosubstrate inhibition of APC(Cdh1). The EMBO Journal (2011) 30, 1818-1829. doi:10.1038/emboj.2011.90; Published online 1 April 2011
机构:
NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Bassermann, Florian
;
Frescas, David
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NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Frescas, David
;
Guardavaccaro, Daniele
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NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Guardavaccaro, Daniele
;
Busino, Luca
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NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Busino, Luca
;
Peschiaroli, Angelo
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NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Peschiaroli, Angelo
;
Pagano, Michele
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NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Howard Hughes Med Inst, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
机构:
Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Choi, Eunyoung
;
Dial, J. Michael
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机构:
Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Dial, J. Michael
;
Jeong, Dah-Eun
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Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Jeong, Dah-Eun
;
Hall, Mark C.
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h-index: 0
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Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Purdue Univ, Purdue Canc Ctr, W Lafayette, IN 47907 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
机构:
NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Bassermann, Florian
;
Frescas, David
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h-index: 0
机构:
NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Frescas, David
;
Guardavaccaro, Daniele
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h-index: 0
机构:
NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Guardavaccaro, Daniele
;
Busino, Luca
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h-index: 0
机构:
NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Busino, Luca
;
Peschiaroli, Angelo
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Peschiaroli, Angelo
;
Pagano, Michele
论文数: 0引用数: 0
h-index: 0
机构:
NYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
Howard Hughes Med Inst, New York, NY 10016 USANYU, Sch Med, Inst Canc, Dept Pathol, New York, NY 10016 USA
机构:
Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Choi, Eunyoung
;
Dial, J. Michael
论文数: 0引用数: 0
h-index: 0
机构:
Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Dial, J. Michael
;
Jeong, Dah-Eun
论文数: 0引用数: 0
h-index: 0
机构:
Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Jeong, Dah-Eun
;
Hall, Mark C.
论文数: 0引用数: 0
h-index: 0
机构:
Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USA
Purdue Univ, Purdue Canc Ctr, W Lafayette, IN 47907 USAPurdue Univ, Dept Biochem, W Lafayette, IN 47907 USA