Acm1 contributes to nuclear positioning by inhibiting Cdh1-substrate interactions

Martinez, Juan S.; Hall, Hana; Bartolowits, Matthew; Hall, Mark

doi:10.4161/cc.11.2.18944

Cited by 7 publications

(9 citation statements)

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“…Currently, there is no evidence that Acm1 directly inhibits the catalytic activity of APC/C toward substrates. Instead, current models for Acm1 action suggest that it acts as a competitive inhibitor of substrate binding (38,40,42,43). However, we cannot rule out general inhibition of the catalytic function of APC/C by Acm1 in addition to its effect on substrate binding.…”

Section: Acm1 Inhibits Proteolysis Of Diverse Cdh1 Substrates-thementioning

confidence: 76%

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Substrate Recognition by the Cdh1 Destruction Box Receptor Is a General Requirement for APC/CCdh1-mediated Proteolysis

Qin

Guimarães

Melesse

et al. 2016

Journal of Biological Chemistry

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Section: Acm1 Inhibits Proteolysis Of Diverse Cdh1 Substrates-thementioning

confidence: 76%

“…pHLP523 was constructed by moving an XbaI and XhoI fragment containing the acm1⌬52-protein A fusion from pHLP400 described previously (41) into p415MET for control by the methionine-repressible MET25 promoter. pHIP032 and pHIP042 were constructed previously (42).…”

Section: Methodsmentioning

confidence: 99%

Substrate Recognition by the Cdh1 Destruction Box Receptor Is a General Requirement for APC/CCdh1-mediated Proteolysis

Qin

Guimarães

Melesse

et al. 2016

Journal of Biological Chemistry

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“…Phosphorylated Acm1 functions with the 14-3-3 proteins Bmh1 and Bmh2, forming stable stoichiometric complexes that inhibit APC/C Cdh1 by blocking the interaction of Cdh1 with substrates (Dial et al., 2007; Martinez et al., 2006). Acm1-Bmh1/Bmh2 complexes contribute to nuclear positioning and spindle morphology by preventing Cdh1 localization to the bud neck, thereby inhibiting Cdh1 from interacting with the protein kinase Hsl1 (Martinez et al., 2012). Levels of Acm1 are cell-cycle regulated, with the protein appearing at G1/S and disappearing in late mitosis.…”

Section: Introductionmentioning

confidence: 99%

Insights into Degron Recognition by APC/C Coactivators from the Structure of an Acm1-Cdh1 Complex

et al. 2013

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SummaryThe anaphase-promoting complex/cyclosome (APC/C) regulates sister chromatid segregation and the exit from mitosis. Selection of most APC/C substrates is controlled by coactivator subunits (either Cdc20 or Cdh1) that interact with substrate destruction motifs—predominantly the destruction (D) box and KEN box degrons. How coactivators recognize D box degrons and how this is inhibited by APC/C regulatory proteins is not defined at the atomic level. Here, from the crystal structure of S. cerevisiae Cdh1 in complex with its specific inhibitor Acm1, which incorporates D and KEN box pseudosubstrate motifs, we describe the molecular basis for D box recognition. Additional interactions between Acm1 and Cdh1 identify a third protein-binding site on Cdh1 that is likely to confer coactivator-specific protein functions including substrate association. We provide a structural rationalization for D box and KEN box recognition by coactivators and demonstrate that many noncanonical APC/C degrons bind APC/C coactivators at the D box coreceptor.

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“…The “pseudo-substrate” theme was adopted by the Mad2 homolog, Mad2b (also named Mad2L2), which mirrors Emi1/Emi2 in inhibiting both activities of APC/C Cdc20 and APC/C Cdh1 through associating with Cdc20 and Cdh1 [195, 196]. Additionally, pseudo-substrate mechanisms were also identified in yeast proteins Acm1 (APC/C Cdh1 modulator 1) [197–199], Mes1 [124, 200], and Mad3p [201]. For example, the budding yeast protein Acm1, which contains two D-box motifs and a KEN-box motif, interacts with the WD40 domain of Cdh1 to inactivate APC/C Cdh1 by preventing interaction of Cdh1 with its target substrates [197–199].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, pseudo-substrate mechanisms were also identified in yeast proteins Acm1 (APC/C Cdh1 modulator 1) [197–199], Mes1 [124, 200], and Mad3p [201]. For example, the budding yeast protein Acm1, which contains two D-box motifs and a KEN-box motif, interacts with the WD40 domain of Cdh1 to inactivate APC/C Cdh1 by preventing interaction of Cdh1 with its target substrates [197–199]. Similarly, the fission yeast protein Mes1, which also contains D-box and KEN-box motifs, inhibits the E3 ligase activity of the APC/C through a pseudo-substrate mechanism [124, 200].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis

Zhang

Wan

Dai

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The Anaphase Promoting Complex/Cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase that primarily governs cell cycle progression. APC/C is composed of at least 14 core subunits and recruits its substrates for ubiquitination via one of the two adaptor proteins, Cdc20 or Cdh1, in M or M/early G1 phase, respectively. Furthermore, recent studies have shed light on crucial functions for APC/C in maintaining genomic integrity, neuronal differentiation, cellular metabolism and tumorigenesis. To gain better insight into the in vivo physiological functions of APC/C in regulating various cellular processes, particularly development and tumorigenesis, a number of mouse models of APC/C core subunits, coactivators or inhibitors have been established and characterized. However, due to their essential role in cell cycle regulation, most of the germline knockout mice targeting the APC/C pathway are embryonic lethal, indicating the need for generating conditional knockout mouse models to assess the role in tumorigenesis for each APC/C signaling component in specific tissues. In this review, we will first provide a brief introduction of the ubiquitin-proteasome system (UPS) and the biochemical activities and cellular functions of the APC/C E3 ligase. We will then focus primarily on characterizing genetic mouse models used to understand the physiological roles of each APC/C signaling component in embryogenesis, cell proliferation, development and carcinogenesis. Finally, we discuss future research directions to further elucidate the physiological contributions of APC/C components during tumorigenesis and validate their potentials as a novel class of anti-cancer targets.

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Acm1 contributes to nuclear positioning by inhibiting Cdh1-substrate interactions

Cited by 7 publications

References 50 publications

Substrate Recognition by the Cdh1 Destruction Box Receptor Is a General Requirement for APC/CCdh1-mediated Proteolysis

Substrate Recognition by the Cdh1 Destruction Box Receptor Is a General Requirement for APC/CCdh1-mediated Proteolysis

Insights into Degron Recognition by APC/C Coactivators from the Structure of an Acm1-Cdh1 Complex

Functional characterization of Anaphase Promoting Complex/Cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis

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