The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing

Lischetti, Tiziana; Zhang, Gang; Sedgwick, Garry G.; Bolaños-García, Víctor M.; Nilsson, Jakob

doi:10.1038/ncomms6563

Cited by 56 publications

(65 citation statements)

References 42 publications

(61 reference statements)

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“…Most APC/C substrates are recruited by interaction with the seven-blade β-propeller WD40 repeat domain in the C-terminal half of the APC/C activator subunit (He et al, 2013). This domain contains binding pockets that recognize APC/C degrons, of which there are three major types: the destruction box (D box) (Glotzer et al, 1991), the KEN box (Pfleger and Kirschner, 2000) and the ABBA motif (Burton et al, 2011; Lischetti et al, 2014; Lu et al, 2014; Di Fiore et al, 2015; Diaz-Martinez et al, 2015) (Figure 1). A fourth sequence, the CRY motif, also binds the WD40 domain (Alfieri et al, 2016; Yamaguchi et al, 2016), but only a single instance (in Cdc20) has been identified to date (Reis et al, 2006).…”

Section: Substrate Recognition By the Apc/cmentioning

confidence: 99%

Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex

2016

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Summary The anaphase-promoting complex or cyclosome (APC/C) is a ubiquitin ligase that polyubiquitinates specific substrates at precise times in the cell cycle, thereby triggering the events of late mitosis in a strict order. The robust substrate specificity of the APC/C prevents the potentially deleterious degradation of non-APC/C substrates, and also averts the cell cycle errors and genomic instability that could result from mistimed degradation of APC/C targets. The APC/C recognizes short linear sequence motifs, or degrons, on its substrates. The specific and timely modification and degradation of APC/C substrates is likely to be modulated by variations in degron sequence and context. We discuss the extensive affinity, specificity and selectivity determinants encoded in APC/C degrons, and we describe some of the extrinsic mechanisms that control APC/C-substrate recognition. As an archetype for protein motif-driven regulation of cell function, the APC/C-substrate interaction provides insights into the general properties of post-translational regulatory systems.

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Section: Substrate Recognition By the Apc/cmentioning

confidence: 99%

Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex

2016

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“…The yeast protein Acm1 utilizes a similar motif known as the 'A motif' in addition to its KEN box to interact with and thereby inhibit the CDC20 yeast ortholog Cdh1 (Enquist-Newman et al, 2008;He et al, 2013). Because recent reports have shown the existence of a similar motif in BUBR1 (dubbed the Phe box or ICDC20BD) that is important for a stable BUBR1-CDC20 interaction and for SAC activity (Diaz-Martinez et al, 2015;Lischetti et al, 2014), we tested whether this region in BUB1 is involved in the localization of CDC20 to kinetochores. CDC20 localizes strongly to kinetochores in nocodazole-treated cells, and this depends on BUB1 (Fig.…”

Section: ) Lap-bub1mentioning

confidence: 99%

Dissecting the roles of human BUB1 in the spindle assembly checkpoint

Vleugel

Hoek

Tromer

et al. 2015

Journal of Cell Science

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Mitotic chromosome segregation is initiated by the anaphase promoting complex/cyclosome (APC/C) and its co-activator CDC20 (forming APC/C CDC20 ). APC/C CDC20 is inhibited by the spindle assembly checkpoint (SAC) when chromosomes have not attached to spindle microtubules. Unattached kinetochores catalyze the formation of a diffusible APC/C CDC20 inhibitor that comprises BUBR1 (also known as BUB1B), BUB3, MAD2 (also known as MAD2L1) and a second molecule of CDC20. Recruitment of these proteins to the kinetochore, as well as SAC activation, rely on the mitotic kinase BUB1, but the molecular mechanism by which BUB1 accomplishes this in human cells is unknown. We show that kinetochore recruitment of BUBR1 and BUB3 by BUB1 is dispensable for SAC activation. Unlike its yeast and nematode orthologs, human BUB1 does not associate stably with the MAD2 activator MAD1 (also known as MAD1L1) and, although required for accelerating the loading of MAD1 onto kinetochores, BUB1 is dispensable for the maintenance of steady-state levels of MAD1 there. Instead, we identify a 50-amino-acid segment that harbors the recently reported ABBA motif close to a KEN box as being crucial for the role of BUB1 in SAC signaling. The presence of this segment correlates with SAC activity and efficient binding of CDC20 but not of MAD1 to kinetochores.

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“…Therefore, these data suggest that the Drosophila BubR1 KAN motif may have an important role in Cdc20/Fzy kinetochore recruitment. Interestingly, several studies reported the identification of additional conserved motifs in human BubR1: an internal Cdc20 binding domain (IC20BD), also named Phe-box (for its phenylalanine containing region), a D-box located downstream of the Phe-box and the ABBA motif which encompasses the Phe-box (Lischetti et al, 2014; Di Fiore et al, 2015; Diaz-Martinez et al, 2015). These motifs were shown to contribute to Cdc20 binding and its recruitment to kinetochores (Lischetti et al, 2014; Di Fiore et al, 2015), and, although they were not essential for the SAC per se, they appeared to make the SAC more efficient (Lischetti et al, 2014; Di Fiore et al, 2015; Diaz-Martinez et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

A novel mutation in the N-terminal domain of Drosophila BubR1 affects the spindle assembly checkpoint function of BubR1

2016

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The spindle assembly checkpoint (SAC) is a surveillance mechanism that ensures accurate segregation of chromosomes into two daughter cells. BubR1, a key component of the SAC, also plays a role in the mitotic timing since depletion of BubR1 leads to accelerated mitosis. We previously found that mutation of the KEN1-box domain of Drosophila BubR1 (bubR1-KEN1 mutant) affects the binding of BubR1 to Cdc20, the activating co-factor of the APC/C, and does not accelerate the mitotic timing despite resulting in a defective SAC, which was unlike what was reported in mammalian cells. Here, we show that a mutation in a novel Drosophila short sequence (bubR1-KAN mutant) leads to an accelerated mitotic timing as well as SAC failure. Moreover, our data indicate that the level of Fzy, the Drosophila homolog of Cdc20, recruited to kinetochores is diminished in bubR1-KEN1 mutant cells and further diminished in bubR1-KAN mutant cells. Altogether, our data show that this newly identified Drosophila BubR1 KAN motif is required for a functional SAC and suggest that it may play an important role on Cdc20/Fzy kinetochore recruitment.

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The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing

Cited by 56 publications

References 42 publications

Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex

Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex

Dissecting the roles of human BUB1 in the spindle assembly checkpoint

A novel mutation in the N-terminal domain of Drosophila BubR1 affects the spindle assembly checkpoint function of BubR1

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