The Mad1/Mad2 Complex as a Template for Mad2 Activation in the Spindle Assembly Checkpoint

A, De Antoni; Pearson, Chad G.; Cimini, Daniela; Canman, Julie C.; Sala, Valeria; Nezi, Luigi; Mapelli, Marina; Sironi, Lucia; Faretta, Mario; Salmon, Edward D.; Musacchio, Andrea

doi:10.1016/j.cub.2005.01.038

Cited by 391 publications

(619 citation statements)

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“…The protein Mad2 is present in two stable conformations differing in the spatial arrangement of a 'safety-belt' that is either open (O-Mad2) or closed (C-Mad2) (De Antoni et al, 2005;Luo et al, 2004;Sironi et al, 2002). O-Mad2 is able to bind Cdc20, though the resulting complex is rather transient.…”

Section: Template Model Of Mad2-activationmentioning

confidence: 99%

“…Central to the SACnetwork is a kinetochore-bound template complex made up from Mad1 and C-Mad2. This template complex recruits O-Mad2 and stabilizes an intermediate conformation (O-Mad2*), which can bind Cdc20 efficiently and switches to closed conformation upon Cdc20-binding, tightening the connection between both with the 'safety-belt' (De Antoni et al, 2005;Luo et al, 2004;Vink et al, 2006).The CMad2:Cdc20 complex formed by this mechanism has been given the name ''template-model'' (De Antoni et al, 2005). Mad2-activation at the kinetochores is commonly seen as the central element of the SAC.…”

Section: Template Model Of Mad2-activationmentioning

confidence: 99%

“…A more comprehensive model of the human SAC, including the Mad2 and BubR1 pathway, has been proposed by Ibrahim et al (2008a;2008b, 2009Ibrahim and Henze, 2014). A mathematical model for checkpoint activation based on the ''Mad2 template'' model by De Antoni et al (2005) is supported with in vitro experiments by Simonetta et al (2009). Mistry et al (2008) constructed an elaborated model for the evolution over time of the kinetochore attachment states' distribution.…”

Section: Introductionmentioning

confidence: 99%

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Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Ibrahim

2015

OMICS: A Journal of Integrative Biology

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Correct DNA segregation is a fundamental process that ensures the precise and reliable inheritance of genomic information for the propagation of cell life. Eukaryotic cells have evolved a conserved surveillance control mechanism for DNA segregation named the Spindle Assembly Checkpoint (SAC).The SAC ensures that the sister chromatids of the duplicated genome are not separated and distributed to the spindle poles before all chromosomes have been properly linked to the microtubules of the mitotic spindle. Biochemically, the SAC delays cell cycle progression by preventing activation of the anaphase-promoting complex (APC/C) or cyclosome whose activation by Cdc20 is required for sister-chromatid separation; this marks the transition into anaphase. In response to activation of the checkpoint, various species control the activity of both APC/C and Cdc20. However, the underlying regulatory pathways remain largely elusive. In this study, five possible model variants of APC/C regulation were constructed, namely BubR1, Mad2, MCC, MCF2, and an all-pathways model variant. These models were validated with experimental data from the literature. A wide range of parameter values has been tested to find the critical values of the APC/C binding rate. The results show that all variants are able to capture the wild-type behavior of the APC/C. However, only one model variant, which included both MCC as well as BubR1 as potent inhibitors of the APC/C, was able to reproduce both wild-type and mutant type behavior of APC/C regulation. In conclusion, the presented work informs the regulation of fundamental processes such as SAC and APC/C in cell biology and has successfully distinguished between five competing dynamical models using a systems biology approach. The results attest that systems-level approaches are vital for molecular and cell biology.

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Section: Template Model Of Mad2-activationmentioning

confidence: 99%

Section: Template Model Of Mad2-activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Ibrahim

2015

OMICS: A Journal of Integrative Biology

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“…Mad1 then itself recruits Mad2, leading to the "activation" of the checkpoint cascade . Specifically, Mad1 forms a dimer with two Mad2 binding sites that can each bind one Mad2 dimer (De Antoni et al 2005;Sironi et al 2002). Interestingly, the two subunits within the Mad2 dimer are not equivalent, as each protein adopts a different conformation.…”

Section: Brief Description Of the Spindle Assembly Checkpointmentioning

confidence: 99%

“…Interestingly, the two subunits within the Mad2 dimer are not equivalent, as each protein adopts a different conformation. One subunit binds tightly Mad1 in the so-called "closed" conformation, while the other subunit, in the so-called "open" conformation can bind to Cdc20, the target of the spindle checkpoint (De Antoni et al 2005;Luo et al 2000). This binding process releases open Mad2 from the Mad1:Mad2 complex and results in the closing of its conformation on Cdc20.…”

Section: Brief Description Of the Spindle Assembly Checkpointmentioning

confidence: 99%

The Spindle Assembly Checkpoint: Clock or Domino?

Medina-Redondo

Meraldi

2011

Results and Problems in Cell Differentiation

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In each cell division, the newly duplicated chromosomes must be evenly distributed between the sister cells. Errors in this process during meiosis or mitosis are equally fatal: improper segregation of the chromosome 21 during human meiosis leads to Down syndrome (Conley, Aneuploidy: etiology and mechanisms, pp 1985), whereas in somatic cells, aneuploidy has been linked to carcinogenesis, by unbalancing the ratio of oncogenes and tumor suppressors (Holland and Cleveland, Nat Rev Mol Cell Biol 10(7): 478-487, 2009; Yuen et al., Curr Opin Cell Biol 17(6):576-582, 2005). Eukaryotic cells have developed a mechanism, known as the spindle assembly checkpoint, to detect erroneous attachment of chromosomes to the mitotic/meiotic spindle and delay the cell cycle to give enough time to resolve these defects. Research in the last 20 years, has demonstrated that the spindle assembly checkpoint is not only a pure checkpoint pathway, but plays a constitutive role in every cell cycle. Here, we review our current knowledge of how the spindle assembly checkpoint is integrated into the cell cycle machinery, and discuss some of the questions that have to be addressed in the future.

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Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

2019

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In mitosis, the spindle assembly checkpoint (SAC) monitors the formation of microtubule‐kinetochore attachments during capture of chromosomes by the mitotic spindle. Spindle assembly is complete once there are no longer any unattached kinetochores. Here, we will discuss the mechanism and key components of spindle checkpoint signalling. Unattached kinetochores bind the principal spindle checkpoint kinase monopolar spindle 1 (MPS1). MPS1 triggers the recruitment of other spindle checkpoint proteins and the formation of a soluble inhibitor of anaphase, thus preventing exit from mitosis. On microtubule attachment, kinetochores become checkpoint silent due to the actions of PP2A‐B56 and PP1. This SAC responsive period has to be coordinated with mitotic spindle formation to ensure timely mitotic exit and accurate chromosome segregation. We focus on the molecular mechanisms by which the SAC permissive state is created, describing a central role for CDK1‐cyclin B1 and its counteracting phosphatase PP2A‐B55. Furthermore, we discuss how CDK1‐cyclin B1, through its interaction with MAD1, acts as an integral component of the SAC, and actively orchestrates checkpoint signalling and thus contributes to the faithful execution of mitosis.

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The Mad1/Mad2 Complex as a Template for Mad2 Activation in the Spindle Assembly Checkpoint

Cited by 391 publications

References 44 publications

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

Systems Biology Modeling of Five Pathways for Regulation and Potent Inhibition of the Anaphase-Promoting Complex (APC/C): Pivotal Roles for MCC and BubR1

The Spindle Assembly Checkpoint: Clock or Domino?

Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

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