Mad2 binding is not sufficient for complete Cdc20 sequestering in mitotic transition control (an in silico study)
Bashar Ibrahim1, Peter Dittrich, Stephan Diekmann
1Bio Systems Analysis Group, Institute of Computer Science, Friedrich-Schiller-University Jena, Ernst-Abbe-Platz 1-4, D-07743 Jena, Germany.
Biophysical Chemistry
|February 26, 2008
Summary
Mathematical modeling supports the Template model for spindle assembly checkpoint regulation. However, it only partially inhibits Cdc20, suggesting additional factors are needed for complete metaphase arrest during mitosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biophysics
Background:
- Successful mitosis requires metaphase arrest until centromere attachment.
- The spindle assembly checkpoint (SAC) controls the onset of anaphase by regulating the Anaphase-Promoting Complex (APC).
- Mad2 inhibits APC by sequestering Cdc20; Mad1 recruits Mad2 to kinetochores.
Purpose of the Study:
- To mathematically compare the dynamical behavior of the Template and Exchange models for SAC regulation.
- To evaluate the ability of the Template model to explain observed SAC functions.
Main Methods:
- Derivation of a mathematical description for two proposed biochemical models.
- Simulation analysis using experimentally determined parameter values.
Main Results:
- Simulation analysis supports the Template model over the Exchange model.
- The Template model, with experimental parameters, reduces Cdc20 concentration by only half.
- Neither amplification nor p31(comet) inhibition improved the model's description of SAC regulation.
Conclusions:
- The Template model exhibits appropriate metaphase-to-anaphase switching but does not fully account for SAC regulation.
- Additional reaction partners or an extended mechanism may be necessary for complete Cdc20 inhibition and robust SAC function.
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