Mad2 binding is not sufficient for complete Cdc20 sequestering in mitotic transition control (an in silico study).
For successful mitosis, metaphase has to be arrested until all centromeres are properly attached. The onset of anaphase, which is initiated by activating the APC, is controlled by the spindle assembly checkpoint (M)SAC. Mad2, which is a constitutive member of the (M)SAC, is supposed to inhibit the activity of the APC by sequestering away its co-activator Cdc20. Mad1 recruits Mad2 to unattached kinetochores and is compulsory for the establishment of the Mad2 and Cdc20 complexes. Recently, based on results from in vivo and in vitro studies, two biochemical models were proposed: the Template and the Exchange model. Here, we derive a mathematical description to compare the dynamical behaviour of the two models. Our simulation analysis supports the Template model. Using experimentally determined values for the model parameters, the Cdc20 concentration is reduced down to only about half. Thus, although the Template model displays good metaphase-to-anaphase switching behaviour, it is not able to completely describe (M)SAC regulation. This situation is neither improved by amplification nor by p31(comet) inhibition. We speculate that either additional reaction partners are required for total inhibition of Cdc20 or an extended mechanism has to be introduced for (M)SAC regulation.
Ibrahim
Bashar
B
Bio Systems Analysis Group, Institute of Computer Science, Friedrich-Schiller-University Jena, Ernst-Abbe-Platz 1-4, D-07743 Jena, Germany.
Dittrich
Peter
P
Diekmann
Stephan
S
Schmitt
Eberhard
E
D000705:Anaphase; D064173:Anaphase-Promoting Complex-Cyclosome; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019295:Computational Biology; D003198:Computer Simulation; D007700:Kinetics; D008677:Metaphase; D008938:Mitosis; D008954:Models, Biological; D011485:Protein Binding; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism
D018797:Cell Cycle Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome