Editing Spindle checkpoint (section)

==== New model for SAC deactivation in ''S. cerevisiae'': the mechanical switch ====
A new mechanism has been suggested to explain how end-on microtubule attachment at the kinetochore is able to disrupt specific steps in SAC signaling.  In an unattached kinetochore, the first step in the formation of the MCC is phosphorylation of Spc105 by the kinase Mps1.  Phosphorylated Spc105 is then able to recruit the downstream signaling proteins Bub1 and 3; Mad 1,2, and 3; and Cdc20.  Association with Mad1 at unattached kinetochores causes Mad2 to undergo a conformational change that converts it from an open form (O-Mad2) to a closed form (C-Mad2.)  The C-Mad2 bound to Mad1 then dimerizes with a second O-Mad2 and catalyzes its closure around Cdc20.  This C-Mad2 and Cdc20 complex, the MCC, leaves Mad1 and C-Mad2 at the kinetochore to form another MCC.  The MCCs each sequester two Cdc20 molecules to prevent their interaction with the APC/C, thereby maintaining the SAC.<ref name="Morgan" />  Mps1's phosphorylation of Spc105 is both necessary and sufficient to initiate the SAC signaling pathway, but this step can only occur in the absence of microtubule attachment to the kinetochore.  Endogenous Mps1 is shown to associate with the calponin-homology (CH) domain of Ndc80, which is located in the outer kinetochore region that is distant from the chromosome.  Though Mps1 is docked in the outer kinetochore, it is still able to localize within the inner kinetochore and phosphorylate Spc105 because of flexible hinge regions on Ndc80.  However, the mechanical switch model proposes that end-on attachment of a microtubule to the kinetochore deactivates the SAC through two mechanisms. The presence of an attached microtubule increases the distance between the Ndc80 CH domain and  Spc105. Additionally, Dam1/DASH, a large complex consisting of 160 proteins that forms a ring around the attached microtubule, acts as a barrier between the two proteins.  Separation prevents interactions between Mps1 and Spc105 and thus inhibits the SAC signaling pathway.<ref>{{cite journal | vauthors = Aravamudhan P, Goldfarb AA, Joglekar AP | title = The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling | journal = Nature Cell Biology | volume = 17 | issue = 7 | pages = 868–79 | date = July 2015 | pmid = 26053220 | pmc = 4630029 | doi = 10.1038/ncb3179 }}</ref>

This model is not applicable to SAC regulation in higher order organisms, including animals.  A main facet of the mechanical switch mechanism is that in ''S. cerevisiae'' the structure of the kinetochore only allows for attachment of one microtubule. Kinetochores in animals, on the other hand, are much more complex meshworks that contain binding sites for a multitude of microtubules.<ref>{{Cite book|title=Molecular Biology of The Cell (6th ed.)|vauthors = Alberts B, Johnson A, Lewis J, Morgan D, Raff M, Roberts K,Walter P|publisher=Garland Science, Taylor & Francis Group|year=2015|isbn=978-0-8153-4432-2|location=New York, NY|pages=988}}</ref>  Microtubule attachment at all of the kinetochore binding sites is not necessary for deactivation of the SAC and progression to anaphase.  Therefore, microtubule-attached and microtubule-unattached states coexist in the animal kinetochore while the SAC is inhibited.  This model does not include a barrier that would prevent Mps1 associated with an attached kinetochore from phosphorylating Spc105 in an adjacent unattached kinetochore. Furthermore, the yeast Dam1/DASH complex is not present in animal cells.