![]() The Mad1 C-terminus has repeatedly been implicated in kinetochore binding 12 13 14 some studies have suggested a role for the N-terminus 15 16. Another structure of the C-terminal part following α2 showed another intermolecular coiled-coil (α3) and a globular head 12 (see Figs 1A and 4A). The structure of the C-terminal end of this coiled-coil (α1) together with the Mad2-binding site bound to Mad2 as well as a C-terminal helix (α2) indicated that α1 mediates Mad1 dimerization 2. The Mad1 part N-terminal to the Mad2-binding site is predicted to form a long coiled-coil. This raises the question whether the remaining parts only have a structural role. Mad1 has approximately 80 kDa yet, the stretch that binds Mad2 is <20 amino acids long. Hence, Mad1 is important to present Mad2 at unattached kinetochores. Consistent with the important role of the Mad1:Mad2 complex in initiating Cdc20 inhibition, preventing the Mad1:Mad2 interaction abolishes checkpoint activity 8 9 10 11. Similar dependencies exist in other organisms 1. In S. pombe, the kinases Ark1 and Mph1, as well as Bub1 and Bub3, are required to bring Mad1:Mad2 to unattached kinetochores 7. This enables binding of Mad3 (BubR1 in many organisms) to Cdc20 to form the mitotic checkpoint complex (MCC), which is a potent inhibitor of the APC/C 4 5 6. At unattached kinetochores, Mad1-bound Mad2 dimerizes with soluble Mad2 to induce binding of the latter to Cdc20 1 3, an essential co-activator of the anaphase-promoting complex/cyclosome (APC/C) 4. Mad1 forms a tetrameric complex with the checkpoint protein Mad2 2. Mad1 is part of the spindle assembly checkpoint, a conserved mitotic signalling pathway that protects genome integrity by monitoring chromosome attachment to the mitotic spindle and delaying anaphase until all chromosomes have achieved proper attachment 1.
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