When Mad met Bub - PubMed (original) (raw)

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When Mad met Bub

Katharina Overlack et al. EMBO Rep. 2014 Apr.

Abstract

The faithful segregation of chromosomes into daughter cells is essential for cellular and organismal viability. Errors in this process cause aneuploidy, a hallmark of cancer and several congenital diseases. For proper separation, chromosomes attach to microtubules of the mitotic spindle via their kinetochores, large protein structures assembled on centromeric chromatin. Kinetochores are also crucial for a cell cycle feedback mechanism known as the spindle assembly checkpoint (SAC). The SAC forces cells to remain in mitosis until all chromosomes are properly attached to microtubules. At the beginning of mitosis, the SAC proteins--Mad1, Mad2, Bub1, Bub3, BubR1, Mps1, and Cdc20--are recruited to kinetochores in a hierarchical and interdependent fashion (Fig 1A). There they monitor, in ways that are not fully clarified, the formation of kinetochore-microtubule attachments. Two studies recently published in EMBO reports by the groups of Silke Hauf and Jakob Nilsson, and a recent study by London and Biggins in Genes & Development, shed new light on the conserved SAC protein Mad1.

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Figure 1

Figure 1

Control of mitotic progression by the SAC. (A) The SAC is active in prometaphase and turns off when chromosomes are bi-oriented (metaphase). Kinetochores are shown as green or red dots, depending on whether or not they are bound to microtubules. SAC proteins are recruited to “red” kinetochores, where they assemble the MCC, which inhibits the APC/C. (B) Mad1/C-Mad2 forms a 2:2 tetramer. Mad1/C-Mad2 at kinetochores acts as a receptor for O-Mad2, facilitating the transformation of O-Mad2 into C-Mad2 bound to Cdc20. (C) Mad2 binds a Mad2-binding motif in Mad1 (green) with the help of its “seatbelt” (red). The CTD of Mad1 is near the Mad2-binding region, and the RLK motif neighbors the CTD. Please see the text for details of our proposed model of how Mad1/C-Mad2 and Bub1/Bub3 catalyze rapid MCC formation. The coloring scheme emphasizes the copy to template relationship of the MCC product with the catalytic platform.

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