Kinetochore‐catalyzed MCC formation: A structural perspective

Abstract

The spindle assembly checkpoint (SAC) is a cellular surveillance mechanism that functions to ensure accurate chromosome segregation during mitosis. Macromolecular complexes known as kinetochores, act as the interface of sister chromatid attachment to spindle microtubules. In response to unattached kinetochores, the SAC activates its effector, the mitotic checkpoint complex (MCC), which delays mitotic exit until all sister chromatid pairs have achieved successful attachment to the bipolar mitotic spindle. Formation of the MCC (composed of Mad2, BubR1, Bub3 and Cdc20) is regulated by an Mps1 kinase‐dependent phosphorylation signaling cascade which assembles and repositions components of the MCC onto a catalytic scaffold. This scaffold functions to catalyze the conversion of the HORMA‐domain protein Mad2 from an “inactive” open‐state (O‐Mad2) into an “active” closed‐Mad2 (C‐Mad2), and simultaneous Cdc20 binding. Here, our current understanding of the molecular mechanisms underlying the kinetic barrier to C‐Mad2:Cdc20 formation will be reviewed. Recent progress in elucidating the precise molecular choreography orchestrated by the catalytic scaffold to rapidly assemble the MCC will be examined, and unresolved questions will be highlighted. Ultimately, understanding how the SAC rapidly activates the checkpoint not only provides insights into how cells maintain genomic integrity during mitosis, but also provides a paradigm for how cells can utilize molecular switches, including other HORMA domain‐containing proteins, to make rapid changes to a cell's physiological state.

The minimal intrinsic stochasticity of constitutively expressed eukaryotic genes is sub-Poissonian

“…The protein products of these genes contribute to the spindle assembly checkpoint (SAC, also known as mitotic checkpoint). This signalling pathway operates during cell division to detect chromosomes that are not correctly attached to the mitotic spindle and halts the execution of anaphase as a response (46)(47)(48)(49). SAC signalling involves several protein-protein interactions, and the relative ratio of SAC proteins is important for SAC function (44,50,51).…”

Development of MPS1 Inhibitors: Recent Advances and Perspectives

“…The SAC signal is released after the completion of kinetochore−microtubule bond formation. 31 The MPS1 pathway facilitates the recruitment of SAC-related proteins through a sequential multitarget phosphorylation cascade in the presence of unattached kinetochores forming the mitotic checkpoint complex (MCC) assembly also termed the SAC effector (Figure 3B). 32 MPS1 recognizes unattached mitotic sites by binding to the microtubule receptor NDC80 complex (NDC80C) to initiate checkpoint signaling.…”

“…The SAC prevents the onset of anaphase mitosis until all kinetochore–microtubule bonding is completed, as shown in the lower dashed box of Figure A. The SAC signal is released after the completion of kinetochore–microtubule bond formation …”

Molecular mechanism of Mad2 conformational conversion promoted by the Mad2-interaction motif of Cdc20

“…1a-c). This conformational change of Mad2 is a conserved feature of HORMA domain proteins 8,22,23 in which a HORMA-domain closure motif (here Cdc20 MIM ) is topologically linked within the closed state.…”