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Journal Article

Cryo-EM of mitotic checkpoint complex-bound APC/C reveals reciprocal and conformational regulation of ubiquitin ligation.

MPS-Authors
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Dube,  P.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Haselbach,  D.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Stark,  H.
Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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Supplementary Material (public)

2339805_Suppl_1.pdf
(Supplementary material), 2MB

2339805_Suppl_2.mp4
(Supplementary material), 5MB

2339805_Suppl_3.mp4
(Supplementary material), 3MB

2339805_Suppl_4.mp4
(Supplementary material), 2MB

2339805_Suppl_5.pdf
(Supplementary material), 9MB

Citation

Yamaguchi, M., VanderLinden, R., Weissmann, F., Qiao, R., Dube, P., Brown, N. G., et al. (2016). Cryo-EM of mitotic checkpoint complex-bound APC/C reveals reciprocal and conformational regulation of ubiquitin ligation. Molecular Cell, 63(4), 593-607. doi:10.1016/j.molcel.2016.07.003.


Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-42BE-A
Abstract
The mitotic checkpoint complex (MCC) coordinates proper chromosome biorientation on the spindle with ubiquitination activities of CDC20-activated anaphase-promoting complex/cyclosome (APC/C(CDC20)). APC/C(CDC20) and two E2s, UBE2C and UBE2S, catalyze ubiquitination through distinct architectures for linking ubiquitin (UB) to substrates and elongating polyUB chains, respectively. MCC, which contains a second molecule of CDC20, blocks APC/C(CDC20)-UBE2C-dependent ubiquitination of Securin and Cyclins, while differentially determining or inhibiting CDC20 ubiquitination to regulate spindle surveillance, checkpoint activation, and checkpoint termination. Here electron microscopy reveals conformational variation of APC/C(CDC20)-MCC underlying this multifaceted regulation. MCC binds APC/C-bound CDC20 to inhibit substrate access. However, rotation about the CDC20-MCC assembly and conformational variability of APC/C modulate UBE2C-catalyzed ubiquitination of MCC's CDC20 molecule. Access of UBE2C is limiting for subsequent polyubiquitination by UBE2S. We propose that conformational dynamics of APC/C(CDC20)-MCC modulate E2 activation and determine distinctive ubiquitination activities as part of a response mechanism ensuring accurate sister chromatid segregation.