EMD-4026
Human Anaphase-Promoting Complex/Cyclosome (APC/C) APC15 deletion mutant bound to Mitotic Checkpoint Complex (MCC) and the E2 UBE2S poised for UB chain synthesis.
EMD-4026
Single-particle5.7 Å
Deposition: 12/06/2016Map released: 17/08/2016
Last modified: 12/07/2017
Sample Organism:
Homo sapiens
Sample: Human Anaphase-Promoting Complex/Cyclosome (APC/C) APC15 deletion mutant bound to Mitotic Checkpoint Complex (MCC) and the E2 UBE2S poised for UB chain synthesis.
Deposition Authors: Stark H, Schulman BA, Peters JM
Sample: Human Anaphase-Promoting Complex/Cyclosome (APC/C) APC15 deletion mutant bound to Mitotic Checkpoint Complex (MCC) and the E2 UBE2S poised for UB chain synthesis.
Deposition Authors: Stark H, Schulman BA, Peters JM
Cryo-EM of Mitotic Checkpoint Complex-Bound APC/C Reveals Reciprocal and Conformational Regulation of Ubiquitin Ligation.
Yamaguchi M 
,
VanderLinden R,
Weissmann F ,
Qiao R,
Dube P,
Brown NG ,
Haselbach D ,
Zhang W,
Sidhu SS ,
Peters JM,
Stark H,
Schulman BA
(2016) Mol. Cell , 63 , 593 - 607
,
VanderLinden R,
Weissmann F ,
Qiao R,
Dube P,
Brown NG ,
Haselbach D ,
Zhang W,
Sidhu SS ,
Peters JM,
Stark H,
Schulman BA
(2016) Mol. Cell , 63 , 593 - 607
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.
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.