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TitleA unique binding mode of Nek2A to the APC/C allows its ubiquitination during prometaphase.
Journal, issue, pagesEMBO Rep, Vol. 21, Issue 6, Page e49831, Year 2020
Publish dateJun 4, 2020
AuthorsClaudio Alfieri / Thomas Tischer / David Barford /
PubMed AbstractThe anaphase-promoting complex (APC/C) is the key E3 ubiquitin ligase which directs mitotic progression and exit by catalysing the sequential ubiquitination of specific substrates. The activity of ...The anaphase-promoting complex (APC/C) is the key E3 ubiquitin ligase which directs mitotic progression and exit by catalysing the sequential ubiquitination of specific substrates. The activity of the APC/C in mitosis is restrained by the spindle assembly checkpoint (SAC), which coordinates chromosome segregation with the assembly of the mitotic spindle. The SAC effector is the mitotic checkpoint complex (MCC), which binds and inhibits the APC/C. It is incompletely understood how the APC/C switches substrate specificity in a cell cycle-specific manner. For instance, it is unclear how in prometaphase, when APC/C activity towards cyclin B and securin is repressed by the MCC, the kinase Nek2A is ubiquitinated. Here, we combine biochemical and structural analysis with functional studies in cells to show that Nek2A is a conformational-specific binder of the APC/C-MCC complex (APC/C ) and that, in contrast to cyclin A, Nek2A can be ubiquitinated efficiently by the APC/C in conjunction with both the E2 enzymes UbcH10 and UbcH5. We propose that these special features of Nek2A allow its prometaphase-specific ubiquitination.
External linksEMBO Rep / PubMed:32307883 / PubMed Central
MethodsEM (single particle)
Resolution3.8 - 3.9 Å
Structure data

10516

6tlj

EMDB-10516, PDB-6tlj:
Cryo-EM structure of the Anaphase-promoting complex/Cyclosome, in complex with the Mitotic checkpoint complex (APC/C-MCC) at 3.8 angstrom resolution
Method: EM (single particle) / Resolution: 3.8 Å

10518

6tm5

EMDB-10518, PDB-6tm5:
Cryo-EM structure of the Anaphase-promoting complex/Cyclosome, in complex with the Nek2A substrate at 3.9 angstrom resolution
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsCELL CYCLE / E3 ligase / Complex / Mitotic checkpoint complex / E3 ubiquitin Ligase

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