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A unique binding mode of Nek2A to the APC /C allows its ubiquitination during prometaphase
Author(s) -
Alfieri Claudio,
Tischer Thomas,
Barford David
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201949831
Subject(s) - prometaphase , library science , biology , computer science , genetics , cancer , cell cycle , anaphase
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 MCC ) 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.