Escape from the checkpoint: Nek2A binds a unique conformation of the APC /C‐ MCC complex

Cell division depends on the timely degradation of numerous proteins by the anaphase‐promoting complex/cyclosome ( APC /C). The APC /C is a large E3 ubiquitin ligase that in complex with Cdc20 recognises degrons in its substrates. The ability of APC /C‐Cdc20 to bind degrons is prevented by the binding of the mitotic checkpoint complex ( MCC ) which constitutes the “wait anaphase” signal. Curiously, the mitotic kinase Nek2A is insensitive to the presence of the MCC . How Nek2A avoids MCC inhibition has been unclear but now work from Alfieri and colleagues published in this issue of EMBO reports provides an explanation [1]. It shows that Nek2A is able to bind a specific open conformation of the APC /C‐ MCC complex that allows Nek2A ubiquitination. A dimer of Nek2A binds two distinct binding pockets on the APC /C through C‐terminal MR motifs and thus independently of degrons. One of the MR binding pockets is only available for interaction in the open form of APC /C‐ MCC explaining Nek2A selectivity for this conformation. Whether other substrates bind the APC /C directly without using canonical degrons will be important to determine.