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

Abstract

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.

Figure 1. Nek2A binds the APC/C‐MCC complex in a unique conformation

Nek2A is a mitotic kinase that is degraded by the APC/C despite this being inhibited by the spindle assembly checkpoint. The APC/C is inhibited by the checkpoint generated MCC, and two specific conformations of this complex exist referred to as closed and open. In the closed form, the APC/C‐MCC is more strongly inhibited and the IR motif of Cdc20^MCC binds APC8 preventing Nek2A binding. In the open form of APC/C‐MCC, this Cdc20^MCC‐APC8 interaction is weaker allowing Nek2A to bind APC8 through one of its MR motifs. The second MR motif of the Nek2A dimer binds to an APC2/4 interface hereby stabilising the interaction. This unique binding mechanism possibly positions Nek2A lysine residues for efficient ubiquitination by UbcH10 or UbcH5 (modified from ref. 1)