Abstract
Ordered progression of mitosis requires precise control in abundance of mitotic regulators. The anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase plays a key role by directing ubiquitin-mediated destruction of targets in a temporally and spatially defined manner. Specificity in APC/C targeting is conferred through recognition of substrate D-box and KEN degrons, while the specificity of ubiquitination sites, as another possible regulated dimension, has not yet been explored. Here, we present the first analysis of ubiquitination sites in the APC/C substrate ubiquitome. We show that KEN is a preferred ubiquitin acceptor in APC/C substrates and that acceptor sites are enriched in predicted disordered regions and flanked by serine residues. Our experimental data confirm a role for the KEN lysine as an ubiquitin acceptor contributing to substrate destruction during mitotic progression. Using Aurora A and Nek2 kinases as examples, we show that phosphorylation on the flanking serine residue could directly regulate ubiquitination and subsequent degradation of substrates. We propose a novel layer of regulation in substrate ubiquitination, via phosphorylation adjacent to the KEN motif, in APC/C-mediated targeting.
Highlights
Faithful cell division requires a robust and efficient network to regulate the precise ordering of events
Using Aurora A and Nek2 kinases as examples, we show that phosphorylation on the flanking serine residue could directly regulate ubiquitination and subsequent degradation of substrates
We propose a novel layer of regulation in substrate ubiquitination, via phosphorylation adjacent to the KEN motif, in anaphase promoting complex/cyclosome (APC/C)-mediated targeting
Summary
Faithful cell division requires a robust and efficient network to regulate the precise ordering of events. Once the cells reach metaphase, these mitotic regulators are irreversibly inactivated by targeted protein degradation This is mediated by the ubiquitin-proteasome system, where the substrates are modified with ubiquitin chains that recruit them to the 26S proteasome [2,3]. In rapid and tightly controlled processes like mitotic exit, these enzymes have two critical issues to solve: the specificity in substrate recognition that controls the timing of substrate ubiquitination and the specificity in building the ubiquitin chain that decides the efficiency and outcome of ubiquitination.
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