Abstract
Studies on multisite phosphorylation networks of cyclin-dependent kinase (CDK) targets have opened a new level of signaling complexity by revealing signal processing routes encoded into disordered proteins. A model target, the CDK inhibitor Sic1, contains linear phosphorylation motifs, docking sites, and phosphodegrons to empower an N-to-C terminally directed phosphorylation process. Here, we uncover a signal processing mechanism involving multi-step competition between mutually diversional phosphorylation routes within the S-CDK-Sic1 inhibitory complex. Intracomplex phosphorylation plays a direct role in controlling Sic1 degradation, and provides a mechanism to sequentially integrate both the G1- and S-CDK activities while keeping S-CDK inhibited towards other targets. The competing phosphorylation routes prevent premature Sic1 degradation and demonstrate how integration of MAPK from the pheromone pathway allows one to tune the competition of alternative phosphorylation paths. The mutually diversional phosphorylation circuits may be a general way for processing multiple kinase signals to coordinate cellular decisions in eukaryotes.
Highlights
Studies on multisite phosphorylation networks of cyclin-dependent kinase (CDK) targets have opened a new level of signaling complexity by revealing signal processing routes encoded into disordered proteins
Recent works on multisite phosphorylation networks of cyclin-dependent kinase (CDK) have revealed a new level of signal processing complexity that is based on signaling routes encoded into disordered proteins or disordered regions of proteins[1,2,3,4]
We show that the diversionary route can be primed by MAPK from the pheromone pathway to ensure G1 arrest, or alternatively, the diversion can be outcompeted by priming phosphorylations within the phospho-degron route by the G1-CDK complex, which accumulates after the Start decision
Summary
Studies on multisite phosphorylation networks of cyclin-dependent kinase (CDK) targets have opened a new level of signaling complexity by revealing signal processing routes encoded into disordered proteins. Its inhibitory function keeps CDK activity low via tight nanomolar affinity, the substrate function involves phosphorylation-induced degradation of CKI via the ubiquitin–proteasome pathway at G1/S, to unleash free S-phase CDK activity[19,20] In such a mutually antagonistic relationship, Sic[1], an intrinsically disordered protein with 10 CDK phosphorylation sites, inhibits the S-phase CDK complex in budding yeast, whereas the same S-CDK targets it for degradation by multisite phosphorylation of the Sic[1] N terminus at G1/S transition (Fig. 1a). This paper will lay out a mechanism that enables the disordered Sic[1] molecule, with its linearily encoded phosphorylation pattern, to act as a processor that integrates multiple kinase inputs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
