A processive phosphorylation circuit with multiple kinase inputs and mutually diversional routes controls G1/S decision

Rainis Venta, Ervin Valk, Mihkel Örd, Oleg Košik, Kaur Pääbo, Artemi Maljavin, Rait Kivi, Ilona Faustova, Nastassia Shtaida, Martin Lepiku, Kaidi Möll, Andreas Doncic, Mardo Kõivomägi and Mart Loog ()
Additional contact information
Rainis Venta: University of Tartu
Ervin Valk: University of Tartu
Mihkel Örd: University of Tartu
Oleg Košik: University of Tartu
Kaur Pääbo: University of Tartu
Artemi Maljavin: University of Tartu
Rait Kivi: University of Tartu
Ilona Faustova: University of Tartu
Nastassia Shtaida: University of Tartu
Martin Lepiku: University of Tartu
Kaidi Möll: University of Tartu
Andreas Doncic: Stanford University
Mardo Kõivomägi: University of Tartu
Mart Loog: University of Tartu

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15685-z

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