A new linear cyclin docking motif that mediates exclusively S‐phase CDK‐specific signaling. (19th November 2020)

• Record Type: Journal Article
• Authors: Faustova, Ilona; Bulatovic, Luka; Matiyevskaya, Frida; Valk, Ervin; Örd, Mihkel; Loog, Mart
• Is Part Of: EMBO journal. Volume 40:Number 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-19
• Subjects: cell cycle -- cyclin docking -- cyclin‐dependent kinase -- phosphorylation -- short linear motifs; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020105839
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Cyclin‐dependent kinases (CDKs), the master regulators of cell division, are activated by different cyclins at different cell cycle stages. In addition to being activators of CDKs, cyclins recognize various linear motifs to target CDK activity to specific proteins. We uncovered a cyclin docking motif, NLxxxL, that contributes to phosphorylation‐dependent degradation of the CDK inhibitor Far1 at the G1/S stage in the yeast Saccharomyces cerevisiae . This motif is recognized exclusively by S‐phase CDK (S‐CDK) Clb5/6‐Cdc28 and is considerably more potent than the conventional RxL docking motif. The NLxxxL and RxL motifs were found to overlap in some target proteins, suggesting that cyclin docking motifs can evolve to switch from one to another for fine‐tuning of cell cycle events. Using time‐lapse fluorescence microscopy, we show how different docking connections temporally control phosphorylation‐driven target degradation. This also revealed a differential function of the phosphoadaptor protein Cks1, as Cks1 docking potentiated degron phosphorylation of RxL‐containing but not of NLxxxL‐containing substrates. The NLxxxL motif was found to govern S‐cyclin‐specificity in multiple yeast CDK targets including Fin1, Lif1, and Slx4, suggesting its wider importance. Synopsis: Short linear motifs (SLiMs) mediate protein interactions e.g. between cyclin‐dependent kinase (CDK) substrates and cyclins. A new cyclin docking motif uncovered in yeast CDK substrates targets them specifically for phosphorylation by S‐phase CDK. A cyclin docking motif with consensus NLxxxL contributes to phosphorylation‐dependent degradation of the yeast CDK inhibitor Far1 at the G1/S stage. The NLxxxL motif is present in multiple yeast CDK substrates and exclusively mediates phosphorylation by Clb5/6‐Cdk1 (S‐CDK) complexes. The NLxxxL motif is homologous to the canonical RxL cyclin‐docking motif, but more potent in promoting phosphorylation. In addition to directing the timing of phosphorylation, cyclin‐docking specificity can affect the reversal of Cdk1‐dependent phosphorylation during mitotic exit. Abstract : The short linear motif NLxxxl present in several yeast cyclin‐dependent kinase substrates like Far1 and Slx4 targets them specifically to Clb5‐Cdk1 complexes active in S‐phase.