Cyclin-Specific Docking Mechanisms Reveal the Complexity of M-CDK Function in the Cell Cycle.

Mihkel Örd,Ervin Valk,Rainis Venta,Mart Loog,Kaidi Möll

doi:10.1016/j.molcel.2019.04.026

Abstract

SummaryCyclin-dependent kinases (CDKs) coordinate hundreds of molecular events during the cell cycle. Multiple cyclins are involved, but the global role of cyclin-specific phosphorylation has remained unsolved. We uncovered a cyclin docking motif, LxF, that mediates binding of replication factor Cdc6 to mitotic cyclin. This interaction leads to phospho-adaptor Cks1-mediated inhibition of M-CDK to facilitate Cdc6 accumulation and sequestration in mitosis. The LxF motif and Cks1 also mediate the mutual inhibition between M-CDK and the tyrosine kinase Swe1. Additionally, the LxF motif is critical for targeting M-CDK to phosphorylate several mitotic regulators; for example, Spo12 is targeted via LxF to release the phosphatase Cdc14. The results complete the full set of G1, S, and M-CDK docking mechanisms and outline the unified role of cyclin specificity and CDK activity thresholds. Cooperation of cyclin and Cks1 docking creates a variety of CDK thresholds and switching orders, including combinations of last in, first out (LIFO) and first in, first out (FIFO) ordering.

Highlights

To accomplish one of the most complex biological tasks, the assembly of an extra copy of the cell, cyclin-dependent kinases (CDKs) coordinate hundreds of events during the cell cycle (Morgan, 2007)
Cdc6 Inhibits Mitotic CDK, but Not G1, S, or G2-CDK Using purified Cdc6 and four cyclin-Cdk1 complexes, we found that it is a poor substrate for Cln2 (G1-CDK) and Clb2 (M-CDK) complexes, Cdc6 was efficiently phosphorylated by both Clb5 (S-CDK) and Clb3 (G2-CDK) complexes (Figure 1A)
A mutation in the hp of M-cyclin enhanced the phosphorylation of Cdc6. Such a remarkable cyclin-specific phosphorylation profile suggested that the interaction between Cdc6 and M-CDK could be inhibitory, whereas the S-CDK hp interaction promotes phosphorylation

Summary

Introduction

To accomplish one of the most complex biological tasks, the assembly of an extra copy of the cell, cyclin-dependent kinases (CDKs) coordinate hundreds of events during the cell cycle (Morgan, 2007). In this process, CDKs catalyze thousands of phosphorylation events. According to the threshold model, accumulating CDK activity triggers all major cell cycle events at different thresholds (Stern and Nurse, 1996; Coudreuse and Nurse, 2010; Swaffer et al, 2016). The threshold model was derived from elegant work on fission yeast, where doses of CDK inhibitor were used to determine CDK activity thresholds for S phase and mitotic transitions (Coudreuse and Nurse, 2010), and it has served as a basic framework for CDK function

Methods

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Discussion

Conclusion