Distinct surfaces on Cdc5/PLK Polo-box domain orchestrate combinatorial substrate recognition during cell division.
Ahmad W Almawi1,2, Laurence Langlois-Lemay3, Stephen Boulton4
1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Scientific Reports
|February 27, 2020
Summary
Polo-like kinases (Plks) use their polo-box domain to bind Dbf4 and substrates. This study reveals how Cdc5 interacts with Dbf4 independently of phosphorylation, impacting cell cycle regulation.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Polo-like kinases (Plks) are crucial regulators of the cell cycle.
- The polo-box domain of Plks recognizes phosphorylated substrates, enhancing their activity.
- Cdc5, the sole Plk in Saccharomyces cerevisiae, interacts with the Dbf4-dependent kinase complex.
Purpose of the Study:
- To elucidate the structural basis of Cdc5 polo-box domain interactions.
- To investigate the binding of Dbf4 and phosphorylated substrates to Cdc5.
- To understand the role of non-canonical interactions in Plk function.
Main Methods:
- X-ray crystallography of the Cdc5 polo-box domain.
- Co-crystallization with peptides from Dbf4 and a phosphorylated substrate.
- Biochemical assays to assess peptide binding in solution.
- Analysis of mutant phenotypes.
Main Results:
- Crystal structures revealed simultaneous, non-competitive binding of Dbf4 and phospho-peptide.
- An additional binding site on the Cdc5 polo-box domain for Dbf4 was identified.
- Mutations disrupting Dbf4 binding caused an early anaphase arrest.
- This phenotype differs from typical cdc5 mutant defects.
Conclusions:
- The polo-box domain mediates non-canonical, phosphorylation-independent interactions with regulatory proteins like Dbf4.
- Combinatorial recognition of substrates by Plks is crucial for precise cell cycle control.
- These findings offer mechanistic insights into Plk regulation and substrate specificity.
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