Centromeric binding and activity of Protein Phosphatase 4.

Zoltan Lipinszki,Martin R Singleton,Stephane Lefevre,Matthew S Savoian,David M Glover,Marcin R Przewloka

doi:10.1038/ncomms6894

Zoltan Lipinszki, Martin R Singleton + Show 4 more

Open Access

https://doi.org/10.1038/ncomms6894

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Abstract

The cell division cycle requires tight coupling between protein phosphorylation and dephosphorylation. However, understanding the cell cycle roles of multimeric protein phosphatases has been limited by the lack of knowledge of how their diverse regulatory subunits target highly conserved catalytic subunits to their sites of action. Phosphoprotein phosphatase 4 (PP4) has been recently shown to participate in the regulation of cell cycle progression. We now find that the EVH1 domain of the regulatory subunit 3 of Drosophila PP4, Falafel (Flfl), directly interacts with the centromeric protein C (CENP-C). Unlike other EVH1 domains that interact with proline-rich ligands, the crystal structure of the Flfl amino-terminal EVH1 domain bound to a CENP-C peptide reveals a new target-recognition mode for the phosphatase subunit. We also show that binding of Flfl to CENP-C is required to bring PP4 activity to centromeres to maintain CENP-C and attached core kinetochore proteins at chromosomes during mitosis.

Highlights

The cell division cycle requires tight coupling between protein phosphorylation and dephosphorylation
We have previously demonstrated that Drosophila phosphatase 4 (PP4) has critical roles in cell cycle progression[8]
As with other members of the PP2A family, the specificity of PP4 is thought to lie with interactions governed by its regulatory subunits

Summary

Introduction

The cell division cycle requires tight coupling between protein phosphorylation and dephosphorylation. R3 orthologues are conserved throughout evolution with similar domain architecture and have been found from yeasts to human[11,17,18,19] (Fig. 1a) They possess a predicted, conserved pleckstrin homology (PH) superfamily-like domain and Smk-1/ DUF625 (Domain with Unknown Function 625, which is present in Smk-1 protein, a component of the IIs longevity pathway that regulates aging in Caenorhabditis elegans20) domain occupying the amino-terminal region of the protein. These domains are followed by a variable number of ARM (armadillo/HEAT repeats) in the middle and a carboxy-terminal unstructured (low complexity region) tail, which varies in length between different species (Fig. 1a)

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