Voltage sensitive phosphatases: emerging kinship to protein tyrosine phosphatases from structure-function research.

Kirstin Hobiger,Thomas Friedrich

doi:10.3389/fphar.2015.00020

Abstract

The transmembrane protein Ci-VSP from the ascidian Ciona intestinalis was described as first member of a fascinating family of enzymes, the voltage sensitive phosphatases (VSPs). Ci-VSP and its voltage-activated homologs from other species are stimulated by positive membrane potentials and dephosphorylate the head groups of negatively charged phosphoinositide phosphates (PIPs). In doing so, VSPs act as control centers at the cytosolic membrane surface, because they intervene in signaling cascades that are mediated by PIP lipids. The characteristic motif CX5RT/S in the active site classifies VSPs as members of the huge family of cysteine-based protein tyrosine phosphatases (PTPs). Although PTPs have already been well-characterized regarding both, structure and function, their relationship to VSPs has drawn only limited attention so far. Therefore, the intention of this review is to give a short overview about the extensive knowledge about PTPs in relation to the facts known about VSPs. Here, we concentrate on the structural features of the catalytic domain which are similar between both classes of phosphatases and their consequences for the enzymatic function. By discussing results obtained from crystal structures, molecular dynamics simulations, and mutagenesis studies, a possible mechanism for the catalytic cycle of VSPs is presented based on that one proposed for PTPs. In this way, we want to link the knowledge about the catalytic activity of VSPs and PTPs.

Highlights

Phosphorylation and dephosphorylation of cellular substrates, such as proteins, lipids, carbohydrates or nucleic acids, are crucial for the precise spatiotemporal transduction of signals across the cellular space
Since the activity of voltage sensitive phosphatases (VSPs) is switchable by voltage stimulation, these enzymes have been mainly characterized by electrophysiological methods
Taking their structural identity and sequence pattern into account, VSPs can be classified as members of the huge protein family of cysteine-based protein tyrosine phosphatases (PTPs)

Summary

INTRODUCTION

Phosphorylation and dephosphorylation of cellular substrates, such as proteins, lipids, carbohydrates or nucleic acids, are crucial for the precise spatiotemporal transduction of signals across the cellular space. While phosphorylation of substrates is mediated by kinases, phosphatases attack their substrates by hydrolyzing covalently attached phosphate groups In this context, protein tyrosine phosphatases (PTPs1) come into play with their dephosphorylation activity toward a diverse pool of cellular substrates. Protein tyrosine phosphatases (PTPs1) come into play with their dephosphorylation activity toward a diverse pool of cellular substrates Members of this huge protein family are involved in multiple processes like endo- and exocytosis, cell differentiation, cell proliferation and migration – to list only a few examples. Voltage-sensitive phosphatases (VSPs) belong to the PTP family due to their homology in amino acid sequence of the active site and similarities in their structure of the catalytic domain. By linking the knowledge about these phosphatases, we want to answer the question if the results achieved for VSPs can be integrated into the set of principles which have already been described in more detail for PTPs

Kinship of VSPs and PTPs

STRUCTURAL ELEMENTS DEFINING THE PHOSPHATASE ACTIVITY OF PTPs