Domain-to-domain coupling in voltage-sensing phosphatase

Abstract

Voltage-sensing phosphatase (VSP) consists of a transmembrane voltage sensor and a cytoplasmic enzyme region. The enzyme region contains the phosphatase and C2 domains, is structurally similar to the tumor suppressor phosphatase PTEN, and catalyzes the dephosphorylation of phosphoinositides. The transmembrane voltage sensor is connected to the phosphatase through a short linker region, and phosphatase activity is induced upon membrane depolarization. Although the detailed molecular characteristics of the voltage sensor domain and the enzyme region have been revealed, little is known how these two regions are coupled. In addition, it is important to know whether mechanism for coupling between the voltage sensor domain and downstream effector function is shared among other voltage sensor domain-containing proteins. Recent studies in which specific amino acid sites were genetically labeled using a fluorescent unnatural amino acid have enabled detection of the local structural changes in the cytoplasmic region of Ciona intestinalis VSP that occur with a change in membrane potential. The results of those studies provide novel insight into how the enzyme activity of the cytoplasmic region of VSP is regulated by the voltage sensor domain.

Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes

“…Interestingly, previous studies indicate that two (p.Y155C and p.R173C) of the four mutations shared across both phenotypes result in inactivation of PTEN (Gicquel, Vabres, Bonneau, Mercie, Handiri et al, 2003;Han et al, 2000;Maehama, Taylor, & Dixon, 2001;Rodriguez-Escudero et al, 2011;Waite & Eng, 2002) and also converge within the inter-domain region. Evolutionarily, the loss of phosphatase activity by mutation but preservation of the phosphatase-C2 domain across species suggests that domain coupling may have a more significant impact on function than phosphoryl group removal or binding (Haynie & Xue, 2015;Sakata, Matsuda, Kawanabe, & Okamura, 2017).…”

Molecular mechanisms of coupling to voltage sensors in voltage-evoked cellular signals

“…Gallery of protein structures of VGICs and VSP (taken from ref. 157). K v 1.2–K v 2.1 chimera: human voltage-gated potassium channel (PDB ID: 2R9R), TPC1: plant two-pore cation channel (PDB ID: 5E1J), Ca v 1.1: human skeletal muscle-type voltage-gated calcium channel (PDB ID: 5GJV), Na v PaS: insect voltage-gated sodium channel (PDB ID: 5X0M), HCN1: human hyperpolarization-activated cyclic nucleotide-gated channel (PDB ID: 5U6O), Slo1: large conductance calcium-activated voltage-gated potassium channel from Aplysia (PDB ID: 5TJ6), Ci-VSP: sea squirt voltage-sensing phosphatase (full length model based on coordinates from PDB ID: 3AWF and PDB ID: 4G7V), mH v 1cc: mouse voltage-gated proton channel in a chimeric form containing part of S2–S3 from Ci-VSP and the coiled coil structure of GCN4 (dimer model based on coordinates from PDB ID: 3WKV).…”

“…Amino acid sequence of S4 ( a ) and the X-ray crystal structure of the VSD of Ci-VSP with its membrane topology ( b : taken from ref. 157). …”

Membrane properties that shape the evolution of membrane enzymes

“…In part, this is because it is difficult to establish and manipulate these gradients in the model membrane milieu in which membrane enzymes are often characterized. However, the notion that there may be interesting discoveries waiting to be made in this area is supported by studies of the voltage sensing lipid phosphatase [58]. While the phosphatase domain of this enzyme is water soluble, it is tethered to a transmembrane domain that closely resembles the tetraspan voltage sensor domain present in voltage-gated ion channels [59-61] (Figure 1A).…”

“…Black lines indicate expected membrane boundaries. This figure is adapted from [58]. B) The DesK temperature sensor protein homodimer, with the transmembrane region represented in cartoon form and the cytosolic domain depicted as based on its crystal structure (3GIG) [155], which is that of a non-symmetric dimer.…”