Abstract
Voltage-sensing phosphatases (VSP) contain a voltage sensor domain (VSD) similar to that of voltage-gated ion channels but lack a pore-gate domain. A VSD in a VSP regulates the cytoplasmic catalytic region (CCR). However, the mechanisms by which the VSD couples to the CCR remain elusive. Here we report a membrane interface (named 'the hydrophobic spine'), which is essential for the coupling of the VSD and CCR. Our molecular dynamics simulations suggest that the hydrophobic spine of Ciona intestinalis VSP (Ci-VSP) provides a hinge-like motion for the CCR through the loose membrane association of the phosphatase domain. Electrophysiological experiments indicate that the voltage-dependent phosphatase activity of Ci-VSP depends on the hydrophobicity and presence of an aromatic ring in the hydrophobic spine. Analysis of conformational changes in the VSD and CCR suggests that the VSP has two states with distinct enzyme activities and that the second transition depends on the hydrophobic spine.
Highlights
Changes in membrane potential induce structural changes in membrane proteins such as ion channels, transporters, and receptors, and underlie membrane excitability, neurotransmitter and hormone release, muscle contraction (Proenza et al, 2002), cell proliferation (Jehle et al, 2011), and reactive oxygen species production (DeCoursey, 2013)
molecular dynamics (MD) simulation of the cytoplasmic catalytic region of voltage-sensing phosphatase (VSP) reveals the possible function of the VSP hydrophobic spine
To examine the overall propensity of the catalytic region (CCR) of the VSP to bind to phospholipid bilayers, we first performed twelve 2-ms CG MD simulations in a system made of a 1-palmitoyl-2-oleoyl-glycero-3phosphocholine (POPC) bilayer, a water layer, and the CCR of Ciona intestinalis-VSP (Ci-VSP), whose crystal structure has already been determined (Matsuda et al, 2011; Liu et al, 2012)
Summary
Changes in membrane potential induce structural changes in membrane proteins such as ion channels, transporters, and receptors, and underlie membrane excitability, neurotransmitter and hormone release, muscle contraction (Proenza et al, 2002), cell proliferation (Jehle et al, 2011), and reactive oxygen species production (DeCoursey, 2013). Voltage-sensor domains (VSDs) are sophisticated protein modules that sense changes in transmembrane voltage and regulate downstream effectors. VSDs consist of four transmembrane helices and a fourth helix that contains a signature pattern of positively charged residues that align to form salt bridges with acidic residues on the other helices. In classical voltage-gated ion channels (VGICs), VSDs are connected to a pore-gate domain (PGD) composed of two transmembrane helices that form an ion-permeation pathway. VSPs contain a VSD and PTEN-like cytoplasmic catalytic region (CCR), which consists of a phosphatase domain (PD) and C2 domain (Murata et al, 2005; Okamura et al, 2018).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
