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      The hydrophobic nature of a novel membrane interface regulates the enzyme activity of a voltage-sensing phosphatase


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          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.

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          Most cited references40

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          Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor.

          Changes in membrane potential affect ion channels and transporters, which then alter intracellular chemical conditions. Other signalling pathways coupled to membrane potential have been suggested but their underlying mechanisms are unknown. Here we describe a novel protein from the ascidian Ciona intestinalis that has a transmembrane voltage-sensing domain homologous to the S1-S4 segments of voltage-gated channels and a cytoplasmic domain similar to phosphatase and tensin homologue. This protein, named C. intestinalis voltage-sensor-containing phosphatase (Ci-VSP), displays channel-like 'gating' currents and directly translates changes in membrane potential into the turnover of phosphoinositides. The activity of the phosphoinositide phosphatase in Ci-VSP is tuned within a physiological range of membrane potential. Immunocytochemical studies show that Ci-VSP is expressed in Ciona sperm tail membranes, indicating a possible role in sperm function or morphology. Our data demonstrate that voltage sensing can function beyond channel proteins and thus more ubiquitously than previously realized.
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            Recognition of transmembrane helices by the endoplasmic reticulum translocon.

            Membrane proteins depend on complex translocation machineries for insertion into target membranes. Although it has long been known that an abundance of nonpolar residues in transmembrane helices is the principal criterion for membrane insertion, the specific sequence-coding for transmembrane helices has not been identified. By challenging the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments, we have determined the basic features of this code, including a 'biological' hydrophobicity scale. We find that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. Our results indicate that direct protein-lipid interactions are critical during translocon-mediated membrane insertion.
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              Distribution of amino acids in a lipid bilayer from computer simulations.

              We have calculated the distribution in a lipid bilayer of small molecules mimicking 17 natural amino acids in atomistic detail by molecular dynamics simulation. We considered both charged and uncharged forms for Lys, Arg, Glu, and Asp. The results give detailed insight in the molecular basis of the preferred location and orientation of each side chain as well the preferred charge state for ionizable residues. Partitioning of charged and polar side chains is accompanied by water defects connecting the side chains to bulk water. These water defects dominate the energetic of partitioning, rather than simple partitioning between water and a hydrophobic phase. Lys, Glu, and Asp become uncharged well before reaching the center of the membrane, but Arg may be either charged or uncharged at the center of the membrane. Phe has a broad distribution in the membrane but Trp and Tyr localize strongly to the interfacial region. The distributions are useful for the development of coarse-grained and implicit membrane potentials for simulation and structure prediction. We discuss the relationship between the distribution in membranes, bulk partitioning to cyclohexane, and several amino acid hydrophobicity scales.

                Author and article information

                Role: Reviewing Editor
                Role: Senior Editor
                eLife Sciences Publications, Ltd
                28 November 2018
                : 7
                : e41653
                [1 ]deptIntegrative Physiology, Department of Physiology, Graduate School of Medicine Osaka University OsakaJapan
                [2 ]deptGraduate School of Frontier Biosciences Osaka University OsakaJapan
                [3 ]deptSchool of Medical Technology Teikyo University TokyoJapan
                [4 ]deptInstitute for Protein Research Osaka University OsakaJapan
                [5 ]deptDepartment of Physiology, Division of Life Sciences, Faculty of Medicine Osaka Medical College OsakaJapan
                University of Wisconsin-Madison United States
                The University of Texas at Austin United States
                University of Wisconsin-Madison United States
                Author information
                © 2018, Kawanabe et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                : 01 September 2018
                : 28 November 2018
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP15K18516
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 16H02617
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 25253016
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003382, Core Research for Evolutional Science and Technology;
                Award ID: JPMJCR14M3
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001700, Ministry of Education, Culture, Sports, Science and Technology;
                Award ID: 15H05901
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Research Article
                Structural Biology and Molecular Biophysics
                Custom metadata
                Electrophysiological and fluorometric studies of Ci-VSP expressed in Xenopus oocyte revealed two states of the enzyme region with distinct enzyme activity and distinct coupling to the voltage sensor.

                Life sciences
                voltage sensor,ascidian,phosphoinositide,phosphatase,membrane interaction,domain to domain coupling,c. intestinalis


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