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Regulation of KCNQ/Kv7 family voltage-gated K channels by lipids.
Taylor KC, Sanders CR
(2017) Biochim Biophys Acta Biomembr 1859: 586-597
MeSH Terms: Amino Acid Sequence, Binding Sites, Cell Membrane, Epilepsy, Benign Neonatal, Fatty Acids, Unsaturated, Hearing Loss, Bilateral, Humans, Hydrophobic and Hydrophilic Interactions, KCNQ1 Potassium Channel, Long QT Syndrome, Membrane Lipids, Models, Molecular, Phosphatidylinositol 4,5-Diphosphate, Protein Binding, Protein Isoforms, Protein Structure, Secondary
Show Abstract · Added November 21, 2018
Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) subfamily of voltage-gated K channels, which are regulated by both PIP and PUFAs and play a variety of important roles in human health and disease. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
Copyright © 2016 Elsevier B.V. All rights reserved.
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Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein.
Mercredi PY, Bucca N, Loeliger B, Gaines CR, Mehta M, Bhargava P, Tedbury PR, Charlier L, Floquet N, Muriaux D, Favard C, Sanders CR, Freed EO, Marchant J, Summers MF
(2016) J Mol Biol 428: 1637-55
MeSH Terms: Cell Membrane, HIV-1, Lipids, Liposomes, Magnetic Resonance Spectroscopy, Membrane Microdomains, Phosphatidylinositol 4,5-Diphosphate, Phosphatidylserines, Protein Binding, Protein Structure, Tertiary, gag Gene Products, Human Immunodeficiency Virus
Show Abstract · Added November 21, 2018
Assembly of HIV-1 particles is initiated by the trafficking of viral Gag polyproteins from the cytoplasm to the plasma membrane, where they co-localize and bud to form immature particles. Membrane targeting is mediated by the N-terminally myristoylated matrix (MA) domain of Gag and is dependent on the plasma membrane marker phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Recent studies revealed that PI(4,5)P2 molecules containing truncated acyl chains [tr-PI(4,5)P2] are capable of binding MA in an "extended lipid" conformation and promoting myristoyl exposure. Here we report that tr-PI(4,5)P2 molecules also readily bind to non-membrane proteins, including HIV-1 capsid, which prompted us to re-examine MA-PI(4,5)P2 interactions using native lipids and membrane mimetic liposomes and bicelles. Liposome binding trends observed using a recently developed NMR approach paralleled results of flotation assays, although the affinities measured under the equilibrium conditions of NMR experiments were significantly higher. Native PI(4,5)P2 enhanced MA binding to liposomes designed to mimic non-raft-like regions of the membrane, suggesting the possibility that binding of the protein to disordered domains may precede Gag association with, or nucleation of, rafts. Studies with bicelles revealed a subset of surface and myr-associated MA residues that are sensitive to native PI(4,5)P2, but cleft residues that interact with the 2'-acyl chains of tr-PI(4,5)P2 molecules in aqueous solution were insensitive to native PI(4,5)P2 in bicelles. Our findings call to question extended-lipid MA:membrane binding models, and instead support a model put forward from coarse-grained simulations indicating that binding is mediated predominantly by dynamic, electrostatic interactions between conserved basic residues of MA and multiple PI(4,5)P2 and phosphatidylserine molecules.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein.
Hamilton PJ, Belovich AN, Khelashvili G, Saunders C, Erreger K, Javitch JA, Sitte HH, Weinstein H, Matthies HJG, Galli A
(2014) Nat Chem Biol 10: 582-589
MeSH Terms: Amino Acid Substitution, Amphetamine, Animals, Behavior, Animal, Cell Membrane, Central Nervous System Stimulants, Dopamine, Dopamine Plasma Membrane Transport Proteins, Drosophila melanogaster, Gene Expression, Humans, Locomotion, Models, Molecular, Neurons, Phosphatidylinositol 4,5-Diphosphate, Protein Structure, Tertiary, Transgenes
Show Abstract · Added February 17, 2015
Phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates the function of ion channels and transporters. Here, we demonstrate that PIP2 directly binds the human dopamine (DA) transporter (hDAT), a key regulator of DA homeostasis and a target of the psychostimulant amphetamine (AMPH). This binding occurs through electrostatic interactions with positively charged hDAT N-terminal residues and is shown to facilitate AMPH-induced, DAT-mediated DA efflux and the psychomotor properties of AMPH. Substitution of these residues with uncharged amino acids reduces hDAT-PIP2 interactions and AMPH-induced DA efflux without altering the hDAT physiological function of DA uptake. We evaluated the significance of this interaction in vivo using locomotion as a behavioral assay in Drosophila melanogaster. Expression of mutated hDAT with reduced PIP2 interaction in Drosophila DA neurons impairs AMPH-induced locomotion without altering basal locomotion. We present what is to our knowledge the first demonstration of how PIP2 interactions with a membrane protein can regulate the behaviors of complex organisms.
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17 MeSH Terms
Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate.
Buchmayer F, Schicker K, Steinkellner T, Geier P, Stübiger G, Hamilton PJ, Jurik A, Stockner T, Yang JW, Montgomery T, Holy M, Hofmaier T, Kudlacek O, Matthies HJ, Ecker GF, Bochkov V, Galli A, Boehm S, Sitte HH
(2013) Proc Natl Acad Sci U S A 110: 11642-7
MeSH Terms: Amphetamine, HEK293 Cells, Humans, Phosphatidylinositol 4,5-Diphosphate, Second Messenger Systems, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added February 19, 2015
Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP2 by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP2-synthesis. We tested the effects of the verified scarcity of PIP2 on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP2 in pull-down assays. On decreased PIP2 availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP2 reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP2. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP2-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP2 binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.
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6 MeSH Terms
Phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids regulate the phosphorylation of syntaxin N-terminus by modulating both its position and local structure.
Khelashvili G, Galli A, Weinstein H
(2012) Biochemistry 51: 7685-98
MeSH Terms: Amino Acid Sequence, Humans, Molecular Dynamics Simulation, Molecular Sequence Data, Phosphatidylcholines, Phosphatidylinositol 4,5-Diphosphate, Phosphorylation, Protein Conformation, Protein Isoforms, Qa-SNARE Proteins, SNARE Proteins, Sequence Alignment
Show Abstract · Added February 19, 2015
Syntaxin (STX) is a N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein that binds to the plasma membrane and regulates ion channels and neurotransmitter transporters. Experiments have established the involvement of the N-terminal segment of STX in direct protein-protein interactions and have suggested a critical role for the phosphorylation of serine 14 (S14) by casein kinase-2 (CK2). Because the organization of STX in the plasma membrane was shown to be regulated by phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids, we investigated the mechanistic involvement of PIP(2) lipids in modulating both the membrane interaction and the phosphorylation of STX, using a computational strategy that integrates mesoscale continuum modeling of protein-membrane interactions, with all-atom molecular dynamics (MD) simulations. Iterative applications of this protocol produced quantitative evaluations of lipid-type demixing due to the protein and identified conformational differences between STX immersed in PIP(2)-containing and PIP(2)-depleted membranes. Specific sites in STX were identified to be important for the electrostatic interactions with the PIP(2) lipids attracted to the protein, and the segregation of PIP(2) lipids near the protein is shown to have a dramatic effect on the positioning of the STX N-terminal segment with respect to the membrane/water interface. This PIP(2)-dependent repositioning is shown to modulate the extent of exposure of S14 to large reagents representing the CK2 enzyme and hence the propensity for phosphorylation. The prediction of STX sites involved in such PIP(2)-dependent regulation of STX phosphorylation at S14 offers experimentally testable probes of the mechanisms and models presented in this study, through structural modifications that can modulate the effects.
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12 MeSH Terms
Membrane-bound myo1c powers asymmetric motility of actin filaments.
Pyrpassopoulos S, Feeser EA, Mazerik JN, Tyska MJ, Ostap EM
(2012) Curr Biol 22: 1688-92
MeSH Terms: Acanthamoeba castellanii, Actin Cytoskeleton, Blood Proteins, Cell Membrane, Chromatin Assembly and Disassembly, Lipid Bilayers, Molecular Motor Proteins, Movement, Myosin Type I, Phosphatidylinositol 4,5-Diphosphate, Phosphoproteins
Show Abstract · Added May 19, 2014
Class I myosins are molecular motors that link cellular membranes to the actin cytoskeleton and play roles in membrane tension generation, membrane dynamics, and mechanosignal transduction. The widely expressed myosin-Ic (myo1c) isoform binds tightly to phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)] via a pleckstrin homology domain located in the myo1c tail, which is important for its proper cellular localization. In this study, we found that myo1c can power actin motility on fluid membranes composed of physiological concentrations of PtdIns(4,5)P(2) and that this motility is inhibited by high concentrations of anionic phospholipids. Strikingly, this motility occurs along curved paths in a counterclockwise direction (i.e., the actin filaments turn in leftward circles). A biotinylated myo1c construct containing only the motor domain and the lever arm anchored via streptavidin on a membrane containing biotinylated lipid can also generate asymmetric motility, suggesting that the tail domain is not required for the counterclockwise turning. We found that the ability to produce counterclockwise motility is not a universal characteristic of myosin-I motors, as membrane-bound myosin-Ia (myo1a) and myosin-Ib (myo1b) are able to power actin gliding, but the actin gliding has no substantial turning bias. This work reveals a possible mechanism for establishing asymmetry in relationship to the plasma membrane.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Direct modification and activation of a nuclear receptor-PIP₂ complex by the inositol lipid kinase IPMK.
Blind RD, Suzawa M, Ingraham HA
(2012) Sci Signal 5: ra44
MeSH Terms: Binding Sites, Blotting, Western, Cell Nucleus, Chromatin Immunoprecipitation, HEK293 Cells, Humans, Kinetics, Models, Molecular, Molecular Structure, Mutation, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphatidylinositol 4,5-Diphosphate, Phosphatidylinositol Phosphates, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Protein Structure, Tertiary, RNA Interference, Signal Transduction, Steroidogenic Factor 1, Substrate Specificity
Show Abstract · Added August 18, 2015
Phosphatidylinositol 4,5-bisphosphate (PIP₂) is best known as a plasma membrane-bound regulatory lipid. Although PIP₂ and phosphoinositide-modifying enzymes coexist in the nucleus, their nuclear roles remain unclear. We showed that inositol polyphosphate multikinase (IPMK), which functions both as an inositol kinase and as a phosphoinositide 3-kinase (PI3K), interacts with the nuclear receptor steroidogenic factor 1 (SF-1) and phosphorylates its bound ligand, PIP₂. In vitro studies showed that PIP₂ was not phosphorylated by IPMK if PIP₂ was displaced or blocked from binding to the large hydrophobic pocket of SF-1 and that the ability to phosphorylate PIP₂ bound to SF-1 was specific to IPMK and did not occur with type 1 p110 PI3Ks. IPMK-generated SF-1-PIP₃ (phosphatidylinositol 3,4,5-trisphosphate) was dephosphorylated by the lipid phosphatase PTEN. Consistent with the in vitro activities of IPMK and PTEN on SF-1-PIP(n), SF-1 transcriptional activity was reduced by silencing IPMK or overexpressing PTEN. This ability of lipid kinases and phosphatases to directly remodel and alter the activity of a non-membrane protein-lipid complex establishes a previously unappreciated pathway for promoting lipid-mediated signaling in the nucleus.
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22 MeSH Terms
Function of the syndecan-4 cytoplasmic domain in oligomerization and association with α-actinin in turkey muscle satellite cells.
Shin J, Song Y, McFarland DC, Velleman SG
(2012) Mol Cell Biochem 363: 437-44
MeSH Terms: Actinin, Animals, Cell Membrane, Cells, Cultured, Cytoplasm, Male, Microscopy, Confocal, Phosphatidylinositol 4,5-Diphosphate, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Multimerization, Protein Structure, Tertiary, RNA Interference, Satellite Cells, Skeletal Muscle, Syndecan-4, Transfection, Turkeys, Vinculin
Show Abstract · Added March 3, 2014
Syndecan-4 (S4) is a cell membrane heparan sulfate proteoglycan that plays a role in satellite cell mediated myogenesis. S4 modulates the proliferation of myogenic satellite cells, but the mechanism of how S4 functions during myogenesis is not well understood. In other cell systems, S4 has been shown to form oligomers in the cell membrane and interact through its cytoplasmic domain with the cytoskeletal protein α-actinin. This study addressed if S4 forms oligomers and interacts with α-actinin in muscle. The S4 cytoplasmic domain was found to interact with α-actinin in a phosphatidylinositol-4,5-bisphosphate dependent manner, but did not associate with vinculin. Through confocal microscopy, both S4 and syndecan-4 without the cytoplasmic domain were localized to the cell membrane. Although the cytoplasmic domain was necessary for the interaction with α-actinin, S4 oligomer formation occurred in the absence of the cytoplasmic domain. These data indicated that S4 function in skeletal muscle is mediated through the formation of oligomers and interaction with the cytoskeletal protein α-actinin.
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18 MeSH Terms
Integrin adhesion and force coupling are independently regulated by localized PtdIns(4,5)2 synthesis.
Legate KR, Takahashi S, Bonakdar N, Fabry B, Boettiger D, Zent R, Fässler R
(2011) EMBO J 30: 4539-53
MeSH Terms: Animals, Carrier Proteins, Cell Adhesion, Cells, Cultured, Focal Adhesions, Integrins, Membrane Proteins, Mice, Phosphatidylinositol 4,5-Diphosphate, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Talin, Vinculin
Show Abstract · Added February 25, 2014
The 90-kDa isoform of the lipid kinase PIP kinase Type I γ (PIPKIγ) localizes to focal adhesions (FAs), where it provides a local source of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). Although PtdIns(4,5)P(2) regulates the function of several FA-associated molecules, the role of the FA-specific pool of PtdIns(4,5)P(2) is not known. We report that the genetic ablation of PIPKIγ specifically from FAs results in defective integrin-mediated adhesion and force coupling. Adhesion defects in cells deficient in FAPtdIns(4,5)P(2) synthesis are corrected within minutes while integrin-actin force coupling remains defective over a longer period. Talin and vinculin, but not kindlin, are less efficiently recruited to new adhesions in these cells. These data demonstrate that the specific depletion of PtdIns(4,5)P(2) from FAs temporally separates integrin-ligand binding from integrin-actin force coupling by regulating talin and vinculin recruitment. Furthermore, it suggests that force coupling relies heavily on locally generated PtdIns(4,5)P(2) rather than bulk membrane PtdIns(4,5)P(2).
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13 MeSH Terms
Serum withdrawal-induced accumulation of phosphoinositide 3-kinase lipids in differentiating 3T3-L6 myoblasts: distinct roles for Ship2 and PTEN.
Mandl A, Sarkes D, Carricaburu V, Jung V, Rameh L
(2007) Mol Cell Biol 27: 8098-112
MeSH Terms: Animals, Catalysis, Cell Differentiation, Cell Proliferation, Cell Survival, HeLa Cells, Humans, Inositol Polyphosphate 5-Phosphatases, Insulin, Mice, Mutant Proteins, Myoblasts, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphatidylinositol 4,5-Diphosphate, Phosphatidylinositol Phosphates, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt, Rats, Serum
Show Abstract · Added December 10, 2018
Phosphoinositide 3-kinase (PI3K) activation and synthesis of phosphatidylinositol-3,4-bisphosphate (PI-3,4-P2) and phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3) lipids mediate growth factor signaling that leads to cell proliferation, migration, and survival. PI3K-dependent activation of Akt is critical for myoblast differentiation induced by serum withdrawal, suggesting that in these cells PI3K signaling is activated in an unconventional manner. Here we investigate the mechanisms by which PI3K signaling and Akt are regulated during myogenesis. We report that PI-3,4-P2 and PI-3,4,5-P3 accumulated in the plasma membranes of serum-starved 3T3-L6 myoblasts due to de novo synthesis and increased lipid stability. Surprisingly, only newly synthesized lipids were capable of activating Akt. Knockdown of the lipid phosphatase PTEN moderately increased PI3K lipids but significantly increased Akt phosphorylation and promoted myoblast differentiation. Knockdown of the lipid phosphatase Ship2, on the other hand, dramatically increased the steady-state levels of PI-3,4,5-P3 but did not affect Akt phosphorylation and increased apoptotic cell death. Together, these results reveal the existence of two distinct pools of PI3K lipids in differentiating 3T3-L6 myoblasts: a pool of nascent lipids that is mainly dephosphorylated by PTEN and is capable of activating Akt and promoting myoblast differentiation and a stable pool that is dephosphorylated by Ship2 and is unable to activate Akt.
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