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Jeevan B Gc, Bernard S Gerstman, Robert V Stahelin, Prem P Chapagain
The Ebola virus is a lipid-enveloped virus that obtains its lipid coat from the plasma membrane of the host cell it infects during the budding process. The Ebola virus protein VP40 localizes to the inner leaflet of the plasma membrane and forms the viral matrix, which provides the major structure for the Ebola virus particles. VP40 is initially a dimer that rearranges to a hexameric structure that mediates budding. VP40 hexamers and larger filaments have been shown to be stabilized by PI(4,5)P2 in the plasma membrane inner leaflet...
October 19, 2016: Physical Chemistry Chemical Physics: PCCP
Wataru Matsuzaki, Hiromasa Takahashi, Hiroyuki Nakamura, Toshihiko Murayama
Ceramide kinase (CerK) and ceramide-1-phosphate (C1P) are involved in various cellular functions, while regulation of the enzyme activity has not been well elucidated. We herein investigated the effects of several glycerophospholipids on human recombinant CerK activity with CaCl2 and MgCl2 by measuring the formation of fluorescent labeled C1P in vitro. CerK activities were 44.1±11.4 (pmol/µg/min) with vehicle, 137±29 with 2 mM CaCl2, and 144±32 with 2 mM MgCl2 in the glycerol/albumin buffer. The addition of glycerophospholipids such as phosphatidylcholine, phosphatidylinositol (PI), PI 4,5-bisphosphate (PI(4,5)P2), and phosphatidic acid had no effect on CerK activity with CaCl2, although PI(4,5)P2 and phosphatidic acid bound to CerK in the lipid-protein overlay assay...
2016: Biological & Pharmaceutical Bulletin
Elmer Hoekstra, Asha M Das, Marcella Willemsen, Marloes Swets, Peter J K Kuppen, Christien J van der Woude, Marco J Bruno, Jigisha P Shah, Timo L M Ten Hagen, John D Chisholm, William G Kerr, Maikel P Peppelenbosch, Gwenny M Fuhler
Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such "oncogenic" kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene...
September 28, 2016: Oncotarget
Carter J Swanson, Ruth F Sommese, Karl J Petersen, Michael Ritt, Joshua Karslake, David D Thomas, Sivaraj Sivaramakrishnan
Protein kinase C α (PKCα) is a nodal regulator in several intracellular signaling networks. PKCα is composed of modular domains that interact with each other to dynamically regulate spatial-temporal function. We find that PKCα specifically, rapidly and reversibly self-assembles in the presence of calcium in vitro. This phenomenon is dependent on, and can be modulated by an intramolecular interaction between the C1a and C2 protein domains of PKCα. Next, we monitor self-assembly of PKC-mCitrine fusion proteins using time-resolved and steady-state homoFRET...
2016: PloS One
Kristen E Rennoll-Bankert, M Sayeedur Rahman, Mark L Guillotte, Stephanie S Lehman, Magda Beier-Sexton, Joseph J Gillespie, Abdu F Azad
Rickettsiae are obligate intracellular pathogens that induce their uptake into non-phagocytic cells; however, the events instigating this process are incompletely understood. Importantly, diverse Rickettsia species are predicted to utilize divergent mechanisms to colonize host cells, as nearly all adhesins and effectors involved in host cell entry are differentially encoded in diverse Rickettsia species. One particular effector, RalF, a sec-7 domain containing protein that functions as a guanine nucleotide exchange factor of ADP-ribosylation factors (Arfs), is critical for R...
October 3, 2016: Infection and Immunity
Baptiste Fischer, Kevin Lüthy, Jone Paesmans, Charlotte De Koninck, Ine Maes, Jef Swerts, Sabine Kuenen, Valerie Uytterhoeven, Patrik Verstreken, Wim Versées
Mutations in TBC1D24 cause severe epilepsy and DOORS syndrome, but the molecular mechanisms underlying these pathologies are unresolved. We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. Cocrystallization and biochemistry showed that this pocket binds phosphoinositides phosphorylated at the 4 and 5 positions. The most prevalent patient mutations affect the phosphoinositide-binding pocket and inhibit lipid binding...
September 26, 2016: Nature Structural & Molecular Biology
Bradley A Webb, Katharine A White, Bree K Grillo-Hill, André Schönichen, Changhoon Choi, Diane L Barber
The Na-H exchanger NHE1 contributes to intracellular pH (pHi) homeostasis in normal cells and the constitutively increased pHi in cancer. NHE1 activity is allosterically regulated by intracellular protons, with greater activity at lower pHi. However, the molecular mechanism for pH-dependent NHE1 activity remains incompletely resolved. We report that an evolutionarily conserved cluster of histidine residues located in the C-terminal cytoplasmic domain between two phosphatidylinositol 4,5-bisphosphate-binding sites (PI(4,5)P2) of NHE1 confers pH-dependent PI(4,5)P2-binding and regulates NHE1 activity...
September 20, 2016: Journal of Biological Chemistry
Lauren O'Neil, Kathryn Andenoro, Isabella Pagano, Laura Carroll, Leah Langer, Zachary Dell, Davina Perera, Bradley W Treece, Frank Heinrich, Mathias Lösche, John F Nagle, Stephanie Tristram-Nagle
Efficient assembly of HIV-1 at the plasma membrane (PM) of the T-cell specifically requires PI(4,5)P2. It was previously shown that a highly basic region (HBR) of the matrix protein (MA) on the Gag precursor polyprotein Pr55(Gag) is required for membrane association. MA is N-terminally myristoylated, which enhances its affinity to membranes. In this work we used X-ray scattering and neutron reflectivity to determine how the physical properties and structure of lipid bilayers respond to the addition of binding domain peptides, either in the myristoylated form (MA31myr) or without the myristoyl group (MA31)...
September 15, 2016: Biochimica et Biophysica Acta
Simon J Bulley, Alaa Droubi, Jonathan H Clarke, Karen E Anderson, Len R Stephens, Phillip T Hawkins, Robin F Irvine
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic lipid kinases with physiological functions that are incompletely understood, not the least because genetic deletion and cell transfection have led to contradictory data. Here, we used the genetic tractability of DT40 cells to create cell lines in which endogenous PI5P4Kα was removed, either stably by genetic deletion or transiently (within 1 h) by tagging the endogenous protein genomically with the auxin degron. In both cases, removal impacted Akt phosphorylation, and by leaving one PI5P4Kα allele present but mutating it to be kinase-dead or have PI4P 5-kinase activity, we show that all of the effects on Akt phosphorylation were dependent on the ability of PI5P4Kα to synthesize phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] rather than to remove PI5P...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Preeti Sinha, Ranjeet Kumar Paswan, Anjali Kumari, Sanjay Kumar, Sanjeeva Bimal, Pradeep Das, Chandra Shekhar Lal
In this work, we have described the expression of ecto-ATPDase on the external surface of Leishmania donovani. This enzyme has the ability to hydrolyze extracellular ATP. There is a low level of ATP hydrolysis in the absence of divalent cation 2.5 ± 0.51 nM Pi 10(7) cells/h which shows the divalent cation-dependent activity of this enzyme in the intact parasite. However, MgCl2 stimulated the ATP hydrolysis to a greater extent compared with CaCl2 and ZnCl2. This activity was also observed when replaced by MnCl2...
December 2016: Current Microbiology
Mahtab Tavasoli, Abass Al-Momany, Xin Wang, Laiji Li, John Clark Edwards, Barbara J Ballermann
The chloride intracellular channel (CLIC) 5A is expressed at very high levels in renal glomeruli, in both endothelial cells (EC) and podocytes. CLIC5A stimulates Rac1- and PI[4,5]P2-dependent ERM (ezrin, radixin, moesin) activation. ERM proteins, in turn, function in lumen formation and in the development of actin-based cellular projections. In mice lacking CLIC5A, ERM phosphorylation is profoundly reduced in podocytes, but preserved in glomerular EC. Since glomerular EC also express CLIC4, we reasoned if CLIC4 activates ERM proteins like CLIC5A, then CLIC4 could compensate for the CLIC5A loss in glomerular EC...
August 31, 2016: American Journal of Physiology. Renal Physiology
P Junková, J Prchal, V Spiwok, R Pleskot, J Kadlec, L Krásný, R Hynek, R Hrabal, T Ruml
The Mason-Pfizer monkey virus is a type D retrovirus, which assembles its immature particles in the cytoplasm prior to their transport to the host cell membrane. The association with the membrane is mediated by the N-terminally myristoylated matrix protein. To reveal the role of particular residues which are involved in the capsid-membrane interaction, covalent labelling of arginine, lysine and tyrosine residues of the Mason-Pfizer monkey virus matrix protein bound to artificial liposomes containing 95% of phosphatidylcholine and 5% phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2 ) was performed...
August 31, 2016: Proteins
Matt Petrie, Joseph Esquibel, Greg Kabachinski, Stephanie Maciuba, Hirohide Takahashi, J Michael Edwardson, Thomas F J Martin
Neurotransmitters and peptide hormones are secreted by regulated vesicle exocytosis. CAPS (also known as CADPS) is a 145-kDa cytosolic and peripheral membrane protein required for vesicle docking and priming steps that precede Ca(2+)-triggered vesicle exocytosis. CAPS binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and SNARE proteins and is proposed to promote SNARE protein complex assembly for vesicle docking and priming. We characterized purified soluble CAPS as mainly monomer in equilibrium with small amounts of dimer...
September 30, 2016: Journal of Biological Chemistry
Kailash Gulshan, Gregory Brubaker, Heather Conger, Shuhui Wang, Renliang Zhang, Stanley L Hazen, Jonathan D Smith
RATIONALE: The molecular mechanism by which ATP-binding cassette transporter A1 (ABCA1) mediates cellular binding of apolipoprotein A-I (apoA1) and nascent high-density lipoprotein (HDL) assembly is not well understood. OBJECTIVE: To determine the cell surface lipid that mediates apoA1 binding to ABCA1-expressing cells and the role it plays in nascent HDL assembly. METHODS AND RESULTS: Using multiple biochemical and biophysical methods, we found that apoA1 binds specifically to phosphatidylinositol (4,5) bis-phosphate (PIP2)...
September 16, 2016: Circulation Research
Julia Patzig, Michelle S Erwig, Stefan Tenzer, Kathrin Kusch, Payam Dibaj, Wiebke Möbius, Sandra Goebbels, Nicole Schaeren-Wiemers, Klaus-Armin Nave, Hauke B Werner
Myelination of axons facilitates rapid impulse propagation in the nervous system. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular cause of many pathological features, including the frequently observed myelin outfoldings, remained unknown. Using label-free quantitative proteomics, we find that the presence of myelin outfoldings correlates with a loss of cytoskeletal septins in myelin. Regulated by phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2)-levels, myelin septins (SEPT2/SEPT4/SEPT7/SEPT8) and the PI(4,5)P2-adaptor anillin form previously unrecognized filaments that extend longitudinally along myelinated axons...
2016: ELife
Mark R Bleackley, Jennifer A E Payne, Brigitte M E Hayes, Thomas Durek, David J Craik, Thomas M A Shafee, Ivan K H Poon, Mark D Hulett, Nicole L van der Weerden, Marilyn A Anderson
The plant defensin NaD1 is a potent antifungal molecule that also targets tumor cells with a high efficiency. We examined the features of NaD1 that contribute to these two activities by producing a series of chimeras with NaD2, a defensin that has relatively poor activity against fungi and no activity against tumor cells. All plant defensins have a common tertiary structure known as a cysteine-stabilized α-β motif which consists of an α helix and a triple-stranded β-sheet stabilized by four disulfide bonds...
October 2016: Antimicrobial Agents and Chemotherapy
Pirta Hotulainen, Juha Saarikangas
The post-synaptic spines of neuronal dendrites are highly elaborate membrane protrusions. Their anatomy, stability and density are intimately linked to cognitive performance. The morphological transitions of spines are powered by coordinated polymerization of actin filaments against the plasma membrane, but how the membrane-associated polymerization is spatially and temporally regulated has remained ill defined. Here, we discuss our recent findings showing that dendritic spines can be initiated by direct membrane bending by the I-BAR protein MIM/Mtss1...
May 2016: Communicative & Integrative Biology
Rahul Yadav, Ravi Vattepu, Moriah R Beck
Actin cytoskeleton remodeling requires the coordinated action of a large number of actin binding proteins that reorganize the actin cytoskeleton by promoting polymerization, stabilizing filaments, causing branching, or crosslinking filaments. Palladin is a key cytoskeletal actin binding protein whose normal function is to enable cell motility during development of tissues and organs of the embryo and in wound healing, but palladin is also responsible for regulating the ability of cancer cells to become invasive and metastatic...
October 9, 2016: Journal of Molecular Biology
Jonathan Pacheco, Laura Dominguez, A Bohórquez-Hernández, Alexander Asanov, Luis Vaca
STIM1 and Orai1 are the main components of a widely conserved Calcium influx pathway known as store-operated calcium entry (SOCE). STIM1 is a calcium sensor, which oligomerizes and activates Orai channels when calcium levels drop inside the endoplasmic reticulum (ER). The series of molecular rearrangements that STIM1 undergoes until final activation of Orai1 require the direct exposure of the STIM1 domain known as SOAR (Stim Orai Activating Region). In addition to these complex molecular rearrangements, other constituents like lipids at the plasma membrane, play critical roles orchestrating SOCE...
2016: Scientific Reports
Beichen Xie, Phuoc My Nguyen, Alenka Guček, Antje Thonig, Sebastian Barg, Olof Idevall-Hagren
Insulin secretion from pancreatic β cells is regulated by the blood glucose concentration and occurs through Ca(2+)-triggered exocytosis. The activities of multiple ion channels in the β cell plasma membrane are required to fine-tune insulin secretion in order to maintain normoglycemia. Phosphoinositide lipids in the plasma membrane often gate ion channels, and variations in the concentration of these lipids affect ion-channel open probability and conductance. Using light-regulated synthesis or depletion of plasma membrane phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2), we found that this lipid positively regulated both depolarization- and glucose-triggered Ca(2+) influx in a dose-dependent manner...
July 21, 2016: Cell Chemical Biology
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