Identification and Dynamics of the Human ZDHHC16-ZDHHC6 Palmitoylation Cascade
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Increased O-Glcnacylation Rapidly Decreases GABAAR Currents in Hippocampus but Depresses Neuronal Output L
www.nature.com/scientificreports OPEN Increased O-GlcNAcylation rapidly decreases GABAAR currents in hippocampus but depresses neuronal output L. T. Stewart1,3, K. Abiraman1,3, J. C. Chatham2 & L. L. McMahon1 ✉ O-GlcNAcylation, a post-translational modifcation involving O-linkage of β-N-acetylglucosamine to Ser/Thr residues on target proteins, is increasingly recognized as a critical regulator of synaptic function. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. An acute increase in O-GlcNAcylation can afect neuronal communication by inducing long-term depression (LTD) of excitatory transmission at hippocampal CA3-CA1 synapses, as well as suppressing hyperexcitable circuits in vitro and in vivo. Despite these fndings, to date, no studies have directly examined how O-GlcNAcylation modulates the efcacy of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable efect on the excitation/inhibition balance. The overall efect of increased O-GlcNAc is reduced synaptically-driven spike probability via synaptic depression and decreased intrinsic excitability. Our results position O-GlcNAcylation as a novel regulator of the overall excitation/inhibition balance and neuronal output. Synaptic integration and spike initiation in neurons is controlled by synaptic inhibition, which strongly infu- ences neuronal output and information processing1. Importantly, the balance of excitation to inhibition (E/I) is crucial to the proper functioning of circuits, and E/I imbalances have been implicated in a number of neurode- velopmental disorders and neurodegenerative diseases including schizophrenia, autism spectrum disorders, and Alzheimer’s disease2–5. -
Pore Formation: an Ancient Yet Complex Form of Attack ⁎ Ioan Iacovache, F
Available online at www.sciencedirect.com Biochimica et Biophysica Acta 1778 (2008) 1611–1623 www.elsevier.com/locate/bbamem Review Pore formation: An ancient yet complex form of attack ⁎ Ioan Iacovache, F. Gisou van der Goot , Lucile Pernot Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Faculty of Life Sciences, Station 15, CH 1015 Lausanne, Switzerland Received 13 November 2007; received in revised form 3 January 2008; accepted 4 January 2008 Available online 12 February 2008 Abstract Bacteria, as well as higher organisms such as sea anemones or earthworms, have developed sophisticated virulence factors such as the pore- forming toxins (PFTs) to mount their attack against the host. One of the most fascinating aspects of PFTs is that they can adopt a water-soluble form at the beginning of their lifetime and become an integral transmembrane protein in the membrane of the target cells. There is a growing understanding of the sequence of events and the various conformational changes undergone by these toxins in order to bind to the host cell surface, to penetrate the cell membranes and to achieve pore formation. These points will be addressed in this review. © 2008 Elsevier B.V. All rights reserved. Keywords: Pore-forming toxin; Perforin; Cholesterol-dependent cytolysin; Aerolysin; Actinoporin Contents 1. Introduction..............................................................1611 2. Structural classification of pore-forming toxins............................................1612 2.1. α-PFT .............................................................1612 2.1.1. Colicins........................................................1612 2.1.2. Actinoporins .....................................................1612 2.1.3. Insecticidal pore-forming toxins of the Cry family..................................1615 2.2. The ß-PFTs ..........................................................1615 2.2.1. S. aureus PFTs....................................................1615 2.2.2. -
REVIEW G-Protein-Coupled Receptors, Cholesterol and Palmitoylation: Facts
371 REVIEW G-protein-coupled receptors, cholesterol and palmitoylation: facts about fats Bice Chini and Marco Parenti1 Cellular and Molecular Pharmacology Section, CNR Institute of Neuroscience, Via Vanvitelli 32, 20129 Milan, Italy 1Department of Experimental Medicine, University of Milano-Bicocca, Monza, Italy (Correspondence should be addressed to B Chini; Email: [email protected]) Abstract G-protein-coupled receptors (GPCRs) are integral membrane proteins, hence it is not surprising that a number of their structural and functional features are modulated by both proteins and lipids. The impact of interacting proteins and lipids on the assembly and signalling of GPCRs has been extensively investigated over the last 20–30 years, and a further impetus has been given by the proposal that GPCRs and/or their immediate signalling partners (G proteins) can partition within plasma membrane domains, termed rafts and caveolae, enriched in glycosphingolipids and cholesterol. The high content of these specific lipids, in particular of cholesterol, in the vicinity of GPCR transmembranes can affect GPCR structure and/or function. In addition, most GPCRs are post-translationally modified with one or more palmitic acid(s), a 16-carbon saturated fatty acid, covalently bound to cysteine(s) localised in the carboxyl-terminal cytoplasmic tail. The insertion of palmitate into the cytoplasmic leaflet of the plasma membrane can create a fourth loop, thus profoundly affecting GPCR structure and hence the interactions with intracellular partner proteins. This review briefly highlights how lipids of the membrane and the receptor themselves can influence GPCR organisation and functioning. Journal of Molecular Endocrinology (2009) 42, 371–379 G-protein-coupled receptors–cholesterol of phospholipids. -
Toxigence of Anthrax Vaccine Strains
UDC 579.62 hps://doi.org/10.31548/ujvs2020.03.009 TOXIGENCE OF ANTHRAX VACCINE STRAINS G. A. ZAVIRIYHA, Candidate of Agricultural Sciences hps://orcid.org/0000-0002-46028477 "State Center for Innovave Biotechnology", Kyiv, Ukraine Е-mail: [email protected] U. N. YANENKO, Candidate of Veterinary Sciences hps://orcid.org/ 0000-0001-5678-3356 "State Center for Innovave Biotechnology", Kyiv, Ukraine Е-mail: [email protected], N. I. KOSYANCHUK, Candidate of Veterinary Sciences, Associate Professor Department of Veterinary Hygiene Named Aer Professor A. K. Skorokhodko hps://orcid.org/ 0000-0002- 3055-8107 Naonal University of Life and Environmental Sciences of Ukraine, Kyiv, Ukraine Е-mail: [email protected] Abstract. The arcle presents the results of the studying of anthrax strains and Bacillus anthracis-like strains on the formaon of toxins. We found that anthrax vaccine strains acvely produce exotoxins to the culture fluid. The amount of specific protein is different under the same incubaon condions and depends on the individual characteriscs of the microorganism populaon, because of this, different ters of the toxin are registered. Strain B. anthracis K-79 Z (vaccine) with the same number of planng microbial cells and growing on the same culture medium and at the same temperature produces by two orders of magnitude more exotoxin than strains B. anthracis Tsenkovsky II IBM 92Z (virulent), B. anthracis Stern 34F2, (vaccine), B. anthracis 55 (vaccine), B. anthracis SB (vaccine), B. anthracis Tsenkovsky I (vaccine, аpathogenic). The amount of exotoxin may change if the pH of the medium changes. The acvity of exotoxin producon, when the pH changes, depends on the characteriscs of the anthrax strain. -
Palmitoylation and Oxidation of the Cysteine Rich Region of SNAP-25 and Their Effects on Protein Interactions
Brigham Young University BYU ScholarsArchive Theses and Dissertations 2007-07-17 Palmitoylation and Oxidation of the Cysteine Rich Region of SNAP-25 and their Effects on Protein Interactions Derek Luberli Martinez Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/etd Part of the Neuroscience and Neurobiology Commons BYU ScholarsArchive Citation Martinez, Derek Luberli, "Palmitoylation and Oxidation of the Cysteine Rich Region of SNAP-25 and their Effects on Protein Interactions" (2007). Theses and Dissertations. 985. https://scholarsarchive.byu.edu/etd/985 This Thesis is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. by Brigham Young University in partial fulfillment of the requirements for the degree of Brigham Young University All Rights Reserved BRIGHAM YOUNG UNIVERSITY GRADUATE COMMITTEE APPROVAL and by majority vote has been found to be satisfactory. ________________________ ______________________________________ Date ________________________ ______________________________________ Date ________________________ ______________________________________ Date ________________________ ______________________________________ Date BRIGHAM YOUNG UNIVERSITY As chair of the candidate’s graduate committee, I have read the format, citations and bibliographical style are consistent -
Regulation of G Protein-Coupled Receptors by Palmitoylation and Cholesterol Alan D Goddard and Anthony Watts*
Goddard and Watts BMC Biology 2012, 10:27 http://www.biomedcentral.com/1741-7007/10/27 COMMENTARY Open Access Regulation of G protein-coupled receptors by palmitoylation and cholesterol Alan D Goddard and Anthony Watts* See research article www.biomedcentral.com/content/1471-2121/13/6 directed to elucidating GPCR crystal structures and a Abstract number of the structures obtained seem to indicate the Due to their membrane location, G protein-coupled presence of receptor dimers. Intriguingly, the β2-adrenergic receptors (GPCRs) are subject to regulation by soluble receptor (β2AR) crystalized with cholesterol molecules and integral membrane proteins as well as membrane and a post-translationally added palmitate group from components, including lipids and sterols. GPCRs also each protomer forming most of the dimer interface [3], undergo a variety of post-translational modifications, suggesting a role for lipids and sterols, in addition to including palmitoylation. A recent article by Zheng et protein-protein interactions, in GPCR dimeri zation. al. in BMC Cell Biology demonstrates cooperative roles However, it was not clear whether this accurately repre- for receptor palmitoylation and cholesterol binding in sented the conformation of the dimer within native lipid GPCR dimerization and G protein coupling, underlining bilayers. A recent study in BMC Cell Biology by Zheng et the complex regulation of these receptors. al. [4] has revealed a complex interplay between choles- terol, palmitate, receptor dimeri zation and G protein activation. Their study showed that reducing cholesterol Commentary levels or preventing palmitoylation of the μ-opioid G protein-coupled receptors (GPCRs) represent the receptor (OPRM1) reduced receptor dimerization and largest family of integral membrane proteins encoded by Gα association. -
Phospholipase D in Cell Proliferation and Cancer
Vol. 1, 789–800, September 2003 Molecular Cancer Research 789 Subject Review Phospholipase D in Cell Proliferation and Cancer David A. Foster and Lizhong Xu The Department of Biological Sciences, Hunter College of The City University of New York, New York, NY Abstract trafficking, cytoskeletal reorganization, receptor endocytosis, Phospholipase D (PLD) has emerged as a regulator of exocytosis, and cell migration (4, 5). A role for PLD in cell several critical aspects of cell physiology. PLD, which proliferation is indicated from reports showing that PLD catalyzes the hydrolysis of phosphatidylcholine (PC) to activity is elevated in response to platelet-derived growth factor phosphatidic acid (PA) and choline, is activated in (PDGF; 6), fibroblast growth factor (7, 8), epidermal growth response to stimulators of vesicle transport, endocyto- factor (EGF; 9), insulin (10), insulin-like growth factor 1 (11), sis, exocytosis, cell migration, and mitosis. Dysregula- growth hormone (12), and sphingosine 1-phosphate (13). PLD tion of these cell biological processes occurs in the activity is also elevated in cells transformed by a variety development of a variety of human tumors. It has now of transforming oncogenes including v-Src (14), v-Ras (15, 16), been observed that there are abnormalities in PLD v-Fps (17), and v-Raf (18). Thus, there is a growing body of expression and activity in many human cancers. In this evidence linking PLD activity with mitogenic signaling. While review, evidence is summarized implicating PLD as a PLD has been associated with many aspects of cell physiology critical regulator of cell proliferation, survival signaling, such as membrane trafficking and cytoskeletal organization cell transformation, and tumor progression. -
Ubiquitin-Dependent Folding of the Wnt Signaling Coreceptor LRP6
RESEARCH ARTICLE Ubiquitin-dependent folding of the Wnt signaling coreceptor LRP6 Elsa Perrody1†, Laurence Abrami1†, Michal Feldman1, Beatrice Kunz1, Sylvie Urbe´ 2, F Gisou van der Goot1* 1Global Health Institute, Ecole Polytechnique Fe´de´rale de Lausanne, Lausanne, Switzerland; 2Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom Abstract Many membrane proteins fold inefficiently and require the help of enzymes and chaperones. Here we reveal a novel folding assistance system that operates on membrane proteins from the cytosolic side of the endoplasmic reticulum (ER). We show that folding of the Wnt signaling coreceptor LRP6 is promoted by ubiquitination of a specific lysine, retaining it in the ER while avoiding degradation. Subsequent ER exit requires removal of ubiquitin from this lysine by the deubiquitinating enzyme USP19. This ubiquitination-deubiquitination is conceptually reminiscent of the glucosylation-deglucosylation occurring in the ER lumen during the calnexin/ calreticulin folding cycle. To avoid infinite futile cycles, folded LRP6 molecules undergo palmitoylation and ER export, while unsuccessfully folded proteins are, with time, polyubiquitinated on other lysines and targeted to degradation. This ubiquitin-dependent folding system also controls the proteostasis of other membrane proteins as CFTR and anthrax toxin receptor 2, two poor folders involved in severe human diseases. DOI: 10.7554/eLife.19083.001 *For correspondence: gisou. [email protected] Introduction † These authors contributed While protein folding may be extremely efficient, the presence of multiple domains, in soluble or equally to this work membrane proteins, greatly reduces the efficacy of the overall process. Thus, a set of enzymes and Competing interests: The chaperones assist folding and ensure that a sufficient number of active molecules reach their final authors declare that no destination (Brodsky and Skach, 2011; Ellgaard et al., 2016). -
Molecular Mechanism of Fusion Pore Formation Driven by the Neuronal SNARE Complex
Molecular mechanism of fusion pore formation driven by the neuronal SNARE complex Satyan Sharmaa,1 and Manfred Lindaua,b aLaboratory for Nanoscale Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany and bSchool of Applied and Engineering Physics, Cornell University, Ithaca, NY 14850 Edited by Axel T. Brunger, Stanford University, Stanford, CA, and approved November 1, 2018 (received for review October 2, 2018) Release of neurotransmitters from synaptic vesicles begins with a systems in which various copy numbers of syb2 were incorporated narrow fusion pore, the structure of which remains unresolved. To in an ND while the t-SNAREs were present on a liposome have obtain a structural model of the fusion pore, we performed coarse- been used experimentally to study SNARE-mediated mem- grained molecular dynamics simulations of fusion between a brane fusion (13, 17). The small dimensions of the ND compared nanodisc and a planar bilayer bridged by four partially unzipped with a spherical vesicle makes such systems ideally suited for MD SNARE complexes. The simulations revealed that zipping of SNARE simulations without introducing extreme curvature, which is well complexes pulls the polar C-terminal residues of the synaptobrevin known to strongly influence the propensity of fusion (18–20). 2 and syntaxin 1A transmembrane domains to form a hydrophilic MARTINI-based CGMD simulations have been used in several – core between the two distal leaflets, inducing fusion pore forma- studies of membrane fusion (16, 21 23). To elucidate the fusion tion. The estimated conductances of these fusion pores are in good pore structure and the mechanism of its formation, we performed agreement with experimental values. -
2515256420945820 Reticulum–Lipid Droplet Nexus Journals.Sagepub.Com/Home/Ctc
Revisiting the Gregarious Lipid Droplet: Maintaining contacts to regulate energy homeostasis in the cell and beyond-Review Contact Volume 3: 1–16 Seipin-Mediated Contacts as Gatekeepers ! The Author(s) 2020 Article reuse guidelines: of Lipid Flux at the Endoplasmic sagepub.com/journals-permissions DOI: 10.1177/2515256420945820 Reticulum–Lipid Droplet Nexus journals.sagepub.com/home/ctc Veijo T. Salo1,2 , Maarit Holtt€ a-Vuori€ 1,2 and Elina Ikonen1,2 Abstract Lipid droplets (LDs) are dynamic cellular hubs of lipid metabolism. While LDs contact a plethora of organelles, they have the most intimate relationship with the endoplasmic reticulum (ER). Indeed, LDs are initially assembled at specialized ER subdomains, and recent work has unraveled an increasing array of proteins regulating ER-LD contacts. Among these, seipin, a highly conserved lipodystrophy protein critical for LD growth and adipogenesis, deserves special attention. Here, we review recent insights into the role of seipin in LD biogenesis and as a regulator of ER-LD contacts. These studies have also highlighted the evolving concept of ER and LDs as a functional continuum for lipid partitioning and pinpointed a role for seipin at the ER-LD nexus in controlling lipid flux between these compartments. Keywords seipin, endoplasmic reticulum–lipid droplet contacts, lipid droplet biogenesis Lipid droplets (LDs) are intracellular storage organelles mutations in seipin also result in hereditary spastic para- composed of a core of hydrophobic neutral lipids (NLs), plegias (Windpassinger et al., 2004) and a severe form of mainly triglycerides (TAG) and sterol esters, surrounded encephalopathy (Guillen-Navarro et al., 2013). Seipin is by a phospholipid (PL) monolayer (Henne et al., 2018). -
Palmitoylation of the Tyrosine Kinase Lck Mediates Fas Signaling
Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling Askar M. Akimzhanov1 and Darren Boehning1 Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030 Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 13, 2015 (received for review May 26, 2015) Palmitoylation is the posttranslational modification of proteins with These cysteines are dispensable for the catalytic activity of Lck, a 16-carbon fatty acid chain through a labile thioester bond. The and mutagenesis of either site does not prevent palmitoylation or reversibility of protein palmitoylation and its profound effect on membrane binding (16–18). Simultaneous mutation of cysteine 3 protein function suggest that this modification could play an impor- and cysteine 5 produces a palmitoylation-deficient mutant of Lck tant role as an intracellular signaling mechanism. Evidence that that is unable to propagate T-cell receptor signaling, demonstrating palmitoylation of proteins occurs with the kinetics required for a critical role for palmitoylation in regulating Lck function (16, 17, signal transduction is not clear, however. Here we show that en- 19). The regulatory mechanisms controlling Lck palmitoylation gagement of the Fas receptor by its ligand leads to an extremely remain largely unknown, however. rapid and transient increase in palmitoylation levels of the tyrosine We have previously demonstrated that Lck is an essential kinase Lck. Lck palmitoylation kinetics are consistent with the acti- component of the Fas signaling pathway (20). Lck is required for γ vation of downstream signaling proteins, such as Zap70 and PLC- 1. -
Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis
biomolecules Review Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis Robert M. Schilke y, Cassidy M. R. Blackburn y , Temitayo T. Bamgbose and Matthew D. Woolard * Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; [email protected] (R.M.S.); [email protected] (C.M.R.B.); [email protected] (T.T.B.) * Correspondence: [email protected]; Tel.: +1-(318)-675-4160 These authors contributed equally to this work. y Received: 12 September 2020; Accepted: 13 October 2020; Published: 15 October 2020 Abstract: Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are important regulators of immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression, respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis. Keywords: atherosclerosis; phospholipases; macrophages; T cells; lipins 1. Introduction All cellular membranes are composed mostly of phospholipids. Phospholipids are amphiphilic compounds with a hydrophilic, negatively charged phosphate group head and two hydrophobic fatty acid tail residues [1]. The glycerophospholipids, phospholipids with glycerol backbones, are the largest group of phospholipids, which are classified by the modification of the head group [1]. The negatively charged phosphate head forms an ionic bond with an amino alcohol. This bridges the glycerol backbone to the nitrogenous functional group (amino alcohol).