Plasma Membrane Sandwich Model Unit Membrane
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Cystine–Glutamate Antiporter Xct Deficiency Suppresses Tumor Growth While Preserving Antitumor Immunity
Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity Michael D. Arensmana, Xiaoran S. Yanga, Danielle M. Leahya, Lourdes Toral-Barzaa, Mary Mileskia, Edward C. Rosfjorda, Fang Wanga, Shibing Dengb, Jeremy S. Myersa, Robert T. Abrahamb, and Christina H. Enga,1 aOncology Research & Development, Pfizer, Pearl River, NY 10965; and bOncology Research & Development, Pfizer, San Diego, CA 92121 Edited by William G. Kaelin Jr., Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and approved April 2, 2019 (received for review September 1, 2018) T cell-invigorating cancer immunotherapies have near-curative Thus, tumor cells may rely on xCT to fulfill the majority of their potential. However, their clinical benefit is currently limited, as cysteine and GSH needs by importing cystine. only a fraction of patients respond, suggesting that these regimens Inhibition of xCT has been investigated as a therapeutic may benefit from combination with tumor-targeting treatments. As strategy for cancer based on observations that elevated xCT ex- oncogenic progression is accompanied by alterations in metabolic pression on tumor cells correlates with poor prognosis (10–12) pathways, tumors often become heavily reliant on antioxidant and that inhibition of xCT in preclinical studies suppresses tumor machinery and may be susceptible to increases in oxidative stress. growth (10, 12–14). However, these studies relied heavily on the The cystine–glutamate antiporter xCT is frequently overexpressed in use of sulfasalazine, a clinical compound used for the treatment cancer and fuels the production of the antioxidant glutathione; thus, of rheumatoid arthritis, ulcerative colitis, and Crohn’s disease. -
Transport of Sugars
BI84CH32-Frommer ARI 29 April 2015 12:34 Transport of Sugars Li-Qing Chen,1,∗ Lily S. Cheung,1,∗ Liang Feng,3 Widmar Tanner,2 and Wolf B. Frommer1 1Department of Plant Biology, Carnegie Institution for Science, Stanford, California 94305; email: [email protected] 2Zellbiologie und Pflanzenbiochemie, Universitat¨ Regensburg, 93040 Regensburg, Germany 3Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305 Annu. Rev. Biochem. 2015. 84:865–94 Keywords First published online as a Review in Advance on glucose, sucrose, carrier, GLUT, SGLT, SWEET March 5, 2015 The Annual Review of Biochemistry is online at Abstract biochem.annualreviews.org Soluble sugars serve five main purposes in multicellular organisms: as sources This article’s doi: of carbon skeletons, osmolytes, signals, and transient energy storage and as 10.1146/annurev-biochem-060614-033904 transport molecules. Most sugars are derived from photosynthetic organ- Copyright c 2015 by Annual Reviews. isms, particularly plants. In multicellular organisms, some cells specialize All rights reserved in providing sugars to other cells (e.g., intestinal and liver cells in animals, ∗ These authors contributed equally to this review. photosynthetic cells in plants), whereas others depend completely on an ex- Annu. Rev. Biochem. 2015.84:865-894. Downloaded from www.annualreviews.org ternal supply (e.g., brain cells, roots and seeds). This cellular exchange of Access provided by b-on: Universidade de Lisboa (UL) on 09/05/16. For personal use only. sugars requires transport proteins to mediate uptake or release from cells or subcellular compartments. Thus, not surprisingly, sugar transport is criti- cal for plants, animals, and humans. -
Distribution of Glucose Transporters in Renal Diseases Leszek Szablewski
Szablewski Journal of Biomedical Science (2017) 24:64 DOI 10.1186/s12929-017-0371-7 REVIEW Open Access Distribution of glucose transporters in renal diseases Leszek Szablewski Abstract Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney. Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three families of glucose transporters: GLUT proteins, sodium-dependent glucose transporters (SGLTs) and SWEET. In kidney, only GLUTs and SGLTs protein are expressed. Mutations within genes that code these proteins lead to different renal disorders and diseases. However, diseases, not only renal, such as diabetes, may damage expression and function of renal glucose transporters. Keywords: Kidney, GLUT proteins, SGLT proteins, Diabetes, Familial renal glucosuria, Fanconi-Bickel syndrome, Renal cancers Background Because glucose is hydrophilic and soluble in water, lipid Maintenance of glucose homeostasis prevents pathological bilayer of plasma membrane is impermeable for it. There- consequences due to prolonged hyperglycemia or fore, transport of glucose into cells depends on carrier pro- hypoglycemia. Hyperglycemia leads to a high risk of vascu- teins that are present in the plasma membrane. In humans, lar complications, nephropathy, neuropathy and retinop- there are three families of glucose transporters: GLUT pro- athy. Hypoglycemia may damage the central nervous teins, encoded by SLC2 genes; sodium-dependent glucose system and lead to a higher risk of death. -
Renal Membrane Transport Proteins and the Transporter Genes
Techno e lo n g Gowder, Gene Technology 2014, 3:1 e y G Gene Technology DOI; 10.4172/2329-6682.1000e109 ISSN: 2329-6682 Editorial Open Access Renal Membrane Transport Proteins and the Transporter Genes Sivakumar J T Gowder* Qassim University, College of Applied Medical Sciences, Buraidah, Kingdom of Saudi Arabia Kidney this way, high sodium diet favors urinary sodium concentration [9]. AQP2 has a role in hereditary and acquired diseases affecting urine- In humans, the kidneys are a pair of bean-shaped organs about concentrating mechanisms [10]. AQP2 regulates antidiuretic action 10 cm long and located on either side of the vertebral column. The of arginine vasopressin (AVP). The urinary excretion of this protein is kidneys constitute for less than 1% of the weight of the human body, considered to be an index of AVP signaling activity in the renal system. but they receive about 20% of blood pumped with each heartbeat. The Aquaporins are also considered as markers for chronic renal allograft renal artery transports blood to be filtered to the kidneys, and the renal dysfunction [11]. vein carries filtered blood away from the kidneys. Urine, the waste fluid formed within the kidney, exits the organ through a duct called the AQP4 ureter. The kidney is an organ of excretion, transport and metabolism. This gene encodes a member of the aquaporin family of intrinsic It is a complicated organ, comprising various cell types and having a membrane proteins. These proteins function as water-selective channels neatly designed three dimensional organization [1]. Due to structural in the plasma membrane. -
Sodium-Coupled Secondary Transporters 11 Insights from Structure-Based Computations
b1151_Chapter-11.qxd 5/5/2011 12:27 PM Page 199 b1151 Molecular Machines FA Sodium-coupled Secondary Transporters 11 Insights from Structure-based Computations Elia Zomot, Ahmet Bakan, Indira H. Shrivastava, Jason DeChancie, Timothy R. Lezon and Ivet Bahar 1. Introduction: Biological Function and Classification The biological membrane bilayer is impermeable to almost all polar or charged molecules. In order for the various solutes to cross this barrier, integral membrane proteins have evolved to provide a hydrophilic environment within the membrane that can bind and translocate these solutes into or out of the cell, often against their electrochemical gradient. These transporters are conventionally classified into three classes on the basis of the energy source used for transport: (1) primary active transporters rely on light, hydrolysis of ATP or redox reactions, (2) secondary active transporters require the electrochemical gradient of ions across the membrane to power the “uphill” transloca- tion of the substrate, and (3) precursor/product antiporters exchange one molecule with its metabolic product independent of another source of energy.1,2 A major family of secondary transporters involves sodium- (and less often proton-) depend- ent symporters that couple the energy-costly translocation of the solute into the cell to that of sodium down its electrochemical gradient. These sodium-coupled transporters are found in all species and participate in a myriad biological functions, e.g. maintenance of efficient neuro- transmission,3,4,5 absorption of nutrients in the intestine,6 regulation of pH and cytoplasmic [Na+]7,8 and osmoregulation9,10 are only some of their physiological functions. Of particular interest among sodium-coupled symporters are two families: the dicarboxylate/ amino-acid:cation symporters (DAACS) and the neurotransmitter sodium symporters (NSS). -
Passive and Active Transport
Passive and Active Transport 1. Thermodynamics of transport 2. Passive-mediated transport 3. Active transport neuron, membrane potential, ion transport Membranes • Provide barrier function – Extracellular – Organelles • Barrier can be overcome by „transport proteins“ – To mediate transmembrane movements of ions, Na+, K+ – Nutrients, glucose, amino acids etc. – Water (aquaporins) 1) Thermodynamics of Transport • Aout <-> Ain (ressembles a chemical equilibration) o‘ • GA - G A = RT ln [A] • ∆GA = GA(in) - GA(out) = RT ln ([A]in/[A]out) • GA: chemical potential of A o‘ • G A: chemical potential of standard state of A • If membrane has a potential, i.e., plasma membrane: -100mV (inside negative) then GA is termed the electrochemical potential of A Two types of transport across a membrane: o Nonmediated transport occurs by passive diffusion, i.e., O2, CO2 driven by chemical potential gradient, i.e. cannot occur against a concentration gradient o Mediated transport occurs by dedicated transport proteins 1. Passive-mediated transport/facilitated diffusion: [high] -> [low] 2. Active transport: [low] -> [high] May require energy in form of ATP or in form of a membrane potential 2) Passive-mediated transport Substances that are too large or too polar to diffuse across the bilayer must be transported by proteins: carriers, permeases, channels and transporters A) Ionophores B) Porins C) Ion Channels D) Aquaporins E) Transport Proteins A) Ionophores Organic molecules of divers types, often of bacterial origin => Increase the permeability of a target membrane for ions, frequently antibiotic, result in collapse of target membrane potential by ion equilibration 1. Carrier Ionophore, make ion soluble in membrane, i.e. valinomycin, 104 K+/sec 2. -
Arxiv:1912.06275V2 [Q-Bio.BM] 18 Feb 2021
General Principles of Secondary Active Transporter Function Oliver Beckstein1, a) and Fiona Naughton1 Department of Physics, Arizona State University, Tempe AZ 85287, USA (Dated: February 19, 2021) Transport of ions and small molecules across the cell membrane against electrochemical gradients is catalyzed by integral membrane proteins that use a source of free energy to drive the energetically uphill flux of the transported substrate. Secondary active transporters couple the spontaneous influx of a “driving” ion such as Na+ or H+ to the flux of the substrate. The thermodynamics of such cyclical non-equilibrium systems are well understood and recent work has focused on the molecular mechanism of secondary active transport. The fact that these transporters change their conformation between an inward-facing and outward-facing conformation in a cyclical fashion, called the alternating access model, is broadly recognized as the molecular framework in which to describe transporter function. However, only with the advent of high resolution crystal structures and detailed computer simulations has it become possible to recognize common molecular-level principles between disparate transporter families. Inverted repeat symmetry in secondary active transporters has shed light on how protein structures can encode a bi-stable two-state system. More detailed analysis (based on experimental structural data and detailed molecular dynamics simulations) indicates that transporters can be understood as gated pores with at least two coupled gates. These gates are not just a convenient cartoon element to illustrate a putative mechanism but map to distinct parts of the transporter protein. Enumerating all distinct gate states naturally includes occluded states in the alternating access picture and also suggests what kind of protein conformations might be observable. -
Mechanisms of Radiopharmaceutical Localization
.::VOLUME 16, LESSON 4::. Mechanisms of Radiopharmaceutical Localization Continuing Education for Nuclear Pharmacists And Nuclear Medicine Professionals By James A. Ponto, MS, RPh, BCNP Chief Nuclear Pharmacists, University of Iowa Hospitals and Clinics and Professor (Clinical), University of Iowa Hospitals and Clinics The University of New Mexico Health Sciences Center, College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Program No. 0039-000-12-164- H04-P 2.5 Contact Hours or .25 CEUs. Initial release date: 7/19/2012 -- Intentionally left blank -- Mechanisms of Radiopharmaceutical Localization By James A. Ponto, MS, RPh, BCNP Editor, CENP Jeffrey Norenberg, MS, PharmD, BCNP, FASHP, FAPhA UNM College of Pharmacy Editorial Board Stephen Dragotakes, RPh, BCNP, FAPhA Michael Mosley, RPh, BCNP Neil Petry, RPh, MS, BCNP, FAPhA James Ponto, MS, RPh, BCNP, FAPhA Tim Quinton, PharmD, BCNP, FAPhA S. Duann Vanderslice, RPh, BCNP, FAPhA John Yuen, PharmD, BCNP Advisory Board Dave Engstrom, PharmD, BCNP Vivian Loveless, PharmD, BCNP, FAPhA Brigette Nelson, MS, PharmD, BCNP Brantley Strickland, BCNP Susan Lardner, BCNP Christine Brown, BCNP Director, CENP Administrator, CE & Web Publisher Kristina Wittstrom, MS, RPh, BCNP, FAPhA Christina Muñoz, M.A. UNM College of Pharmacy UNM College of Pharmacy While the advice and information in this publication are believed to be true and accurate at the time of press, the author(s), editors, or the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, expressed or implied, with respect to the material contained herein. -
Crystal Structure of a Glucose/H Symporter and Its Mechanism of Action
+ Crystal structure of a glucose/H symporter and its mechanism of action Cristina V. Iancua, Jamillah Zamoonb, Sang Bum Wooa, Alexander Aleshinc, and Jun-yong Choea,1 aDepartment of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago,IL 60064; bDepartment of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City 13060, Kuwait; and cDepartment of Infectious Diseases, Sanford Burnham Medical Research Institute, La Jolla, CA 92037 Edited* by H. Ronald Kaback, University of California, Los Angeles, CA, and approved September 26, 2013 (received for review June 25, 2013) + Glucose transporters are required to bring glucose into cells, of a Staphylococcus epidermidis glucose/H symporter (GlcPSe) where it is an essential energy source and precursor in protein by single anomalous dispersion methods. GlcPSe shares high se- and lipid synthesis. These transporters are involved in important quence identity (27–34%) and homology (49–58%) with the hu- common diseases such as cancer and diabetes. Here, we report the man GLUTs (Table S1), is highly specific for glucose, and is + crystal structure of the Staphylococcus epidermidis glucose/H sym- inhibited by the well-characterized inhibitors of human GLUTs porter in an inward-facing conformation at 3.2-Å resolution. The phloretin, cytochalasin B, and forskolin. In contrast to GlcP , + Se Staphylococcus epidermidis glucose/H symporter is homologous XylE transports xylose but not glucose, which is an inhibitor, and is to human glucose transporters, is very specific and has high avidity impervious to inhibition by cytochalasin B (13, 24). On the basis of for glucose, and is inhibited by the human glucose transport inhib- the GlcPSe structure and functional studies of wild-type and mu- itors cytochalasin B, phloretin, and forskolin. -
Amino Acid Transporters As Tetraspanin TM4SF5 Binding Partners Jae Woo Jung1,Jieonkim2,Eunmikim2 and Jung Weon Lee 1,2
Jung et al. Experimental & Molecular Medicine (2020) 52:7–14 https://doi.org/10.1038/s12276-019-0363-7 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Amino acid transporters as tetraspanin TM4SF5 binding partners Jae Woo Jung1,JiEonKim2,EunmiKim2 and Jung Weon Lee 1,2 Abstract Transmembrane 4 L6 family member 5 (TM4SF5) is a tetraspanin that has four transmembrane domains and can be N- glycosylated and palmitoylated. These posttranslational modifications of TM4SF5 enable homophilic or heterophilic binding to diverse membrane proteins and receptors, including growth factor receptors, integrins, and tetraspanins. As a member of the tetraspanin family, TM4SF5 promotes protein-protein complexes for the spatiotemporal regulation of the expression, stability, binding, and signaling activity of its binding partners. Chronic diseases such as liver diseases involve bidirectional communication between extracellular and intracellular spaces, resulting in immune-related metabolic effects during the development of pathological phenotypes. It has recently been shown that, during the development of fibrosis and cancer, TM4SF5 forms protein-protein complexes with amino acid transporters, which can lead to the regulation of cystine uptake from the extracellular space to the cytosol and arginine export from the lysosomal lumen to the cytosol. Furthermore, using proteomic analyses, we found that diverse amino acid transporters were precipitated with TM4SF5, although these binding partners need to be confirmed by other approaches and in functionally relevant studies. This review discusses the scope of the pathological relevance of TM4SF5 and its binding to certain amino acid transporters. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction on the plasma membrane and the mitochondria, lyso- Importing and exporting biological matter in and out of some, and other intracellular organelles. -
Membrane Transport Quiz
Membrane Transport Quiz 1. Which of the following is an example of extracellular fluid? a. Cytosol b. Plasma c. Interstitial Fluid d. Both b and c 2. Which of the following correctly describes passive transport? a. the cell uses ATP in passive transport b. most pumps are examples of passive transport c. diffusion is an example of passive transport d. exocytosis is an example of passive transport 3. Simple diffusion occurs ______________. a. with transporters in the cell membrane b. directly across the cell membrane c. through exocytosis d. through endocytosis 4. Which of the following is an example of active transport? a. Filtration b. Osmosis c. Endocytosis d. Exocytosis e. Both c and d 5. Which type of active transport uses ATP directly? a. Primary Active Transport b. Secondary Active Transport c. Both a and b 6. Which of the following is an example of receptor mediated endocytosis? a. Phagocytosis b. Primary Active Transport c. Exocytosis d. ALL are For use with TCC iTunes University Membrane Transport Lecture. 1 Developed by: Martha Kutter 2009 for the Learning Commons at Tallahassee Community College. 7. A transporter that moves one type of particle in one direction is _______________. a. Uniporter b. Symporter c. Antiporter 8. A transporter the moves two different particles in two different directions is ________. a. Endocytosis b. Exocytosis c. Uniporter d. Symporter e. Antiporter 9. Which of the following is an example of a primary active transporter? a. Na+/Ca2+ transporter on cardiac contractile cells b. Na+ channels on neurons c. Na+/K+ ATPase on all cells d. -
Amino Acids, Peptides, and Proteins
1/11/2018 King Saud University College of Science Department of Biochemistry Biomembranes and Cell Signaling (BCH 452) Chapter 3 Diffusion, Channels and Transport Systems Prepared by Dr. Farid Ataya http://fac.ksu.edu.sa/fataya Lect Topics to be covered No. Role of cell surface carbohydrates in recognise ion, as receptor of antigens, 7 hormones, toxins, viruses and bacteria. Their role in histocompatibility and cell-cell adhesion. Diffusion. 8 Diffusion across biomembranes. Ficks law. Structural types of channels (pores): -type, -barrel, pore forming toxins, ionophores. Functional types of channels (pores): voltage-gated channels e.g. sodium channels, ligand-gated channels e.g. acetylcholine receptor (nicotinic-acetylcholine channel), c-AMP regulated. Gap junctions and nuclear pores. 9 Transport systems: Energetics of transport systems, G calculation in each type. Passive Transport (facilitated diffusion). 1 1/11/2018 No. Topics to be covered Lect Kinetic properties. 9 Passive transport: Glucose transporters (GLUT 1 to5), - C1 , HCO3 exchanger (anion exchanger protein) in erythrocyte membrane Kinetic properties. 10 Active transport: Types of active transport: Primary ATPases (Primary active transporters): P transporters (e.g. Na+, K+, ATPase) First assessment Exam ATP binding cassettes (ABC transports) 11 (e.g. cystic fibrosis transmembrane conductance regulator-chloride transport). Multidrug resistance protein transporter. V transporters, F transporters. Secondary active transporters (e.g. Na+ -dependent transport of glucose and amino acids). To be covered under intestinal brush border Transport of large molecules (Macromolecules) 12 Types: Exocytosis, Endocytosis-pinocytosis and phagocytosis Types of pinocytosis: Absorptive pinocytosis, characteristics and examples. Fluid phase pinocytosis, characteristics and examples The role of cell surface carbohydrates: Glycoproteins Membrane glycoproteins are proteins that contain 1-30% carbohydrate in their structure.