DOCSLIB.ORG

Molecular Dynamics Simulations of Tight Junction Proteins

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Dynamics Simulations of Tight Junction Proteins Molecular Dynamics Simulations of Tight Junction Proteins Eleni Fitsiou This dissertation is submitted for the degree of Doctor of Philosophy August 2020 Department of Chemistry I would like to dedicate this dissertation to my husband Antonios and sons Dimitrios and Ioannis. ii “Wisdom begins in wonder” Socrates iii Declaration I, Eleni Fitsiou, declare that this thesis titled ‘Molecular Dynamics Simulations of Tight Junction Proteins’ has not been submitted in support of an application for another degree at this or any other university. It is the result of my own work and includes nothing that is the outcome of work done in collaboration except where specifically indicated. Where I have quoted from the work of others, the source is always given. Lancaster University, UK iv Abstract Tight junctions (TJs) are specialised cell-cell structures that serve primarily as a barrier to molecular transport through the intercellular space between the cells. The claudin family of proteins are the main structural and functional components of the TJ strands that circumscribe the cells. The detailed molecular organisation at the TJs is not entirely resolved, being relatively inaccessible by current experimental methods. Here, we have employed molecular dynamics simulations using both atomistic and coarse-grained models to investigate the TJ structure formed by claudin-1 using self-assembly coupled with free energy calculations and enhanced sampling techniques. A feature of the studies is that the self-assembly simulations have been carried out using atomistic detail (a first) by simulating only the extracellular domains of claudin-1 in an implied membrane. The results show that the cis-interaction can occur in the absence of trans-interacting partners and that a claudin dimer is the smallest stable unit. The dimers further form higher-order aggregates with a plethora of interacting dimeric interfaces. The trans- interaction of claudins resulted in a compact structure with a minimal pore size confirming the barrier properties of claudin-1. The simulations also enabled the identification of the key regions of the claudin responsible for the trans-interaction, with the identified important amino acids being in agreement with experimental studies. The role of the lipid environment, with a focus on the skin lipids in the stratum granulosum, was also investigated, along with the effect of single-point mutations in claudin-1. The single-point mutation studies were consistent with experimental results. The simulation studies have enhanced our understanding of the assembly and structure of claudin-1 TJs, a notable finding being that kinetic locking is likely to be important in determining the TJ structure. The single-point mutation studies suggest that simulations could serve as screens towards defining potential gene-therapy strategies. v Acknowledgements First of all, I would like to sincerely thank my supervisor Prof. Jamshed Anwar for his support throughout the project. His expertise has been invaluable and his guidance and help has been much appreciated. I would also like to thank Dr Massimo Noro (STFC) for his advice, support and offered opportunities; Dr Gareth Tribello (Queen’s University Belfast) for his invaluable help with the metadynamics simulations; and Dr Mike Pacey for his assistance in resolving issues with HEC. I would like to acknowledge Unilever for funding this project and promoting research. In particular, I would like to thank Scott Singleton and Patrick Warren for organising my visit to Unilever and their valuable feedback on my work. Lastly, I would like to thank my colleagues and friends from the Chemistry Department at Lancaster University, for a very friendly and inclusive environment; especially, the Chemical Theory and Computation group, for their collaboration and assistance over these years. vi Contents 1 INTRODUCTION ..................................................................................................... 1 1.1 Overview .............................................................................................................. 1 1.2 Epithelial Cells, their Junctions and Cellular Transport ...................................... 4 1.2.1 Types of epithelial cells ................................................................................. 5 1.2.2 Cellular transport pathways ......................................................................... 6 1.2.3 Cell – cell junctions ...................................................................................... 7 1.3 Tight Junctions ................................................................................................... 10 1.3.1 Introduction - Tight junctions as multifunctional structures ...................... 10 1.3.2 Tight junctions: description and proposed models ..................................... 11 1.3.3 Claudins are the gate–keepers of tight junctions ........................................ 15 1.4 Structure and Function of Skin .......................................................................... 19 1.4.1 Layers of the skin ........................................................................................ 19 1.4.2 Epidermis layers ......................................................................................... 20 1.4.3 The terminal differentiation process ........................................................... 21 1.4.4 Epidermal barrier and the importance of TJs ............................................ 21 1.4.5 The diversity in lipid composition of plasma membranes ........................... 23 1.4.6 Lipids found in skin epidermis .................................................................... 24 1.5 Critical Review of Recent Literature and Outstanding Research Questions ..... 26 1.6 Aims of the Thesis ............................................................................................. 31 1.7 Thesis Outline .................................................................................................... 31 2 METHODOLOGY: MOLECULAR SIMULATION ......................................... 34 2.1 Molecular Mechanics (Force Field Methods) .................................................... 34 2.2 Statistical Mechanics.......................................................................................... 36 2.2.1 Phase space ................................................................................................. 36 2.2.2 Ergodic hypothesis ...................................................................................... 37 2.2.3 Common statistical ensembles .................................................................... 37 2.3 General Form of Potential Energy Function in Molecular Mechanics .............. 38 2.3.1 Force field terms ......................................................................................... 39 2.3.2 Parametrisation of force fields ................................................................... 43 2.3.3 Classical mechanics: the time evolution of a system .................................. 44 2.3.4 Thermostats and barostats .......................................................................... 46 2.4 Periodic Boundary Conditions ........................................................................... 47 2.4.1 Calculating interactions when PBC are applied ........................................ 48 2.4.2 Sampling phase space ................................................................................. 49 2.5 Thermodynamic Properties ................................................................................ 49 2.5.1 Free energy surface .................................................................................... 50 2.6 Enhanced Sampling Methods............................................................................. 51 2.6.1 Potential of mean force – umbrella sampling ............................................. 51 2.6.2 Metadynamics ............................................................................................. 52 2.6.3 Replica exchange method ........................................................................... 54 2.7 Free Energy Using Molecular Mechanics Poisson Boltzmann Surface Area Method ..................................................................................................................... 56 3 THE MUTUAL INTERACTION OF THE EXTRACELLULAR DOMAIN PARTICLES OF CLAUDIN-1 ................................................................................. 58 vii 3.1 Introduction ........................................................................................................ 58 3.2 Methodology ...................................................................................................... 63 3.2.1 Model building of claudin-1 ........................................................................ 64 3.2.2 MD simulation of a single extracellular domain particle in an implied membrane ............................................................................................................. 66 3.2.3 MD simulation of a full claudin-1 particle in an explicit bilayer membrane .............................................................................................................................. 66 3.2.4 Self-assembly of ECD particles in an implied membrane starting from a grid .............................................................................................................................. 67 3.2.5 The Suzuki 'face-to-face' interface .............................................................
Load more

Recommended publications
  • Quantitative Structure–Activity Relationships (Qsar) Study on Novel 4-Amidinoquinoline and 10- Amidinobenzonaphthyridine Derivatives As Potent Antimalaria Agent
    JCECThe Journal of Engineering and Exact Sciences – JCEC, Vol. 05 N. 03 (2019) journal homepage: https://periodicos.ufv.br/ojs/jcec doi: 10.18540/jcecvl5iss3pp0271-0282 OPEN ACCESS – ISSN: 2527-1075 QUANTITATIVE STRUCTURE–ACTIVITY RELATIONSHIPS (QSAR) STUDY ON NOVEL 4-AMIDINOQUINOLINE AND 10- AMIDINOBENZONAPHTHYRIDINE DERIVATIVES AS POTENT ANTIMALARIA AGENT A. W. MAHMUD1, G. A. SHALLANGWA1 and A. UZAIRU1 1Ahmadu Bello University, Department of Chemistry, Zaria, Kaduna, Nigeria. A R T I C L E I N F O A B S T R A C T Article history: Quantitative structure–activity relationships (QSAR) has been a reliable study in the Received 2019-02-16 development of models that predict biological activities of chemical substances based on Accepted 2019-06-27 Available online 2019-06-30 their structures for the development of novel chemical entities. This study was carried out on 44 compounds of 4-amidinoquinoline and 10-amidinobenzonaphthyridine derivatives to p a l a v r a s - c h a v e develop a model that relates their structures to their activities against Plasmodium QSAR falciparum. Density Functional Theory (DFT) with basis set B3LYP/6-31G was used to ∗ Antimalaria optimize the compounds. Genetic Function Algorithm (GFA) was employed in selecting Plasmodium falciparum descriptors and building the model. Four models were generated and the model with best 4-Amidinoquinolina internal and external validation has internal squared correlation coefficient ( 2) of 0.9288, k e y w o r d s adjusted squared correlation coefficient ( adj) of 0.9103, leave-one-out (LOO) cross- 2 2 QSAR validation coefficient ( cv) value of 0.8924 and external squared correlation coefficient ( ) Antimalaria value of 0.8188.
    [Show full text]
  • 3. Lipid Rafts
    UNIVERSITÀ DEGLI STUDI DI TRIESTE XXX CICLO DEL DOTTORATO DI RICERCA IN NANOTECNOLOGIE Lipid raft formation and protein-lipid interactions in model membranes Settore scientifico-disciplinare: FIS/03 DOTTORANDO Fabio Perissinotto COORDINATORE PROF. Lucia Pasquato SUPERVISORE DI TESI Dr. Loredana Casalis CO-SUPERVISORE DI TESI Dr. Denis Scaini ANNO ACCADEMICO 2016/2017 TABLE OF CONTENTS ABSTRACT ......................................................................................................................................... 4 INTRODUCTION ............................................................................................................................... 6 1. Biological membranes ............................................................................................................... 6 1.1 Lipid composition of cellular membranes ............................................................................ 7 1.2 Membrane proteins ........................................................................................................... 11 2. Physical and structural properties of cell membranes ........................................................... 12 2.1 Lipid-lipid interactions and phase separation .................................................................... 12 2.2 Membrane asymmetry ....................................................................................................... 14 2.3 Lipid diffusion ....................................................................................................................
    [Show full text]
  • Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extracts and Flavonoids from Pistacia Integerrima
    DOI:http://dx.doi.org/10.7314/APJCP.2016.17.1.51 Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extract and Flavonoids from Pistacia integerrima RESEARCH ARTICLE Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extracts and Flavonoids from Pistacia integerrima Abdur Rauf1*, Ghias Uddin2, Muslim Raza3, Bashir Ahmad4, Noor Jehan1, Bina S Siddiqui5, Joseph Molnar6, Akos Csonka6, Diana Szabo6 Abstract Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine- 123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer.
    [Show full text]
  • Doxorubicin and Paclitaxel Cause Different Changes In
    CHANGES IN PLASMA MEMBRANE FLUIDITY OF MCF-7 CELLS 135 POSTÊPY BIOLOGII KOMÓRKI TOM 36, 2009 SUPLEMENT NR 25 (135152) Rola komórek dendrytycznych w odpowiedzi transplantacyjnej* The role of dendritic cells in transplantation Maja Budziszewska1, Anna Korecka-Polak1, Gra¿yna Korczak-Kowalska1,2 1Zak³ad Immunologii, Wydzia³ Biologii, Uniwersytet Warszawski 2 Instytut Transplantologii, Warszawski Uniwersytet Medyczny *Dofinansowanie z grantu MNiSzW nr N N402 268036 Streszczenie: Komórki dendrytyczne (DC) s¹ najwa¿niejszymi komórkami prezentuj¹cymi antygenDOXORUBICIN (APC) limfocytom AND T. StopieñPACLITAXEL dojrza³oci komórki DC ma kluczowe znaczenie dla rodzaju odpowiedzi limfocytów T. Niedojrza³a komórka DC indukujeCAUSE stan DIFFERENT tolerancji, podczas CHANGES gdy dojrza³a IN komórkaPLASMA DC MEMBRANE- pe³n¹ odpowied immunologiczn¹.FLUIDITY Ma toOF ogromne MCF-7 znaczenie BREAST w transplantologii,CANCER CELLS a zw³aszcza w reakcjach odrzucania przeszczepu po transplantacjach narz¹du. Komórka DC dawcy prezentujeDOKSORUBICYNA antygen w sposób I PAKLITAKSEL bezporedni, natomiast POWODUJ¥ komórka RÓ¯NE DC ZMIANYbiorcy drog¹ poredni¹.W P£YNNOCI Komórki B£ONY DC niedojrza³ePLAZMATYCZNEJ lub o w³aciwociach KOMÓREK RAKA tolerogennych PIERSI MCF-7 mog¹ wyd³u¿yæ prze¿ycie przeszczepu allogenicznego. Takie oddzia³ywanie na funkcjê komórekKarolina MATCZAKDC, aby by³y1, Aneta one niewra¿liweKOCEVA-CHYLA na sygna³y1, Krzysztof dojrzewania GWOZDZINSKI in vivo lub2, aktywowanie komórek DC charakteryzuj¹cychZofia JÓWIAK1 siê trwa³ymi w³aciwociami tolerogennymi
    [Show full text]
  • Organi &C Biomolecular Chemistry
    Organic Biomolecular& Chemistry INDEXED IN MEDLINE Incorporating Acta Chemica Scandinavica Instructions for Authors (2004) Also see www.rsc.org/illustrations and www.rsc.org/electronicfiles CONTENTS 1.0 General Policy 1.0 General Policy Organic & Biomolecular Chemistry is a bimonthly journal 1.1 Articles for the publication of original research papers (articles), 1.2 Communications communications, Emerging Areas and Perspectives focusing on 1.3 Emerging Areas all aspects of synthetic, physical and biomolecular organic 1.4 Perspective Articles chemistry. 1.5 Submission of Articles Authors should note that papers that mainly emphasise the novel properties, applications or potential applications of 2.0 Administration materials may be more suited for submission to Journal of Materials Chemistry. (http://www.rsc.org/materials). 3.0 Notes on the Preparation of Papers There is no page charge for papers published in Organic & 3.1 Organisation of Material Biomolecular Chemistry. 3.2 Artwork Guidelines 3.3 Nomenclature Scope of the Journal 3.4 Deposition of Supplementary Data Organic & Biomolecular Chemistry brings together molecular 3.5 Guidelines on submitting files for proof preparation design, synthesis, structure, function and reactivity in one journal. It publishes fundamental work on synthetic, physical 4.0 Experimental and Characterisation Requirements and biomolecular organic chemistry as well as all organic 4.1 Physical Characteristics of Compounds aspects of: chemical biology, medicinal chemistry, natural 4.2 Characterisation of New Compounds
    [Show full text]
  • Interpretation of Molecule Conformations from Drawn Diagrams” by Dana Tenneson, Ph.D., Brown University, May 2008
    Abstract of \Interpretation of Molecule Conformations from Drawn Diagrams" by Dana Tenneson, Ph.D., Brown University, May 2008. In chemistry, molecules are drawn on paper and chalkboards as diagrams consisting of lines, letters, and symbols which represent not only the atoms and bonds in the molecules but concisely encode cues to the 3D geometry of the molecules. Recent efforts into pen-based input methods for chemistry software have made progress at allowing chemists to input 2D diagrams of molecules into a computer simply by drawing them on a digitizer tablet. However, the task of interpreting these parsed sketches into proper 3D models has been largely unsolved due to the difficulty in making the models satisfy both the natural properties of molecule structure and the geometric cues made explicit in the drawing. This dissertation presents a set of techniques developed to solve this model construction problem within the context of an educational application for chemistry students. Our primary contribution is a framework for combining molecular structure knowledge and molecule diagram understanding via augmenting molecular mechanics equations to include drawing-based penalty terms. Additionally, we present an algorithm for generating molecule models from drawn diagrams which leverages domain- specific and diagram-driven heuristics. These heuristics make our process fast and accurate enough for molecule diagram drawing to be used as an interactive technique for model construction on modern Tablet PC computers. Interpretation of Molecule Conformations
    [Show full text]
  • Tight Junction Structure and Function Revisited
    Trends in Cell Biology Review Tight Junction Structure and Function Revisited Tetsuhisa Otani 1,2,3,*,@ and Mikio Furuse1,2,3 Tight junctions (TJs) are intercellular junctions critical for building the epithelial Highlights barrier and maintaining epithelial polarity. The claudin family of membrane pro- Tight junction strand formation and teins play central roles in TJ structure and function. However, recent findings membrane apposition formation are have uncovered claudin-independent aspects of TJ structure and function, and differentially regulated. additional players including junctional adhesion molecules (JAMs), membrane Claudins form charge-selective small lipids, phase separation of the zonula occludens (ZO) family of scaffolding pores, while junctional adhesion mole- proteins, and mechanical force have been shown to play important roles in TJ cules regulate the formation of size- structure and function. In this review, we discuss how these new findings have selective large pores. the potential to transform our understanding of TJ structure and function, and Tight junction proteins regulate epithelial how the intricate network of TJ proteins and membrane lipids dynamically polarity, although how tight junctions interact to drive TJ assembly. form a membrane fence remains unclear. Tight Junctions Regulate Epithelial Barrier and Polarity Tight junction associated membrane proteins regulate tight junction assembly – Tight junctions (TJs) are epithelial intercellular junctions located at the most apical region of cell in conjunction with zonula occludens cell contacts. TJs are structurally defined by electron microscopy. On ultrathin sections, TJs protein phase separation, membrane appear as a region with close apposition of adjacent plasma membranes where adjacent plasma lipids, mechanical force, and polarity signaling proteins.
    [Show full text]
  • Introduction to Bioinformatics (Elective) – SBB1609
    SCHOOL OF BIO AND CHEMICAL ENGINEERING DEPARTMENT OF BIOTECHNOLOGY Unit 1 – Introduction to Bioinformatics (Elective) – SBB1609 1 I HISTORY OF BIOINFORMATICS Bioinformatics is an interdisciplinary field that develops methods and software tools for understanding biologicaldata. As an interdisciplinary field of science, bioinformatics combines computer science, statistics, mathematics, and engineering to analyze and interpret biological data. Bioinformatics has been used for in silico analyses of biological queries using mathematical and statistical techniques. Bioinformatics derives knowledge from computer analysis of biological data. These can consist of the information stored in the genetic code, but also experimental results from various sources, patient statistics, and scientific literature. Research in bioinformatics includes method development for storage, retrieval, and analysis of the data. Bioinformatics is a rapidly developing branch of biology and is highly interdisciplinary, using techniques and concepts from informatics, statistics, mathematics, chemistry, biochemistry, physics, and linguistics. It has many practical applications in different areas of biology and medicine. Bioinformatics: Research, development, or application of computational tools and approaches for expanding the use of biological, medical, behavioral or health data, including those to acquire, store, organize, archive, analyze, or visualize such data. Computational Biology: The development and application of data-analytical and theoretical methods, mathematical modeling and computational simulation techniques to the study of biological, behavioral, and social systems. "Classical" bioinformatics: "The mathematical, statistical and computing methods that aim to solve biological problems using DNA and amino acid sequences and related information.” The National Center for Biotechnology Information (NCBI 2001) defines bioinformatics as: "Bioinformatics is the field of science in which biology, computer science, and information technology merge into a single discipline.
    [Show full text]
  • Structural Elucidation of the Interaction Between Neurodegenerative Disease-Related Tau Protein with Model Lipid Membranes Emmalee Jones
    University of New Mexico UNM Digital Repository Nanoscience and Microsystems ETDs Engineering ETDs 1-28-2015 Structural Elucidation of the Interaction Between Neurodegenerative Disease-Related Tau Protein with Model Lipid Membranes Emmalee Jones Follow this and additional works at: https://digitalrepository.unm.edu/nsms_etds Recommended Citation Jones, Emmalee. "Structural Elucidation of the Interaction Between Neurodegenerative Disease-Related Tau Protein with Model Lipid Membranes." (2015). https://digitalrepository.unm.edu/nsms_etds/16 This Dissertation is brought to you for free and open access by the Engineering ETDs at UNM Digital Repository. It has been accepted for inclusion in Nanoscience and Microsystems ETDs by an authorized administrator of UNM Digital Repository. For more information, please contact [email protected]. Emmalee M. Jones Candidate Nanoscience and Microsystems Engineering Department This dissertation is approved, and it is acceptable in quality and form for publication: Approved by the Dissertation Committee: Eva Chi Chairperson Steven Graves Andrew Shreve Deborah Evans i STRUCTURAL ELUCIDATION OF THE INTERACTION BETWEEN NEURODEGENERATIVE DISEASE-RELATED TAU PROTEIN WITH MODEL LIPID MEMBRANES BY EMMALEE M. JONES B.S., Applied Physics, Brigham Young University, 2009 M.S., Nanoscience and Microsystems Engineering, University of New Mexico, 2013 DISSERTATION Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Nanoscience and Microsystems Engineering The University of New Mexico Albuquerque, New Mexico December, 2014 ii ACKNOWLEDGMENTS I wish to gratefully acknowledge the support of my academic advisor, Dr. Eva Y. Chi of the Department of Chemical and Nuclear Engineering. She is an inspiring and patient mentor who has devoted many hours to me.
    [Show full text]
  • Interplay Between Phospholipids and Digalactosyldiacylglycerol in Phosphate Limited Oats
    University of Gothenburg Faculty of Science 2009 Interplay Between Phospholipids and Digalactosyldiacylglycerol in Phosphate Limited Oats Henrik Tjellström Akademisk avhandling för filosofie doktorsexamen in växtmolekylärbiologi, som enligt beslut i lärarförslagsnämnden i biologi kommer att offentligt försvaras fredagen den 27:e mars 2009, klockan 10.15 i föreläsningssalen, Institutionen för Växt-och Miljövetenskaper, Carl Skottbergsgata 22B, 413 19 Göteborg Examinator: Professor Adrian K. Clarke Fakultetsopponent: Dr Sébastien Mongrand, CNRS, Université Victor Segalen Bordeaux 2, Bordeaux, France Göteborg, Mars 2009 ISBN: 978-91-85529-27-8 Interplay Between Phospholipids and Digalactosyldiacylglycerol in Phosphate Limited Oats Henrik Tjellström University of Gothenburg Dept of Plant and Environmental Sciences Box 461, SE-405 30 Gothenburg, Sweden ABSTRACT Phosphate is an essential nutrient. In most soils it is limiting, which has resulted in that phosphate is supplied as fertilizer to increase crop yield. Through evolution, plants have adapted several mechanisms to increase phosphate uptake from the soil and to household with acquired phosphate. A recent discovered house-holding mechanism is that plants utilize the phosphate bound in the headgroups of phospholipids: under phosphate-limiting conditions, phospholipids can be replaced by the non-phosphate containing lipid digalactosyldiacylglycerol (DGDG), previously assumed to reside in plastid membranes. The extra-plastidial phospholipid-to-DGDG replacement occurs in plasma membrane, tonoplast and mitochondria and has led to discoveries of new enzymes and metabolic pathways in plants. This thesis reports that phosphate limitation-induced biochemical and lipid compositional changes in oat root plasma membranes occur prior to any morphological changes in the oat. The phospholipase kinetics suggests that the plasma membrane is continuously supplied with phospholipids and that the products of plasma membrane lipase activities, phosphatidic acid and diacylglycerol, both are removed from the membrane.
    [Show full text]
  • Adherens Junctions, Desmosomes and Tight Junctions in Epidermal Barrier Function Johanna M
    14 The Open Dermatology Journal, 2010, 4, 14-20 Open Access Adherens Junctions, Desmosomes and Tight Junctions in Epidermal Barrier Function Johanna M. Brandner1,§, Marek Haftek*,2,§ and Carien M. Niessen3,§ 1Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany 2University of Lyon, EA4169 Normal and Pathological Functions of Skin Barrier, E. Herriot Hospital, Lyon, France 3Department of Dermatology, Center for Molecular Medicine, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany Abstract: The skin is an indispensable barrier which protects the body from the uncontrolled loss of water and solutes as well as from chemical and physical assaults and the invasion of pathogens. In recent years several studies have suggested an important role of intercellular junctions for the barrier function of the epidermis. In this review we summarize our knowledge of the impact of adherens junctions, (corneo)-desmosomes and tight junctions on barrier function of the skin. Keywords: Cadherins, catenins, claudins, cell polarity, stratum corneum, skin diseases. INTRODUCTION ADHERENS JUNCTIONS The stratifying epidermis of the skin physically separates Adherens junctions are intercellular structures that couple the organism from its environment and serves as its first line intercellular adhesion to the cytoskeleton thereby creating a of structural and functional defense against dehydration, transcellular network that coordinate the behavior of a chemical substances, physical insults and micro-organisms. population of cells. Adherens junctions are dynamic entities The living cell layers of the epidermis are crucial in the and also function as signal platforms that regulate formation and maintenance of the barrier on two different cytoskeletal dynamics and cell polarity.
    [Show full text]
  • Tight Junctions: from Simple Barriers to Multifunctional Molecular Gates
    Tight Junctions: From simple barriers to multifunctional molecular gates Ceniz Zihni1, Clare Mills1, Karl Matter1# and Maria S Balda1# Department of Cell Biology UCL Institute of Ophthalmology University College London London EC1V 9EL, UK # Address for correspondence UCL Institute of Ophthalmology University College London Bath Street London EC1V 9EL United Kingdom Tel – 44 20 7608 4014/6861 Fax – 44 20 7608 4034 E-mail: [email protected]/[email protected] Main body of text: 5983 words 1 Epithelia and endothelia separate different tissue compartments and protect multicellular organisms form the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Here, we discuss recent advances in our understanding of the molecular architecture and cellular functions of tight junctions. Microscopists in the 19th century described the paracellular space between neighbouring cells within an epithelial sheet to be sealed by a “terminal bar”, a structure later resolved by electron microscopy into a composite of distinct cell-cell junctions that is now called the epithelial junctional complex and is formed by tight junctions, adherens junctions and desmosomes1,2. As the former two junctions are more tightly associated and often reside at the apical end of the lateral membrane, they are often referred to as the apical junctional complex (however, in endothelia, tight junctions and adherens junctions can be intercalated) (Fig.
    [Show full text]