Molecular Dynamics Simulation of the Interactions Between EHD1 EH Domain and Multiple Peptides*
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Membrane Tension Buffering by Caveolae: a Role in Cancer?
Cancer and Metastasis Reviews (2020) 39:505–517 https://doi.org/10.1007/s10555-020-09899-2 Membrane tension buffering by caveolae: a role in cancer? Vibha Singh1 & Christophe Lamaze1 Published online: 30 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Caveolae are bulb-like invaginations made up of two essential structural proteins, caveolin-1 and cavins, which are abundantly present at the plasma membrane of vertebrate cells. Since their discovery more than 60 years ago, the function of caveolae has been mired in controversy. The last decade has seen the characterization of new caveolae components and regulators together with the discovery of additional cellular functions that have shed new light on these enigmatic structures. Early on, caveolae and/ or caveolin-1 have been involved in the regulation of several parameters associated with cancer progression such as cell migration, metastasis, angiogenesis, or cell growth. These studies have revealed that caveolin-1 and more recently cavin-1 have a dual role with either a negative or a positive effect on most of these parameters. The recent discovery that caveolae can act as mechanosensors has sparked an array of new studies that have addressed the mechanobiology of caveolae in various cellular functions. This review summarizes the current knowledge on caveolae and their role in cancer development through their activity in membrane tension buffering. We propose that the role of caveolae in cancer has to be revisited through their response to the mechanical forces encountered by cancer cells during tumor mass development. Keywords Caveolae . Cancer . Mechanosensing . Mechanotransdcution . Membrane tension . -
Distinct EH Domains of the Endocytic TPLATE Complex Confer Lipid and Protein Binding
bioRxiv preprint doi: https://doi.org/10.1101/2020.05.29.122911; this version posted May 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Distinct EH domains of the endocytic TPLATE complex confer lipid and protein binding. Klaas Yperman1,2, Anna C. Papageorgiou3,*, Romain Merceron4,5,*, Steven De Munck4,5, Yehudi Bloch4,5, Dominique Eeckhout1,2, Pieter Tack6, Thomas Evangelidis3, Jelle Van Leene1,2, Laszlo Vincze6, Peter Vandenabeele6,7, Martin Potocký8, Geert De Jaeger1,2, Savvas N. Savvides4,5, Konstantinos Tripsianes3, Roman Pleskot1,2,# & Daniel Van Damme1,2,# * Equal contribution # joint senior authorship 1Ghent University, Department of Plant Biotechnology and Bioinformatics, Technologiepark 71, 9052 Ghent, Belgium. 2VIB Center for Plant Systems Biology, Technologiepark 71, 9052 Ghent, Belgium. 3CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, 62500, Brno, Czech Republic. 4Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium. 5VIB Center for Inflammation Research, 9052 Ghent, Belgium. 6Department of Analytical Chemistry, Ghent University, 9000 Ghent, Belgium 7Archaeometry Research Group, Department of Archaeology, Ghent University, Sint- Pietersnieuwstraat 35, B-9000 Ghent, Belgium 8Institute of Experimental Botany, Academy of Sciences of the Czech Republic, Rozvojová 263, 16502 Prague 6, Czech Republic Abstract Clathrin-mediated endocytosis (CME) is the gatekeeper of the plasma membrane. In contrast to animals and yeasts, CME in plants depends on the TPLATE complex (TPC), an evolutionary ancient adaptor complex. The mechanistic contribution of the individual TPC subunits to plant CME remains however elusive. -
A Trafficome-Wide Rnai Screen Reveals Deployment of Early and Late Secretory Host Proteins and the Entire Late Endo-/Lysosomal V
bioRxiv preprint doi: https://doi.org/10.1101/848549; this version posted November 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 A trafficome-wide RNAi screen reveals deployment of early and late 2 secretory host proteins and the entire late endo-/lysosomal vesicle fusion 3 machinery by intracellular Salmonella 4 5 Alexander Kehl1,4, Vera Göser1, Tatjana Reuter1, Viktoria Liss1, Maximilian Franke1, 6 Christopher John1, Christian P. Richter2, Jörg Deiwick1 and Michael Hensel1, 7 8 1Division of Microbiology, University of Osnabrück, Osnabrück, Germany; 2Division of Biophysics, University 9 of Osnabrück, Osnabrück, Germany, 3CellNanOs – Center for Cellular Nanoanalytics, Fachbereich 10 Biologie/Chemie, Universität Osnabrück, Osnabrück, Germany; 4current address: Institute for Hygiene, 11 University of Münster, Münster, Germany 12 13 Running title: Host factors for SIF formation 14 Keywords: siRNA knockdown, live cell imaging, Salmonella-containing vacuole, Salmonella- 15 induced filaments 16 17 Address for correspondence: 18 Alexander Kehl 19 Institute for Hygiene 20 University of Münster 21 Robert-Koch-Str. 4148149 Münster, Germany 22 Tel.: +49(0)251/83-55233 23 E-mail: [email protected] 24 25 or bioRxiv preprint doi: https://doi.org/10.1101/848549; this version posted November 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. -
Structural Insights Into the Activation Mechanism of Dynamin-Like EHD Atpases
Structural insights into the activation mechanism of dynamin-like EHD ATPases Arthur Alves Meloa,b, Balachandra G. Hegdec, Claudio Shaha,b, Elin Larssond, J. Mario Isase, Séverine Kunza, Richard Lundmarkd,f, Ralf Langene, and Oliver Daumkea,b,1 aCrystallography Department, Max-Delbrück-Centrum for Molecular Medicine, 13125 Berlin, Germany; bInstitute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; cDepartment of Physics, Rani Channamma University, 591 156, Karnataka, India; dMedical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden; eZilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033; and fIntegrative Medical Biology, Umeå University, 901 87, Umeå, Sweden Edited by Pietro De Camilli, Yale University and Howard Hughes Medical Institute, New Haven, CT, and approved January 12, 2017 (received for review August 23, 2016) Eps15 (epidermal growth factor receptor pathway substrate 15)- internal Gly-Pro-Phe (GPF) motif in the linker between the he- homology domain containing proteins (EHDs) comprise a family of lical domain and the EH domain. This interaction locks the EH dynamin-related mechano-chemical ATPases involved in cellular domain to the opposing GTPase domain, from where it delivers its membrane trafficking. Previous studies have revealed the structure C-terminal tail into the active site (14). In this way, the EH domains of the EHD2 dimer, but the molecular mechanisms of membrane were suggested to block a highly conserved second assembly site in recruitment and assembly have remained obscure. Here, we deter- the GTPase domain, which extends across the nucleotide binding mined the crystal structure of an amino-terminally truncated EHD4 site. GTPase domain assembly via this “Ginterface” is a conserved dimer. -
Oxidized Phospholipids Regulate Amino Acid Metabolism Through MTHFD2 to Facilitate Nucleotide Release in Endothelial Cells
ARTICLE DOI: 10.1038/s41467-018-04602-0 OPEN Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells Juliane Hitzel1,2, Eunjee Lee3,4, Yi Zhang 3,5,Sofia Iris Bibli2,6, Xiaogang Li7, Sven Zukunft 2,6, Beatrice Pflüger1,2, Jiong Hu2,6, Christoph Schürmann1,2, Andrea Estefania Vasconez1,2, James A. Oo1,2, Adelheid Kratzer8,9, Sandeep Kumar 10, Flávia Rezende1,2, Ivana Josipovic1,2, Dominique Thomas11, Hector Giral8,9, Yannick Schreiber12, Gerd Geisslinger11,12, Christian Fork1,2, Xia Yang13, Fragiska Sigala14, Casey E. Romanoski15, Jens Kroll7, Hanjoong Jo 10, Ulf Landmesser8,9,16, Aldons J. Lusis17, 1234567890():,; Dmitry Namgaladze18, Ingrid Fleming2,6, Matthias S. Leisegang1,2, Jun Zhu 3,4 & Ralf P. Brandes1,2 Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a cau- sal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipo- proteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2- controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis. -
Spatial Sorting Enables Comprehensive Characterization of Liver Zonation
ARTICLES https://doi.org/10.1038/s42255-019-0109-9 Spatial sorting enables comprehensive characterization of liver zonation Shani Ben-Moshe1,3, Yonatan Shapira1,3, Andreas E. Moor 1,2, Rita Manco1, Tamar Veg1, Keren Bahar Halpern1 and Shalev Itzkovitz 1* The mammalian liver is composed of repeating hexagonal units termed lobules. Spatially resolved single-cell transcriptomics has revealed that about half of hepatocyte genes are differentially expressed across the lobule, yet technical limitations have impeded reconstructing similar global spatial maps of other hepatocyte features. Here, we show how zonated surface markers can be used to sort hepatocytes from defined lobule zones with high spatial resolution. We apply transcriptomics, microRNA (miRNA) array measurements and mass spectrometry proteomics to reconstruct spatial atlases of multiple zon- ated features. We demonstrate that protein zonation largely overlaps with messenger RNA zonation, with the periportal HNF4α as an exception. We identify zonation of miRNAs, such as miR-122, and inverse zonation of miRNAs and their hepa- tocyte target genes, highlighting potential regulation of gene expression levels through zonated mRNA degradation. Among the targets, we find the pericentral Wingless-related integration site (Wnt) receptors Fzd7 and Fzd8 and the periportal Wnt inhibitors Tcf7l1 and Ctnnbip1. Our approach facilitates reconstructing spatial atlases of multiple cellular features in the liver and other structured tissues. he mammalian liver is a structured organ, consisting of measurements would broaden our understanding of the regulation repeating hexagonally shaped units termed ‘lobules’ (Fig. 1a). of liver zonation and could be used to model liver metabolic func- In mice, each lobule consists of around 9–12 concentric lay- tion more precisely. -
Hypoxia-Inducible-Factor Dependent Induction of Netrin-1
bioRxiv preprint doi: https://doi.org/10.1101/561340; this version posted May 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Circadian light-mediated endothelial metabolic reprogramming Yoshimasa Oyama MD, Ph.D.,1* Colleen M. Bartman Ph.D.,1,4* Stephanie Bonney Ph.D.,1,4* J. Scott Lee Ph.D.,1 Lori A. Walker Ph.D.,2 Jun Han Ph.D.,3 Christoph H. Borchers Ph.D.,3 Peter M. Buttrick M.D.,2 Carol M. Aherne Ph.D.1, Nathan Clendenen M.D.,1 Sean P. Colgan Ph.D.1 and Tobias Eckle M.D., Ph.D.1,2,4# *authors contributed equally 1Mucosal Inflammation Program, Departments of Medicine and Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 3Department of Biochemistry and Microbiology, Genome BC Proteomics Centre, University of Victoria, Victoria, BC, Canada; 4Graduate Training Program in Cell Biology, Stem Cells, and Development, University of Colorado Anschutz Medical Campus, Aurora, CO, USA #Correspondence should be addressed to: Tobias Eckle, M.D., Ph.D. Professor of Anesthesiology, Cardiology and Cell Biology Department of Anesthesiology University of Colorado Denver 12700 E 19th Avenue, Mailstop B112, RC 2, Room 7121 Aurora, CO 80045; Office: +1-303-724 -2932 or - 2947, Fax: +1-303-724-2852 Email: [email protected] Short title: Intense light as endothelium-targeting strategy in myocardial ischemia bioRxiv preprint doi: https://doi.org/10.1101/561340; this version posted May 15, 2019. -
Alterations of EHD1/EHD4 Protein Levels Interfere with L1/Ngcam Endocytosis in Neurons and Disrupt Axonal Targeting
6646 • The Journal of Neuroscience, May 12, 2010 • 30(19):6646–6657 Cellular/Molecular Alterations of EHD1/EHD4 Protein Levels Interfere with L1/NgCAM Endocytosis in Neurons and Disrupt Axonal Targeting Chan Choo C. Yap,1 Zofia M. Lasiecka,1 Steven Caplan,2 and Bettina Winckler1 1Department of Neuroscience, University of Virginia Medical School, Charlottesville, Virginia 22936, and 2Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198 Axon growth is regulated by many proteins, including adhesion molecules, which need to be trafficked correctly to axons. The adhesion molecule L1/neuron–glia cell adhesion molecule (NgCAM) travels to axons via an endocytosis-dependent pathway (transcytosis), tra- versing somatodendritic endosomes. The Eps15 homology domain (EHD) family proteins (EHD1–EHD4) play important roles in endo- somal recycling and possibly in endocytosis. We investigated whether EHD1 regulates L1/NgCAM trafficking in neurons. Both short hairpin-mediated downregulation and overexpression of EHD1 led to dendritic mistargeting of NgCAM. Downregulation of EHD1 showed increased endosomal accumulation of NgCAM, whereas, surprisingly, overexpression of EHD1 led to impairment of L1/NgCAM internalization in neurons but not in fibroblasts. Transferrin internalization, however, was unaffected. At longer overexpression times of EHD1, NgCAM endocytosis returned to normal, suggesting rapid upregulation of compensatory endocytic pathways. EHD1 is capable of hetero-oligomerization, and an endogenous complex of EHD1 and EHD4 was identified previously. We therefore tested whether short- term overexpression of other EHD family members showed a similar endocytosis defect. Expression of EHD4, but not of EHD3, also causedadefectinL1/NgCAMendocytosis.OligomerizationofEHD1wasrequiredtocauseNgCAMendocytosisdefects,andsimultaneous expression of EHD1 and EHD4 rescued NgCAM endocytosis. -
Caveolin-3: Structural and Functional Insights Into Its Role in Murine Airway Smooth Muscle Constriction
Caveolin-3: Structural and functional insights into its role in murine airway smooth muscle constriction Inaugural Dissertation submitted to the Faculty of Medicine in partial fulfillment of the requirements for the PhD-Degree of the Faculty of Medicine of the Justus Liebig University Giessen by Maryam Keshavarz from Shiraz, Iran Giessen (2016) From the Institute of Anatomy and Cell Biology Cardiopulmonary Neurobiology Head: Prof. Wolfgang Kummer of the Faculty of Medicine of the Justus Liebig University Giessen First Supervisor and Committee Member: Prof. Dr. Wolfgang Kummer/Prof. Dr. Gabriela Krasteva-Christ Second Supervisor and Committee Member: Prof. Dr. Norbert Weißmann Committee Members: Prof. Dr. Kurt Racké and Prof. Dr. Klaus-Dieter Schlüter Date of Doctoral Defense: 22.12.2016 TABLE OF CONTENTS Table of Contents 1 Introduction ............................................................................................................................... 1 1.1 Lipid raft .............................................................................................................................................. 1 1.2 Caveolae .............................................................................................................................................. 1 1.2.1 Structural and functional role .............................................................................................................. 1 1.2.2 Caveolins .................................................................................................................................................. -
ARTICLES Nature Cell Biology
ARTICLES nature cell biology AMPH-l/P\mphiphysin/Binl functions with RME-l/Ehdl in endocytic recycling RME-lIEHDI (receptor r ediated endocytosis/EpsI5 homology-domain containing I) family proteins are key residents of the recycling endosome, which are required for endosome-to-plasma membrane transport in Caenorhabditis elegans and mammals. Recent studies suggest similarities between the RME-lIEHD proteins and the Dynamin GTPase superfamily of mechanochemical pinchases, which promote membrane fission. Here we show that endogenous C. elegans AMPH-I, the only C. elegans member of the Amphiphysin/BIN. family of BAR (Binl-Amphiphysin-RvsI6Ip/167p}-domain-containing proteins, colocalizes with RME-I on recycling endosomes in vivo, that amph-l-deletion mutants are defective in recycling endosome morphology and function, and that binding of AMPH-I Asn-Pro-Phe(Asp/Glu) sequences to the RME-I EH-domain promotes the recycling of transmembrane cargo. We also show a requirement for human BINI (also known as Amphiphysin 2) in EHDI-regulated endocytic recycling. In vitro, we find that purified recombinant AMPH-I-RME-I complexes produce short, coated membrane tubules that are qualitatively distinct from those produced by either protein alone. Our results indicate that AMPH-I and RME-I cooperatively regulate endocytic recycling, probably through functions required for the production of cargo carriers that exit the recycling endosome for the cell surface. Previous work has shown th It RME-l and mammalian mRme-l /EHD 1 Asn-Pro-Phe-containing partner proteins!2,13. Given the high degree are ATPases that require ATP binding for homo-oligomerization and of overall similarity among RME-l /EHD family members (about 65% function in vivo!-4. -
A Network-Based, Integrative Study to Identify Core Biological Pathways That Drive Breast Cancer Clinical Subtypes
British Journal of Cancer (2012) 106, 1107 – 1116 & 2012 Cancer Research UK All rights reserved 0007 – 0920/12 www.bjcancer.com A network-based, integrative study to identify core biological pathways that drive breast cancer clinical subtypes 1 *,2 3 4 4 2 2 5 2 2 B Dutta , L Pusztai ,YQi, F Andre´ , V Lazar , G Bianchini , N Ueno , R Agarwal , B Wang , CY Shiang , 2 1 6 *,1 GN Hortobagyi , GB Mills , WF Symmans and G Bala´zsi 1Department of Systems Biology – Unit 950, The University of Texas MD Anderson Cancer Center, 7435 Fannin Street, Houston, TX 77054, USA; 2 Department of Breast Medical Oncology – Unit 1354, The University of Texas MD Anderson Cancer Center, PO Box 301439, Houston, 3 4 TX 77230-1439, USA; Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Institute Gustave 5 6 Roussy, Villejuif, France; Department of Medical Oncology, Imperial College, London, UK; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA BACKGROUND: The rapid collection of diverse genome-scale data raises the urgent need to integrate and utilise these resources for biological discovery or biomedical applications. For example, diverse transcriptomic and gene copy number variation data are currently collected for various cancers, but relatively few current methods are capable to utilise the emerging information. METHODS: We developed and tested a data-integration method to identify gene networks that drive the biology of breast cancer clinical subtypes. The method simultaneously overlays gene expression and gene copy number data on protein–protein interaction, transcriptional-regulatory and signalling networks by identifying coincident genomic and transcriptional disturbances in local network neighborhoods. -
RNA SEQ Analysis Indicates That the AE3 Cl-/HCO3
www.nature.com/scientificreports OPEN RNA SEQ Analysis Indicates that − − the AE3 Cl /HCO3 Exchanger Contributes to Active Transport- Received: 31 March 2017 Accepted: 29 June 2017 Mediated CO2 Disposal in Heart Published: xx xx xxxx Kanimozhi Vairamani1, Hong-Sheng Wang2, Mario Medvedovic3, John N. Lorenz4 & Gary E. Shull1 − − Loss of the AE3 Cl /HCO3 exchanger (Slc4a3) in mice causes an impaired cardiac force-frequency response and heart failure under some conditions but the mechanisms are not known. To better understand the functions of AE3, we performed RNA Seq analysis of AE3-null and wild-type mouse + hearts and evaluated the data with respect to three hypotheses (CO2 disposal, facilitation of Na - loading, and recovery from an alkaline load) that have been proposed for its physiological functions. Gene Ontology and PubMatrix analyses of diferentially expressed genes revealed a hypoxia response and changes in vasodilation and angiogenesis genes that strongly support the CO2 disposal hypothesis. Diferential expression of energy metabolism genes, which indicated increased glucose utilization and decreased fatty acid utilization, were consistent with adaptive responses to perturbations of O2/CO2 balance in AE3-null myocytes. Given that the myocardium is an obligate aerobic tissue and consumes large amounts of O2, the data suggest that loss of AE3, which has the potential to extrude CO2 in the − form of HCO3 , impairs O2/CO2 balance in cardiac myocytes. These results support a model in which the − − − + AE3 Cl /HCO3 exchanger, coupled with parallel Cl and H -extrusion mechanisms and extracellular carbonic anhydrase, is responsible for active transport-mediated disposal of CO2. − − 1 Anion exchanger isoform 3 (AE3; gene symbol Slc4a3), the most abundant Cl /HCO3 exchanger in cardiac muscle , − − mediates electroneutral extrusion of HCO3 in exchange for inward transport of Cl .