Crystal Structure of the PX Domain of SNX27
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Sorting Nexins in Protein Homeostasis Sara E. Hanley1,And Katrina F
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 November 2020 doi:10.20944/preprints202011.0241.v1 Sorting nexins in protein homeostasis Sara E. Hanley1,and Katrina F. Cooper2* 1Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, 08084, USA 1 [email protected] 2 [email protected] * [email protected] Tel: +1 (856)-566-2887 1Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, 08084, USA Abstract: Sorting nexins (SNXs) are a highly conserved membrane-associated protein family that plays a role in regulating protein homeostasis. This family of proteins is unified by their characteristic phox (PX) phosphoinositides binding domain. Along with binding to membranes, this family of SNXs also comprises a diverse array of protein-protein interaction motifs that are required for cellular sorting and protein trafficking. SNXs play a role in maintaining the integrity of the proteome which is essential for regulating multiple fundamental processes such as cell cycle progression, transcription, metabolism, and stress response. To tightly regulate these processes proteins must be expressed and degraded in the correct location and at the correct time. The cell employs several proteolysis mechanisms to ensure that proteins are selectively degraded at the appropriate spatiotemporal conditions. SNXs play a role in ubiquitin-mediated protein homeostasis at multiple levels including cargo localization, recycling, degradation, and function. In this review, we will discuss the role of SNXs in three different protein homeostasis systems: endocytosis lysosomal, the ubiquitin-proteasomal, and the autophagy-lysosomal system. The highly conserved nature of this protein family by beginning with the early research on SNXs and protein trafficking in yeast and lead into their important roles in mammalian systems. -
Structural and Functional Insights Into Sorting Nexin 5/6 Interaction with Bacterial Effector Ince
OPEN Citation: Signal Transduction and Targeted Therapy (2017) 2, e17030; doi:10.1038/sigtrans.2017.30 www.nature.com/sigtrans ARTICLE Structural and functional insights into sorting nexin 5/6 interaction with bacterial effector IncE Qingxiang Sun1,5, Xin Yong1,2,5, Xiaodong Sun3,5, Fan Yang1,2,5, Zhonghua Dai4, Yanqiu Gong1, Liming Zhou3, Xia Zhang1, Dawen Niu1, Lunzhi Dai1, Jia-Jia Liu4 and Da Jia1,2 The endosomal trafficking pathways are essential for many cellular activities. They are also important targets by many intracellular pathogens. Key regulators of the endosomal trafficking include the retromer complex and sorting nexins (SNXs). Chlamydia trachomatis effector protein IncE directly targets the retromer components SNX5 and SNX6 and suppresses retromer-mediated transport, but the exact mechanism has remained unclear. We present the crystal structure of the PX domain of SNX5 in complex with IncE, showing that IncE binds to a highly conserved hydrophobic groove of SNX5. The unique helical hairpin of SNX5/6 is essential for binding, explaining the specificity of SNX5/6 for IncE. The SNX5/6–IncE interaction is required for cellular localization of IncE and its inhibitory function. Mechanistically, IncE inhibits the association of CI-MPR cargo with retromer-containing endosomal subdomains. Our study provides new insights into the regulation of retromer-mediated transport and illustrates the intricate competition between host and pathogens in controlling cellular trafficking. Signal Transduction and Targeted Therapy (2017) 2, e17030; doi:10.1038/sigtrans.2017.30; -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Sorting Nexin 27 Regulates the Lysosomal Degradation of Aquaporin-2 Protein in the Kidney Collecting Duct
cells Article Sorting Nexin 27 Regulates the Lysosomal Degradation of Aquaporin-2 Protein in the Kidney Collecting Duct Hyo-Jung Choi 1,2, Hyo-Ju Jang 1,3, Euijung Park 1,3, Stine Julie Tingskov 4, Rikke Nørregaard 4, Hyun Jun Jung 5 and Tae-Hwan Kwon 1,3,* 1 Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Taegu 41944, Korea; [email protected] (H.-J.C.); [email protected] (H.-J.J.); [email protected] (E.P.) 2 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Taegu 41061, Korea 3 BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Taegu 41944, Korea 4 Department of Clinical Medicine, Aarhus University, Aarhus 8200, Denmark; [email protected] (S.J.T.); [email protected] (R.N.) 5 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; [email protected] * Correspondence: [email protected]; Tel.: +82-53-420-4825; Fax: +82-53-422-1466 Received: 30 March 2020; Accepted: 11 May 2020; Published: 13 May 2020 Abstract: Sorting nexin 27 (SNX27), a PDZ (Postsynaptic density-95/Discs large/Zonula occludens 1) domain-containing protein, cooperates with a retromer complex, which regulates intracellular trafficking and the abundance of membrane proteins. Since the carboxyl terminus of aquaporin-2 (AQP2c) has a class I PDZ-interacting motif (X-T/S-X-F), the role of SNX27 in the regulation of AQP2 was studied. Co-immunoprecipitation assay of the rat kidney demonstrated an interaction of SNX27 with AQP2. -
Molecular Mechanism of Membrane Targeting by the GRP1 PH Domain
Supplemental Material can be found at: http://www.jlr.org/cgi/content/full/M800150-JLR200/DC1 Molecular mechanism of membrane targeting by the GRP1 PH domain † † † Ju He,* Rachel M. Haney, ,§ Mohsin Vora, Vladislav V. Verkhusha,** Robert V. Stahelin, ,§ and Tatiana G. Kutateladze1,* Department of Pharmacology,* University of Colorado Health Sciences Center, Aurora, CO; † Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, IN; Department of Chemistry and Biochemistry and The Walther Center for Cancer Research,§ University of Notre Dame, South Bend, IN; and Department of Anatomy and Structural Biology,** Downloaded from Albert Einstein College of Medicine, Bronx, NY Abstract The general receptor for phosphoinositides iso- Supplementary key words general receptor for phosphoinositides iso- • • • form 1 (GRP1) is recruited to the plasma membrane in re- form 1 pleckstrin homology domain phosphoinositide phosphati- dylinositol 3,4,5-trisphosphate sponse to activation of phosphoinositide 3-kinases and www.jlr.org accumulation of phosphatidylinositol 3,4,5-trisphosphate ʼ [PtdIns(3,4,5)P3]. GRP1 s pleckstrin homology (PH) do- main recognizes PtdIns(3,4,5)P3 with high specificity and af- The signaling lipid phosphatidylinositol 3,4,5-trisphos- finity, however, the precise mechanism of its association phate [PtdIns(3,4,5)P3] is produced in plasma membranes at Albert Einstein College of Medicine Library on July 14, 2008 with membranes remains unclear. Here, we detail the mo- in response to stimulation of cell surface receptors by lecular basis of membrane anchoring by the GRP1 PH do- growth factors and hormones (1). Class I phosphoinositide main. Our data reveal a multivalent membrane docking (PI) 3-kinases phosphorylate the inositol headgroup of the involving PtdIns(3,4,5)P binding, regulated by pH and fa- 3 relatively abundant phosphatidylinositol 4,5-bisphosphate cilitated by electrostatic interactions with other anionic lip- [Ptdns(4,5)P2], transiently elevating the level of PtdIns ids. -
The PX Domain Protein Interaction Network in Yeast
The PX domain protein interaction network in yeast Zur Erlangung des akademischen Grades eines DOKTORS DER NATURWISSENSCHAFTEN (Dr. rer. nat.) der Fakultät für Chemie und Biowissenschaften der Universität Karlsruhe (TH) vorgelegte DISSERTATION von Dipl. Biol. Carolina S. Müller aus Buenos Aires Dekan: Prof. Dr. Manfred Kappes Referent: Dr. Nils Johnsson Korreferent: HD. Dr. Adam Bertl Tag der mündlichen Prüfung: 17.02.2005 I dedicate this work to my Parents and Alex TABLE OF CONTENTS Table of contents Introduction 1 Yeast as a model organism in proteome analysis 1 Protein-protein interactions 2 Protein Domains in Yeast 3 Classification of protein interaction domains 3 Phosphoinositides 5 Function 5 Structure 5 Biochemistry 6 Localization 7 Lipid Binding Domains 8 The PX domain 10 Function of PX domain containing proteins 10 PX domain structure and PI binding affinities 10 Yeast PX domain containing proteins 13 PX domain and protein-protein interactions 13 Lipid binding domains and protein-protein interactions 14 The PX-only proteins Grd19p and Ypt35p and their phenotypes 15 Aim of my PhD work 16 Project outline 16 Searching for interacting partners 16 Confirmation of obtained interactions via a 16 second independent method Mapping the interacting region 16 The Two-Hybrid System 17 Definition 17 Basic Principle of the classical Yeast-Two Hybrid System 17 Peptide Synthesis 18 SPOT synthesis technique 18 Analysis of protein- peptide contact sites based on SPOT synthesis 19 TABLE OF CONTENTS Experimental procedures 21 Yeast two-hybrid assay -
Sorting Nexin-27 Regulates AMPA Receptor Trafficking Through The
RESEARCH ARTICLE Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2 Kirsty J McMillan1†*, Paul J Banks2†, Francesca LN Hellel1, Ruth E Carmichael1, Thomas Clairfeuille3, Ashley J Evans1, Kate J Heesom4, Philip Lewis4, Brett M Collins3, Zafar I Bashir2, Jeremy M Henley1, Kevin A Wilkinson1*, Peter J Cullen1* 1School of Biochemistry, University of Bristol, Bristol, United Kingdom; 2School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom; 3Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia; 4Proteomics facility, School of Biochemistry, University of Bristol, Bristol, United Kingdom Abstract The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies, we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities, and working memory deficits. Focusing on the *For correspondence: synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its [email protected] endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of (KJMM); LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and [email protected] attenuated hippocampal long-term potentiation. Overall, our study provides an additional (KAW); mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and [email protected] (PJC) plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed †These authors contributed function of SNX27 and LRFN2 in a range of neurological conditions. -
Downregulation of Glial Genes Involved in Synaptic Function
RESEARCH ARTICLE Downregulation of glial genes involved in synaptic function mitigates Huntington’s disease pathogenesis Tarik Seref Onur1,2,3†, Andrew Laitman2,4,5†, He Zhao2, Ryan Keyho2, Hyemin Kim2, Jennifer Wang2, Megan Mair1,2,3, Huilan Wang6, Lifang Li1,2, Alma Perez2, Maria de Haro1,2, Ying-Wooi Wan2, Genevera Allen2,7, Boxun Lu6, Ismael Al-Ramahi1,2, Zhandong Liu2,4,5, Juan Botas1,2,3,4* 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; 2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; 3Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, United States; 4Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, United States; 5Department of Pediatrics, Baylor College of Medicine, Houston, United States; 6State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China; 7Departments of Electrical & Computer Engineering, Statistics and Computer Science, Rice University, Houston, United States Abstract Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington’s disease (HD), we profiled the gene expression alterations of *For correspondence: Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared [email protected] these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high- †These authors contributed throughput behavioral assay and found that downregulation of genes involved in synapse assembly equally to this work mitigated pathogenesis and behavioral deficits. -
And Diagnostic Implications During Chronic Inflammation
Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications This information is current as Eliran Ish-Shalom, Yaron Meirow, Moshe Sade-Feldman, of September 27, 2021. Julia Kanterman, Lynn Wang, Olga Mizrahi, Yair Klieger and Michal Baniyash J Immunol 2016; 196:156-167; Prepublished online 25 November 2015; doi: 10.4049/jimmunol.1402877 Downloaded from http://www.jimmunol.org/content/196/1/156 Supplementary http://www.jimmunol.org/content/suppl/2015/11/25/jimmunol.140287 Material 7.DCSupplemental http://www.jimmunol.org/ References This article cites 50 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/196/1/156.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications Eliran Ish-Shalom,*,† Yaron Meirow,*,1 Moshe Sade-Feldman,*,1 Julia Kanterman,* Lynn Wang,* Olga Mizrahi,† Yair Klieger,*,† and Michal Baniyash* Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. -
A Targeted Rnai Screen Identifies Endocytic Trafficking Factors That
Diabetes Volume 67, March 2018 385 A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic b-Cells Teresa Buenaventura,1 Nisha Kanda,1 Phoebe C. Douzenis,1 Ben Jones,2 Stephen R. Bloom,2 Pauline Chabosseau,1 Ivan R. Corrêa Jr.,3 Domenico Bosco,4 Lorenzo Piemonti,5,6 Piero Marchetti,7 Paul R. Johnson,8 A.M. James Shapiro,9 Guy A. Rutter,1 and Alejandra Tomas1 Diabetes 2018;67:385–399 | https://doi.org/10.2337/db17-0639 The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key binding, GLP-1Rs signal through stimulatory G (Gs) pro- target for type 2 diabetes (T2D) treatment. Because endocytic teins to raise intracellular cAMP levels and modulate insulin trafficking of agonist-bound receptors is one of the most secretion from pancreatic b-cells. important routes for regulation of receptor signaling, a better As with other G protein–coupled receptors (GPCRs), SIGNAL TRANSDUCTION understanding of this process may facilitate the develop- GLP-1R signaling is tightly regulated through endocytic ment of new T2D therapeutic strategies. Here, we screened trafficking (2). Activated GLP-1Rs are rapidly internalized – 29 proteins with known functions in G protein coupled recep- and recycled to the plasma membrane or distributed through- fi tor traf cking for their role in GLP-1R potentiation of insulin out endocytic compartments (3). Despite the pivotal role b fi secretion in pancreatic -cells. We identify ve (clathrin, of trafficking in GPCR signaling, neither the molecular dynamin1, AP2, sorting nexins [SNX] SNX27, and SNX1) details nor the key factors responsible for GLP-1R endo- that increase and four (huntingtin-interacting protein 1 cytosis and postendocytic sorting have been thoroughly [HIP1], HIP14, GASP-1, and Nedd4) that decrease insulin investigated. -
Supplementary Information – Postema Et Al., the Genetics of Situs Inversus Totalis Without Primary Ciliary Dyskinesia
1 Supplementary information – Postema et al., The genetics of situs inversus totalis without primary ciliary dyskinesia Table of Contents: Supplementary Methods 2 Supplementary Results 5 Supplementary References 6 Supplementary Tables and Figures Table S1. Subject characteristics 9 Table S2. Inbreeding coefficients per subject 10 Figure S1. Multidimensional scaling to capture overall genomic diversity 11 among the 30 study samples Table S3. Significantly enriched gene-sets under a recessive mutation model 12 Table S4. Broader list of candidate genes, and the sources that led to their 13 inclusion Table S5. Potential recessive and X-linked mutations in the unsolved cases 15 Table S6. Potential mutations in the unsolved cases, dominant model 22 2 1.0 Supplementary Methods 1.1 Participants Fifteen people with radiologically documented SIT, including nine without PCD and six with Kartagener syndrome, and 15 healthy controls matched for age, sex, education and handedness, were recruited from Ghent University Hospital and Middelheim Hospital Antwerp. Details about the recruitment and selection procedure have been described elsewhere (1). Briefly, among the 15 people with radiologically documented SIT, those who had symptoms reminiscent of PCD, or who were formally diagnosed with PCD according to their medical record, were categorized as having Kartagener syndrome. Those who had no reported symptoms or formal diagnosis of PCD were assigned to the non-PCD SIT group. Handedness was assessed using the Edinburgh Handedness Inventory (EHI) (2). Tables 1 and S1 give overviews of the participants and their characteristics. Note that one non-PCD SIT subject reported being forced to switch from left- to right-handedness in childhood, in which case five out of nine of the non-PCD SIT cases are naturally left-handed (Table 1, Table S1). -
Sorting Nexin 9 in Clathrin-Mediated Endocytosis
UMEÅ UNIVERSITY MEDICAL DISSERTATIONS New Series No. 875; ISSN 0346-6612; ISBN 91-7305-599-9 Department of Medical Biochemistry and Biophysics Umeå University, Sweden Editor: The Dean of the Faculty of Medicine Sorting Nexin 9 in Clathrin-mediated Endocytosis Richard Lundmark Department of Medical Biochemistry and Biophysics Umeå University, Sweden Umeå 2004 © Richard Lundmark ISBN 91-7305-599-9 Printed in Sweden at Solfjädern Offset AB Umeå 2004 Tillägnad min älskade familj Samuel, Elias och Ida TABLE OF CONTENTS ABBREVIATIONS ...................................................................................................................2 ABSTRACT...............................................................................................................................3 PUBLICATION LIST ...............................................................................................................4 OVERVIEW ..............................................................................................................................5 1. INTRODUCTION .................................................................................................................5 2. ADAPTOR PROTEIN COMPLEXES..................................................................................6 3. CLATHRIN ...........................................................................................................................6 4. ENDOCYTOSIS....................................................................................................................7