Mechanisms of Membrane Fusion: Disparate Players and Common Principles
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The 16P11.2 Homologs Fam57ba and Doc2a Generate Certain Brain and Body Phenotypes Jasmine M
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by DSpace@MIT Human Molecular Genetics, 2017, Vol. 26, No. 19 3699–3712 doi: 10.1093/hmg/ddx255 Advance Access Publication Date: 7 July 2017 Original Article ORIGINAL ARTICLE The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes Jasmine M. McCammon1, Alicia Blaker-Lee1, Xiao Chen2 and Hazel Sive1,2,* 1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA and 2Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA *To whom correspondence should be addressed at: 455 Main Street, Cambridge, MA 02142, USA. Tel: 617 2588242; Fax: 617 2585578; Email: [email protected] Abstract Deletion of the 16p11.2 CNV affects 25 core genes and is associated with multiple symptoms affecting brain and body, including seizures, hyperactivity, macrocephaly, and obesity. Available data suggest that most symptoms are controlled by haploinsufficiency of two or more 16p11.2 genes. To identify interacting 16p11.2 genes, we used a pairwise partial loss of function antisense screen for embryonic brain morphology, using the accessible zebrafish model. fam57ba, encoding a ceramide synthase, was identified as interacting with the doc2a gene, encoding a calcium-sensitive exocytosis regulator, a ge- netic interaction not previously described. Using genetic mutants, we demonstrated that doc2aþ/À fam57baþ/À double heterozy- gotes show hyperactivity and increased seizure susceptibility relative to wild-type or single doc2aÀ/À or fam57baÀ/À mutants. Additionally, doc2aþ/À fam57baþ/À double heterozygotes demonstrate the increased body length and head size. Single doc2aþ/À and fam57baþ/À heterozygotes do not show a body size increase; however, fam57baÀ/À homozygous mutants show a strongly increased head size and body length, suggesting a greater contribution from fam57ba to the haploinsufficient interaction be- tween doc2a and fam57ba. -
Autism Multiplex Family with 16P11.2P12.2 Microduplication Syndrome in Monozygotic Twins and Distal 16P11.2 Deletion in Their Brother
European Journal of Human Genetics (2012) 20, 540–546 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg ARTICLE Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother Anne-Claude Tabet1,2,3,4, Marion Pilorge2,3,4, Richard Delorme5,6,Fre´de´rique Amsellem5,6, Jean-Marc Pinard7, Marion Leboyer6,8,9, Alain Verloes10, Brigitte Benzacken1,11,12 and Catalina Betancur*,2,3,4 The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5–30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5–30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28–30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40–29.25 Mb), inherited from his apparently healthy father. -
Coatomer-Rich Endoplasmic Reticulum LELIO ORCI*, ALAIN PERRELET*, MARIELLA RAVAZZOLA*, Myltne AMHERDT*, JAMES E
Proc. Nati. Acad. Sci. USA Vol. 91, pp. 11924-11928, December 1994 Cell Biology Coatomer-rich endoplasmic reticulum LELIO ORCI*, ALAIN PERRELET*, MARIELLA RAVAZZOLA*, MYLtNE AMHERDT*, JAMES E. ROTHMANt, AND RANDY SCHEKMAN* *Department of Morphology, University of Geneva Medical School, 1211 Geneva 4, Switzerland; tDivision of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720; and tCellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 Contributed by Randy Schekman, August 30, 1994 ABSTRACT We identify in normal cells the existence of digestion and incubated at normal (370C) or low (220C, 15'C, two distinct sites of the transitional endoplasmic reticulum 40C) temperatures under continuous shaking and gassing with (ER), one housing the Sec23p protein complex (the classical 95% 02/5% CO2. Monolayer cultures ofpancreatic endocrine transitional element), the other the coatomer protein complex cells (24) were exposed to low temperatures as for isolated (the coatomer-rich ER). Experimental conditions that reduce islets. ATP depletion in both preparations was induced at transport from the ER to the Golgi complex lead to the 370C with 10 ImM antimycin or 1 mM dinitrophenol or by overexpression of this newly defined coatomer-rich ER. gassing the cells with N2 instead of the 02/CO2 mixture. At the end of the incubations, the samples were fixed with Progress in the identification and characterization of the 1% glutaraldehyde in 0.1 M sodium phosphate buffer (pH 7.4) carriers involved in membrane traffic from the endoplasmic for 1 hr at the final temperature of the incubation protocol, reticulum (ER) to and through the Golgi complex was pos- washed with buffer, and processed for Epon embedding sible by combining morphological and biochemical methods, (conventional thin sections) or for cryoultramicrotomy ac- cell-free assay systems, and yeast genetics (for review see refs. -
Formation of COPI-Coated Vesicles at a Glance Eric C
© 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs209890. doi:10.1242/jcs.209890 CELL SCIENCE AT A GLANCE Formation of COPI-coated vesicles at a glance Eric C. Arakel1 and Blanche Schwappach1,2,* ABSTRACT unresolved, this review attempts to refocus the perspectives of The coat protein complex I (COPI) allows the precise sorting of lipids the field. and proteins between Golgi cisternae and retrieval from the Golgi KEY WORDS: Arf1, ArfGAP, COPI, Coatomer, Golgi, Endoplasmic to the ER. This essential role maintains the identity of the early reticulum, Vesicle coat secretory pathway and impinges on key cellular processes, such as protein quality control. In this Cell Science at a Glance and accompanying poster, we illustrate the different stages of COPI- Introduction coated vesicle formation and revisit decades of research in the Vesicle coat proteins, such as the archetypal clathrin and the coat context of recent advances in the elucidation of COPI coat structure. protein complexes II and I (COPII and COPI, respectively) are By calling attention to an array of questions that have remained molecular machines with two central roles: enabling vesicle formation, and selecting protein and lipid cargo to be packaged within them. Thus, coat proteins fulfil a central role in the 1Department of Molecular Biology, Universitätsmedizin Göttingen, Humboldtallee homeostasis of the cell’s endomembrane system and are the basis 23, 37073 Göttingen, Germany. 2Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany. of functionally segregated compartments. COPI operates in retrieval from the Golgi to the endoplasmic reticulum (ER) and in intra-Golgi *Author for correspondence ([email protected]) transport (Beck et al., 2009; Duden, 2003; Lee et al., 2004a; Spang, E.C.A., 0000-0001-7716-7149; B.S., 0000-0003-0225-6432 2009), and maintains ER- and Golgi-resident chaperones and enzymes where they belong. -
ADP-Ribosylation Factor, a Small GTP-Binding Protein, Is Required for Binding of the Coatomer Protein Fl-COP to Golgi Membranes JULIE G
Proc. Natl. Acad. Sci. USA Vol. 89, pp. 6408-6412, July 1992 Biochemistry ADP-ribosylation factor, a small GTP-binding protein, is required for binding of the coatomer protein fl-COP to Golgi membranes JULIE G. DONALDSON*, DAN CASSEL*t, RICHARD A. KAHN*, AND RICHARD D. KLAUSNER* *Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, and tLaboratory of Biological Chemistry, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Communicated by Marc Kirschner, April 20, 1992 (receivedfor review February 11, 1992) ABSTRACT The coatomer is a cytosolic protein complex localized to the Golgi complex, although their functions have that reversibly associates with Golgi membranes and is Impli- not been defined. Distinct among these proteins is the ADP- cated in modulating Golgi membrane transport. The associa- ribosylation factor (ARF), originally identified as a cofactor tion of 13-COP, a component of coatomer, with Golgi mem- required for in vitro cholera toxin-catalyzed ADP- branes is enhanced by guanosine 5'-[v-thioltriphosphate ribosylation of the a subunit of the trimeric GTP-binding (GTP[yS]), a nonhydrolyzable analogue of GTP, and by a protein G, (G,.) (19). ARF is an abundant cytosolic protein mixture of aluminum and fluoride ions (Al/F). Here we show that reversibly associates with Golgi membranes (20, 21). that the ADP-ribosylation factor (ARF) is required for the ARF has been shown to be present on Golgi coated vesicles binding of (-COP. Thus, 13-COP contained in a coatomer generated in the presence of GTP[yS], but it is not a com- fraction that has been resolved from ARF does not bind to Golgi ponent of the cytosolic coatomer (22). -
DOC2B (NM 003585) Human Tagged ORF Clone Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC218949L2 DOC2B (NM_003585) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: DOC2B (NM_003585) Human Tagged ORF Clone Tag: mGFP Symbol: DOC2B Synonyms: DOC2BL Vector: pLenti-C-mGFP (PS100071) E. coli Selection: Chloramphenicol (34 ug/mL) Cell Selection: None ORF Nucleotide The ORF insert of this clone is exactly the same as(RC218949). Sequence: Restriction Sites: SgfI-MluI Cloning Scheme: ACCN: NM_003585 ORF Size: 1236 bp This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 DOC2B (NM_003585) Human Tagged ORF Clone – RC218949L2 OTI Disclaimer: The molecular sequence of this clone aligns with the gene accession number as a point of reference only. However, individual transcript sequences of the same gene can differ through naturally occurring variations (e.g. polymorphisms), each with its own valid existence. This clone is substantially in agreement with the reference, but a complete review of all prevailing variants is recommended prior to use. More info OTI Annotation: This clone was engineered to express the complete ORF with an expression tag. Expression varies depending on the nature of the gene. RefSeq: NM_003585.1 RefSeq Size: 2030 bp RefSeq ORF: 1239 bp Locus ID: 8447 UniProt ID: Q14184 MW: 45.8 kDa Gene Summary: There are at least two protein isoforms of the Double C2 protein, namely alpha (DOC2A) and beta (DOC2B), which contain two C2-like domains. -
ADP-Ribosylation Factor and Coatomer Couple Fusion to Vesicle Budding Zvulun Elazar,* Lelio Orci,T Joachim Ostermann,* Myl~Nc Amherdt,* Gary Tanigawa,* and James E
ADP-Ribosylation Factor and Coatomer Couple Fusion to Vesicle Budding Zvulun Elazar,* Lelio Orci,t Joachim Ostermann,* Myl~nc Amherdt,* Gary Tanigawa,* and James E. Rothman* * Program in Cellular Biochemistry and Biophysics, Memorial Sloan Kettering Cancer Center, New York 10021; and ¢Institute of Histology and Embryology, University of Geneva Medical School, 1211 Geneva 4, Switzerland Abstract. The coat proteins required for budding pair directly without an intervening vesicle. Coupling COP-coated vesicles from Golgi membranes, coatomer may therefore result from the sequestration of fuso- and ADP-ribosylation factor (ARF) protein, are shown genic membrane proteins into assembling coated vesi- to be required to reconstitute the orderly process of cles that are only exposed when the coat is removed transport between Golgi cisternae in which fusion of after budding is complete. This mechanism of cou- transport vesicles begins only after budding ends. pling explains the phenomenon of "retrograde transport" When either coat protein is omitted, fusion is uncou- triggered by uncouplers such as the drug brefeldin A. pled from budding-donor and acceptor compartments ow is membrane fusion coupled to vesicle budding? Orci et al., 1989). Purification of COP-coated vesicles (Mal- A transport vesicle must fuse with its target only hotra et al., 1989; Serafini et al., 1991a,b) revealed that their H after its budding from the parental membrane is coats consist of a small GTP-binding protein (ADP-ribosyla- completed. Otherwise, the various membrane-bound com- tion factor, ARF) ~ and a complex of seven distinct proteins partments connected by vesicle shuttles would fuse and the termed coatomer (Waters et al., 1992a; Stenbeck et al., topological organization of the endomembrane system in 1993), whose subunits are or, B, B', 3', ~, e, and ~'-COPs. -
Associated 16P11.2 Deletion in Drosophila Melanogaster
ARTICLE DOI: 10.1038/s41467-018-04882-6 OPEN Pervasive genetic interactions modulate neurodevelopmental defects of the autism- associated 16p11.2 deletion in Drosophila melanogaster Janani Iyer1, Mayanglambam Dhruba Singh1, Matthew Jensen1,2, Payal Patel 1, Lucilla Pizzo1, Emily Huber1, Haley Koerselman3, Alexis T. Weiner 1, Paola Lepanto4, Komal Vadodaria1, Alexis Kubina1, Qingyu Wang 1,2, Abigail Talbert1, Sneha Yennawar1, Jose Badano 4, J. Robert Manak3,5, Melissa M. Rolls1, Arjun Krishnan6,7 & 1234567890():,; Santhosh Girirajan 1,2,8 As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of indi- vidual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interac- tions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes. 1 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. 2 Bioinformatics and Genomics Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. -
Exploring the Relationship Between Gut Microbiota and Major Depressive Disorders
E3S Web of Conferences 271, 03055 (2021) https://doi.org/10.1051/e3sconf/202127103055 ICEPE 2021 Exploring the Relationship between Gut Microbiota and Major Depressive Disorders Catherine Tian1 1Shanghai American School, Shanghai, China Abstract. Major Depressive Disorder (MDD) is a psychiatric disorder accompanied with a high rate of suicide, morbidity and mortality. With the symptom of an increasing or decreasing appetite, there is a possibility that MDD may have certain connections with gut microbiota, the colonies of microbes which reside in the human digestive system. In recent years, more and more studies started to demonstrate the links between MDD and gut microbiota from animal disease models and human metabolism studies. However, this relationship is still largely understudied, but it is very innovative since functional dissection of this relationship would furnish a new train of thought for more effective treatment of MDD. In this study, by using multiple genetic analytic tools including Allen Brain Atlas, genetic function analytical tools, and MicrobiomeAnalyst, I explored the genes that shows both expression in the brain and the digestive system to affirm that there is a connection between gut microbiota and the MDD. My approach finally identified 7 MDD genes likely to be associated with gut microbiota, implicating 3 molecular pathways: (1) Wnt Signaling, (2) citric acid cycle in the aerobic respiration, and (3) extracellular exosome signaling. These findings may shed light on new directions to understand the mechanism of MDD, potentially facilitating the development of probiotics for better psychiatric disorder treatment. 1 Introduction 1.1 Major Depressive Disorder Major Depressive Disorder (MDD) is a mood disorder that will affect the mood, behavior and other physical parts. -
The Structure of the COPI Coat Determined Within the Cell
RESEARCH ADVANCE The structure of the COPI coat determined within the cell Yury S Bykov1,2, Miroslava Schaffer3, Svetlana O Dodonova1†, Sahradha Albert3, Ju¨ rgen M Plitzko3, Wolfgang Baumeister3*, Benjamin D Engel3*, John AG Briggs1,2* 1Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; 2Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom; 3Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Martinsried, Germany Abstract COPI-coated vesicles mediate trafficking within the Golgi apparatus and from the Golgi to the endoplasmic reticulum. The structures of membrane protein coats, including COPI, have been extensively studied with in vitro reconstitution systems using purified components. Previously we have determined a complete structural model of the in vitro reconstituted COPI coat (Dodonova et al., 2017). Here, we applied cryo-focused ion beam milling, cryo-electron tomography and subtomogram averaging to determine the native structure of the COPI coat within vitrified Chlamydomonas reinhardtii cells. The native algal structure resembles the in vitro mammalian structure, but additionally reveals cargo bound beneath b’–COP. We find that all coat components *For correspondence: disassemble simultaneously and relatively rapidly after budding. Structural analysis in situ, [email protected] (WB); maintaining Golgi topology, shows that vesicles change their size, membrane thickness, and cargo [email protected] (BDE); content as they progress from cis to trans, but the structure of the coat machinery remains [email protected] constant. (JAGB) DOI: https://doi.org/10.7554/eLife.32493.001 Present address: †Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Go¨ ttingen, Germany Introduction Vesicular transport between cellular compartments is a fundamental mechanism of eukaryotic cells. -
Strong Synaptic Transmission Impact by Copy Number Variations in Schizophrenia
Strong synaptic transmission impact by copy number variations in schizophrenia Joseph T. Glessnera, Muredach P. Reillyb, Cecilia E. Kima, Nagahide Takahashic, Anthony Albanoa, Cuiping Houa, Jonathan P. Bradfielda, Haitao Zhanga, Patrick M. A. Sleimana, James H. Florya, Marcin Imielinskia, Edward C. Frackeltona, Rosetta Chiavaccia, Kelly A. Thomasa, Maria Garrisa, Frederick G. Otienoa, Michael Davidsond, Mark Weiserd, Abraham Reichenberge, Kenneth L. Davisc,JosephI.Friedmanc, Thomas P. Cappolab, Kenneth B. Marguliesb, Daniel J. Raderb, Struan F. A. Granta,f,g, Joseph D. Buxbaumc, Raquel E. Gurh, and Hakon Hakonarsona,f,g,1 aCenter for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104; bPenn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; cConte Center for the Neuroscience of Mental Disorders and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, 10029; dSheba Medical Center, Tel Hashomer, 52621, Israel; eMount Sinai and Institute of Psychiatry, King’s College, London, SE5 8AF, United Kingdom; fDivision of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104; gDepartment of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and hSchizophrenia Center, Neuropsychiatry Division, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104 Edited by James R. Lupski, Baylor College of Medicine, Houston, TX, and accepted by the Editorial Board April 13, 2010 (received for review January 7, 2010) Schizophrenia is a psychiatric disorder with onset in late adoles- contribute to the complex etiology underlying various psychiatric cence and unclear etiology characterized by both positive and ne- and neurodevelopmental disorders (13, 14). Whereas rare recurrent gative symptoms, as well as cognitive deficits. -
Cryo-Tomography of Coat Complexes ISSN 2059-7983
research papers Visualizing membrane trafficking through the electron microscope: cryo-tomography of coat complexes ISSN 2059-7983 Evgenia A. Markova and Giulia Zanetti* Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, England. Received 8 March 2019 *Correspondence e-mail: [email protected] Accepted 12 April 2019 Coat proteins mediate vesicular transport between intracellular compartments, Keywords: cryo-electron tomography; which is essential for the distribution of molecules within the eukaryotic cell. three-dimensional reconstruction; coat proteins; The global arrangement of coat proteins on the membrane is key to their vesicular transport; COPII; subtomogram function, and cryo-electron tomography and subtomogram averaging have been averaging. used to study membrane-bound coat proteins, providing crucial structural insight. This review outlines a workflow for the structural elucidation of coat proteins, incorporating recent developments in the collection and processing of cryo-electron tomography data. Recent work on coat protein I, coat protein II and retromer performed on in vitro reconstitutions or in situ is summarized. These studies have answered long-standing questions regarding the mechanisms of membrane binding, polymerization and assembly regulation of coat proteins. 1. Introduction Recent advances in cryo-electron microscopy (cryo-EM) have enabled numerous high-resolution studies which have addressed long-standing structural biology questions. The large body of cryo-EM work carried out for protein structure characterization has utilized single-particle electron micro- scopy (Cheng, 2018). Recently, developments in hardware, data collection and data processing have placed cryo-electron tomography (cryo-ET) and subtomogram averaging (STA) at the forefront of structural studies of repetitive assemblies, reaching resolutions comparable to those of single-particle EM (Schur et al., 2016; Wan et al., 2017; Hutchings et al., 2018; Dodonova et al., 2017; Himes & Zhang, 2018).