DOCSLIB.ORG

Tissue-Specific Expression of the Human Glycyl-Trna Synthetase : Connection with the Charcot-Marie-Tooth Disease Jana Alexandrova

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tissue-Specific Expression of the Human Glycyl-Trna Synthetase : Connection with the Charcot-Marie-Tooth Disease Jana Alexandrova Tissue-specific expression of the human Glycyl-tRNA synthetase : connection with the Charcot-Marie-Tooth disease Jana Alexandrova To cite this version: Jana Alexandrova. Tissue-specific expression of the human Glycyl-tRNA synthetase : connection with the Charcot-Marie-Tooth disease. Genomics [q-bio.GN]. Université de Strasbourg, 2014. English. NNT : 2014STRAJ126. tel-01516431 HAL Id: tel-01516431 https://tel.archives-ouvertes.fr/tel-01516431 Submitted on 1 May 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. T&L1# "# D-!2-02 "# *_U,'4#01'2M "# S201 -30% D'1!'.*',# S S!'#,!#1 "3 V'4,2 S.M!'*'2M S A1.#!21 M-*M!3*'0#1 #2 C#**3*'0#1 "# * B'-*-%'# T'113#V1.#!'$'! #6.0#11'-, -$ 2&# &3+, G*7!7*V2RNA 17,2&#21#S !-,,#!2'-, 5'2& 2&# C&0!-2VM0'#VT--2& "'1#1# P0M1#,2M# .0 J, A*#6,"0-4 .-30 *_- 2#,2'-, "3 %0"# "# D-!2#30 "# *_U,'4#01'2M "# S201 -30% S-32#,3# *# S[ 1#.2#+ 0# TRSV "#4,2 * !-++'11'-, "_#6+#, S D'0#!2#30 "# 2&L1# D0T M%*' F03%'#0 D'0#!2#30 "# R#!&#0!&# CNRSQ S201 -30% R..-02#30 #62#0,# D0T A* #, J-0",-4 A11-!'2# .0-$#11-0Q U,'4#01'27 -$ A,25#0.Q B#*%'/3# R..-02#30 #62#0,# D0T T+0 H#,"0'!)1-, A11-!'2# .0-$#11-0Q W7,# S22# U,'4#01'27Q USA E6+',2#30 ',2#0,# D0T G'* #02 E0',' D'0#!2#30 "# R#!&#0!&# CNRSQ S201 -30% ACKNOWLEDGEMENTS First, I would like to thank all the members of the thesis committee, Dr. Albena Jordanova, Associate Professor in Molecular Neurosciences at the University of Antwerp (Belgium), Dr. Tamara Hendrickson, Associate Professor in Biochemistry at Wayne State University (USA) and Dr. Gilbert Eriani, Research Director at CNRS (Strasbourg) for accepting to judge my work. Je remercie le Professeur Eric WESTHOF, de m'avoir accueillie au sein de l'UPR 9002 du CNRS. Un tr s tr s tr s grand Merci Magali ! Je ne pourrais jamais te remercier assez pour tout ce que tu as fait pour moi ces six derni res ann esG bien sr pour tout ce que tu mSas appris en tant que scientifique mais aussi pour ton soutien, tes encouragements et la confiance que tu mSas accord e et celle que tu as r ussi me donner en moi. Mme quand jS tais d sesp r e, tu as toujours trouv les bons mots pour repartir avec encore plus dSenthousiasme et de motivation. Je te remercie pour tous les superbes moments quSon a pass s ensembleG dommage quSon ne puisse pas rester en th se toute sa vieG Un tr s grand Merci aussi tous les gens de notre quipe sans qui la vie au labo nSaurait pas t si agr able ! Merci Caro pour tout ce que tu mSas appris, pour nos belles pauses Icetea avec les plantes carnivores de lSIBMC et lSexp rience photos sous la chaleur accablante. Merci Jolle et Anne pour tous nos moments de rigolade mais aussi pour tous vos conseils. Merci Nassira pour tes encouragements, tes conseils, les grandes discussions scientifiques et pas seulement et pour tous les super moments quSon a partag s. Merci Pupuce (Delphine) dSavoir apport plein de joie et de bonne humeur au quotidien mais aussi dans les moments de d prime, pour les innombrables et inoubliables E soir es et week-end labo F et surtout celles en dehors du laboG Merci Alain pour tous tes conseils et discussions scientifiques du soir, pour mSavoir montr comment d tecter de jolies cellules fluos et que cSest pas du bruit de fondG Un tr s grand Merci tous les amis du labo pour tout ce quSon a partag ces derni res ann es : les pauses caf , soir es, sorties ski, montagneG Merci Micka, Pierre, Patryk, Hagen, Anne So, M lo, Delphine, Franzi et tous les autres que jSai oubli sG Un norme Merci Micka, Pierre, Delphine 2 et Paola : sans vous les derniers mois auraient t tr s prouvantsG merci pour les barbecues, sorties escalade qui mSont presque fait appr cier lS criture de la th se. Un tr s tr s tr s grand Merci mes parents qui mSont toujours encourag e et soutenue, et enfin mais pas en dernier Yannick avec qui on a travers tout le chemin de la Fac et la th se ensemble. CONTENT INTRODUCTION ................................................................................................. 1 I. M RNA AND THE ROAD LEADING TO TRANSLATION ....................................... 1 1. Translation initiation of eukaryotic mRNAs ....................................................... 1 1.1. Cap-dependent initiation GGGG!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 1 1.1.1. Ternary complex formation ...................................................................... 1 1.1.2. The open pre-initiation complex ................................................................ 2 1.1.3. PIC and mRNA recruitment .................................................................... 3 1.1.4. mRNA scanning and start codon recognition ................................................ 4 1.1.5. 80S initiation complex formation .............................................................. 5 !"!#$S - and &S -UTR regulatory elements ................................................................... 5 1.2.1. mRNA localization ............... ......................................................................... 5 1.2.2. !"#$%&'()*!$!+!,&-*.,*/S -UTRs ............................................................... 7 1.2.3. !"#$%&'()*!$!+!,&-*.,*1S -UTRs ............................................................... 9 1.2.4. Structural regulatory elements ................................................................... 9 1.2.5. uORFs ................................................................................................ 11 "#P%&'(')*&+Q#-./01 .......................................................................... 13 * uORF/IRES combinations ................................................................ 14 * The role of uORF peptides ................................................................. 15 1.2.6. Alternative Non-AUG initiation codons ....................................................... 16 1.3. Cap-independent initiation ................................................................................ 17 1.3.1. Cellular IRES ....................................................................................... 18 1.3.2. Canonical initiation factors and IRES recognition ......................................... 20 1.3.3. IRES trans-acting factors and cellular stress ................................................. 20 1.4. Cap-assisted internal initiation .......................................................................... 22 II. Aminoacyl-tRNA synthetases: translation and beyond .............................. 23 1. Aminoacylation: catalysis and specificity ........................................................... 23 1.1. Aminoacylation reaction ................................................................................... 23 1.2. Structure and characterisation of eukaryotic aaRSs ............................................. 24 2. Non-canonical functions of mammalian cytosolic aminoacyl-tRNA synthetases 26 2.1. AaRSs and post-transcriptional regulations ........................................................ 26 S 2.1.1. Yeast DRS regulates its own expression ........................................................ 28 2.1.2. Human MRS regulates ribosomal RNA biogenesis ....................................... .. 29 2.1.3. Human EPRS and the GAIT system .......................................................... 29 2.1.4. Human KRS regulates transcription ........................................................... 30 2.2. Alternative functions related to signalling pathways ........................................... 31 2.2.1. Human aaRSs as cytokines ....................................................................... 31 2.2.2. AaRS as amino acid sensors ...................................................................... 32 3. Human cytosolic aaRSs involved in diseases ....................................................... 33 3.1. Antisynthetase syndrome ................................................................................... 34 3.2. Cancer .............................................................................................................. 34 3.3. Viral infection ................................................................................................... 35 4. GRS alternative functions and roles in diseases .................................................. 36 4.1. Ap4A synthesis ................................................................................................. 38 4.2. IRES mediated translation activation of Poliovirus ............................................. 39 4.3. Anti-GRS syndrome .......................................................................................... 40 4.4. GRS and cancer ................................................................................................ 40 III. GRS AND CHARCOT -M ARIE -T OOTH DISEASE ............................................ 43 1. Charcot-Marie-Tooth ......................................................................................... 43 2. GRS mutants in CMT2D and dSMA-V .............................................................. 45 2.1.
Load more

Recommended publications
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0265809 A1 M0ras Et Al
    US 2OO)4O265809A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0265809 A1 M0ras et al. (43) Pub. Date: Dec. 30, 2004 (54) POLYPEPTIDES DERIVED FROM RETINOIC Publication Classification ACID-RELATED ORPHAN RECEPTOR(ROIR) AND THEIR APPLICATIONS (51) Int. Cl.” ............................ C12Q 1/68; C07H 21/04; C07K 14/705 (76) Inventors: Dino Moras, Lampertheim (FR); (52) U.S. Cl. ......................... 435/6; 435/69.1; 435/320.1; Jean-Paul Renaud, Ostwald (FR); 435/325; 530/350; 536/23.5 Catherine Stehlin, Strasbourg (FR); Jean-Marie Strasbourg, Drusenheim (FR); Roland Schuele, Weisweil (DE); (57) ABSTRACT Eric Friedrich Greiner, Heidelberg (DE) The invention relates to polypeptides derived from the retinoic acid-related orphan receptor (ROR) in mammals, Correspondence Address: characterized in that they are delimited in their N-terminal ?RRET eXtremity by an amino-acid located between positions 1 to 2ND FLOOR 209, and in their C-terminal extremity by an amino-acid located between positions 450 to 452 of the rat RORß, o, or AIRLINGTON, VA 22202 (US) y, or by an amino-acid located at corresponding positions in nuclear receptor ROR of other Subtypes than C, ß and y, (21) Appl. No.: 10/477,116 and/or of the other mammals. The invention also relates to (22) PCT Filed: May 7, 2002 the use of these polypeptides, or of the molecular complexes 39 or the crystals containing them, for carrying out:—a process (86) PCT No.: PCT/EP02/05024 for the screening of a ROR-LBD ligand which is an agonist, or an antagonist of said receptor,—or a process for the (30) Foreign Application Priority Data analysis of the tridimensional structure of the complexes formed with said polypeptides, molecular complexes or May 7, 2001 (EP).......................................
    [Show full text]
  • XIAP's Profile in Human Cancer
    biomolecules Review XIAP’s Profile in Human Cancer Huailu Tu and Max Costa * Department of Environmental Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA; [email protected] * Correspondence: [email protected] Received: 16 September 2020; Accepted: 25 October 2020; Published: 29 October 2020 Abstract: XIAP, the X-linked inhibitor of apoptosis protein, regulates cell death signaling pathways through binding and inhibiting caspases. Mounting experimental research associated with XIAP has shown it to be a master regulator of cell death not only in apoptosis, but also in autophagy and necroptosis. As a vital decider on cell survival, XIAP is involved in the regulation of cancer initiation, promotion and progression. XIAP up-regulation occurs in many human diseases, resulting in a series of undesired effects such as raising the cellular tolerance to genetic lesions, inflammation and cytotoxicity. Hence, anti-tumor drugs targeting XIAP have become an important focus for cancer therapy research. RNA–XIAP interaction is a focus, which has enriched the general profile of XIAP regulation in human cancer. In this review, the basic functions of XIAP, its regulatory role in cancer, anti-XIAP drugs and recent findings about RNA–XIAP interactions are discussed. Keywords: XIAP; apoptosis; cancer; therapeutics; non-coding RNA 1. Introduction X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3), baculoviral IAP repeat-containing protein 4 (BIRC4), and human IAPs like protein (hILP), belongs to IAP family which was discovered in insect baculovirus [1]. Eight different IAPs have been isolated from human tissues: NAIP (BIRC1), BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4), BIRC5 (survivin), BIRC6 (apollon), BIRC7 (livin) and BIRC8 [2].
    [Show full text]
  • Type of the Paper (Article
    Supplementary Material A Proteomics Study on the Mechanism of Nutmeg-induced Hepatotoxicity Wei Xia 1, †, Zhipeng Cao 1, †, Xiaoyu Zhang 1 and Lina Gao 1,* 1 School of Forensic Medicine, China Medical University, Shenyang 110122, P. R. China; lessen- [email protected] (W.X.); [email protected] (Z.C.); [email protected] (X.Z.) † The authors contributed equally to this work. * Correspondence: [email protected] Figure S1. Table S1. Peptide fraction separation liquid chromatography elution gradient table. Time (min) Flow rate (mL/min) Mobile phase A (%) Mobile phase B (%) 0 1 97 3 10 1 95 5 30 1 80 20 48 1 60 40 50 1 50 50 53 1 30 70 54 1 0 100 1 Table 2. Liquid chromatography elution gradient table. Time (min) Flow rate (nL/min) Mobile phase A (%) Mobile phase B (%) 0 600 94 6 2 600 83 17 82 600 60 40 84 600 50 50 85 600 45 55 90 600 0 100 Table S3. The analysis parameter of Proteome Discoverer 2.2. Item Value Type of Quantification Reporter Quantification (TMT) Enzyme Trypsin Max.Missed Cleavage Sites 2 Precursor Mass Tolerance 10 ppm Fragment Mass Tolerance 0.02 Da Dynamic Modification Oxidation/+15.995 Da (M) and TMT /+229.163 Da (K,Y) N-Terminal Modification Acetyl/+42.011 Da (N-Terminal) and TMT /+229.163 Da (N-Terminal) Static Modification Carbamidomethyl/+57.021 Da (C) 2 Table S4. The DEPs between the low-dose group and the control group. Protein Gene Fold Change P value Trend mRNA H2-K1 0.380 0.010 down Glutamine synthetase 0.426 0.022 down Annexin Anxa6 0.447 0.032 down mRNA H2-D1 0.467 0.002 down Ribokinase Rbks 0.487 0.000
    [Show full text]
  • Supplementary Information Method CLEAR-CLIP. Mouse Keratinocytes
    Supplementary Information Method CLEAR-CLIP. Mouse keratinocytes of the designated genotype were maintained in E-low calcium medium. Inducible cells were treated with 3 ug/ml final concentration doxycycline for 24 hours before performing CLEAR-CLIP. One 15cm dish of confluent cells was used per sample. Cells were washed once with cold PBS. 10mls of cold PBS was then added and cells were irradiated with 300mJ/cm2 UVC (254nM wavelength). Cells were then scraped from the plates in cold PBS and pelleted by centrifugation at 1,000g for 2 minutes. Pellets were frozen at -80oC until needed. Cells were then lysed on ice with occasional vortexing in 1ml of lysis buffer (50mM Tris-HCl pH 7.4, 100mM NaCl, 1mM MgCl2, 0.1 mM CaCl2, 1% NP-40, 0.5% Sodium Deoxycholate, 0.1% SDS) containing 1X protease inhibitors (Roche #88665) and RNaseOUT (Invitrogen #10777019) at 4ul/ml final concentration. Next, TurboDNase (Invitrogen #AM2238, 10U), RNase A (0.13ug) and RNase T1 (0.13U) were added and samples were incubated at 37oC for 5 minutes with occasional mixing. Samples were immediately placed on ice and then centrifuged at 16,160g at 4oC for 20 minutes to clear lysate. 25ul of Protein-G Dynabeads (Invitrogen #10004D) were used per IP. Dynabeads were pre-washed with lysis buffer and pre- incubated with 3ul of Wako Anti-Mouse-Ago2 (2D4) antibody. The dynabead/antibody mixture was added to the lysate and rocked for 2 hours at 4oC. All steps after the IP were done on bead until samples were loaded into the polyacrylamide gel.
    [Show full text]
  • The Autism Protein Ube3a/E6AP Remodels Neuronal Dendritic Arborization Via Caspase-Dependent Microtubule Destabilization
    The Journal of Neuroscience, January 10, 2018 • 38(2):363–378 • 363 Neurobiology of Disease The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization Natasha Khatri,1,2 James P. Gilbert,1 Yuda Huo,1 Roozhin Sharaflari,1 Michael Nee,1 Hui Qiao,1 and XHeng-Ye Man1,2 1Department of Biology, Boston University, Boston, Massachusetts 02215, and 2Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118 UBE3A gene copy number variation and the resulting overexpression of the protein E6AP is directly linked to autism spectrum disorders (ASDs).However,theunderlyingcellularandmolecularneurobiologyremainslessclear.HerewereporttheroleofASD-relatedincreased dosage of Ube3A/E6AP in dendritic arborization during brain development. We show that increased E6AP expression in primary cul- tured neurons leads to a reduction in dendritic branch number and length. The E6AP-dependent remodeling of dendritic arborization results from retraction of dendrites by thinning and fragmentation at the tips of dendrite branches, leading to shortening or removal of dendrites. This remodeling effect is mediated by the ubiquitination and degradation of XIAP (X-linked inhibitors of aptosis protein) by E6AP, which leads to activation of caspase-3 and cleavage of microtubules. In vivo, male and female Ube3A 2X ASD mice show decreased XIAP levels, increased caspase-3 activation, and elevated levels of tubulin cleavage. Consistently, dendritic branching and spine density are reduced in cortical neurons of Ube3A 2X ASD mice. In revealing an important role for Ube3A/E6AP in ASD-related developmental alteration in dendritic arborization and synapse formation, our findings provide new insights into the pathogenesis of Ube3A/E6AP- dependent ASD.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Targeting the Ubiquitin System in Glioblastoma', Frontiers in Oncology
    Citation for published version: Licchesi, J 2020, 'Targeting the Ubiquitin System in Glioblastoma', Frontiers in Oncology. https://doi.org/10.3389/fonc.2020.574011 DOI: 10.3389/fonc.2020.574011 Publication date: 2020 Document Version Publisher's PDF, also known as Version of record Link to publication University of Bath Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 24. Sep. 2021 REVIEW published: 25 November 2020 doi: 10.3389/fonc.2020.574011 Targeting the Ubiquitin System in Glioblastoma Nico Scholz 1, Kathreena M. Kurian 2, Florian A. Siebzehnrubl 3 and Julien D. F. Licchesi 1* 1 Department of Biology & Biochemistry, University of Bath, Bath, United Kingdom, 2 Brain Tumour Research Group, Institute of Clinical Neurosciences, University of Bristol, Bristol, United Kingdom, 3 Cardiff University School of Biosciences, European Cancer Stem Cell Research Institute, Cardiff, United Kingdom Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options.
    [Show full text]
  • Structural Biology in Strasbourg, a Tribute to Dino Moras June, 12Th 2019 Auditorium IGBMC
    Structural Biology in Strasbourg, a tribute to Dino Moras June, 12th 2019 Auditorium IGBMC Speakers : Pierre Chambon David Stuart IGBMC, Strasbourg Illkirch, France Oxford University, Oxford, UK Jean-Marc Egly Akio Takenaka IGBMC, Strasbourg Illkirch, France Chiba Institute of Technology, Narashino, Japan Jack Johnson Eric Westhof The Scripps Research Institute, La Jolla IBMC, Strasbourg, France Bruno Klaholz Shigeyuki Yokoyama IGBMC, Strasbourg Illkirch, France RIKEN, Yokohama City, Japan Jean-Marie Lehn Marat Yusupov ISIS, Strasbourg, France IGBMC, Strasbourg Illkirch, France Anders Liljas Giuseppe Zaccai CMPS, Lund University, Sweden IBS, Grenoble, France Jean-Louis Mandel IGBMC, Strasbourg Illkirch, France IGBMC - 1 rue Laurent Fries 67404 Illkirch Cedex - www.igbmc.fr The Institute of Genetics and Molecular and Cellular Biology (IGBMC) organizes the symposium entitled “Structural Biology in Strasbourg, a tribute to Dino Moras” on Wednesday, June 12, 2019 to pay tribute to the scientific endeavor of Professor Dino MORAS, a leading researcher, recognized at the international level for its expertise in Structural Biology. Member of the French Academy of Sciences and former director of the IGBMC, Dino Moras introduced biological crystallography in Strasbourg and promoted the development of Structural Biology in France. With his team, he devoted himself to understanding at the atomic level, the transmission of genetic information from DNA into proteins. He studied the aminoacylation reaction of the transfer RNAs, one of the key steps in the translation of genetic information and highlighted in particular, the partitioning of aminoacyl-tRNA synthetases into two classes and determined the first atomic structure of a complex between a transfer RNA and a class II enzyme.
    [Show full text]
  • Regulation of Apoptosis by XIAP Ubiquitin- Ligase Activity Andrew James Schile
    Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2009 Regulation of Apoptosis by XIAP Ubiquitin- Ligase Activity Andrew James Schile Follow this and additional works at: http://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons Recommended Citation Schile, Andrew James, "Regulation of Apoptosis by XIAP Ubiquitin- Ligase Activity" (2009). Student Theses and Dissertations. Paper 125. This Thesis is brought to you for free and open access by Digital Commons @ RU. It has been accepted for inclusion in Student Theses and Dissertations by an authorized administrator of Digital Commons @ RU. For more information, please contact [email protected]. REGULATION OF APOPTOSIS BY XIAP UBIQUITIN-LIGASE ACTIVITY A Thesis Presented to the Faculty of The Rockefeller University In Partial Fulfillment of the Requirements for The degree of Doctor of Philosophy by Andrew James Schile June 2009 © Copyright by Andrew James Schile 2009 REGULATION OF APOPTOSIS BY XIAP UBIQUITIN-LIGASE ACTIVITY Andrew James Schile, Ph.D. The Rockefeller University 2009 Virtually all animal cells have the known ability to self-destruct by undergoing apoptosis, a morphologically distinct form of programmed cell death. The proper regulation of apoptosis is critical for both development and tissue homeostasis, and inhibition of apoptosis contributes to the development and progression of cancer. Inhibitor of Apoptosis Proteins (IAPs) can bind to and inhibit caspases, the key executioners of apoptosis. Because IAPs are frequently over-expressed in human tumors, they have become major pharmacological targets for developing new cancer therapeutics. Many IAPs contain RING domains that function as E3 ubiquitin-ligases to regulate the abundance of IAPs themselves and their binding partners by engaging the ubiquitin system.
    [Show full text]
  • New Insights Into the Cellular Temporal Response to Proteostatic Stress
    TOOLS AND RESOURCES New insights into the cellular temporal response to proteostatic stress Justin Rendleman1†, Zhe Cheng1†, Shuvadeep Maity1†, Nicolai Kastelic2, Mathias Munschauer2, Kristina Allgoewer1, Guoshou Teo1, Yun Bin Matteo Zhang1, Amy Lei1, Brian Parker1, Markus Landthaler2,3, Lindsay Freeberg4, Scott Kuersten4, Hyungwon Choi5,6, Christine Vogel1* 1Center for Genomics and Systems Biology, Department of Biology, New York University, New York, United States; 2Berlin Institute for Medical Systems Biology, Max Delbru¨ ck Center for Molecular Medicine, Berlin, Germany; 3Integrative Research Institute for the Life Sciences, Institute of Biology, Humboldt University, Berlin, Germany; 4Illumina Inc, Madison, United States; 5National University of Singapore, Singapore; 6Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore Abstract Maintaining a healthy proteome involves all layers of gene expression regulation. By quantifying temporal changes of the transcriptome, translatome, proteome, and RNA-protein interactome in cervical cancer cells, we systematically characterize the molecular landscape in response to proteostatic challenges. We identify shared and specific responses to misfolded proteins and to oxidative stress, two conditions that are tightly linked. We reveal new aspects of the unfolded protein response, including many genes that escape global translation shutdown. A subset of these genes supports rerouting of energy production in the mitochondria. We also find that many genes change at multiple levels, in either the same or opposing directions, and at different time points. We highlight a variety of putative regulatory pathways, including the stress- dependent alternative splicing of aminoacyl-tRNA synthetases, and protein-RNA binding within the 3’ untranslated region of molecular chaperones. These results illustrate the potential of this information-rich resource.
    [Show full text]
  • Structure of Bacteriophage T4 Fibritin M: a Troublesome Packing Arrangement
    805 Acta Cryst. (1998). D54, 805-816 Structure of Bacteriophage T4 Fibritin M: a Troublesome Packing Arrangement SERGEI W. STRELKOV,a'b YIZHI TAO, a MIKHAIL M. St-INEIDER,b VADIM W. MESYANZHINOV b AND MICHAEL G ROSSMANN a* "Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-1392, USA, and hShemyakin- Ovchnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya Street, Moscow 117 871, Russia. E-mail: mgr@indiana, bio.purdue, edu (Received 19 September 1997; accepted 8 December 1997) Abstract flanked by small globular domains at both ends. As in other coiled-coil structures, the amino-acid sequence of Fibritin, a 52 kDa product of bacteriophage T4 gene fibritin (486 residues) has a distinct heptad repeat wac, forms 530 A long fibers, named whiskers, that (abcdefg)n which contains predominantly hydrophobic attach to the phage neck and perform a helper function residues at the a and d positions, while the other posi- during phage assembly. Fibritin is a homotrimer, with its tions are occupied mostly by polar residues. Since seven predominant central domain consisting of 12 consecu- residues make approximately two a-helical turns, the tive c~-helical coiled-coil segments linked together by hydrophobic residues of consecutive heptads are located loops. The central domain is flanked by small globular on one side of the helix, and this provides for the domains at both ends. Fibritin M is a genetically formation of the coiled-coil core (Lupas, 1996). An engineered fragment of the wild type and contains 74 unusual feature of fibritin is that the coiled coil is amino-acid residues corresponding to the last coiled-coil interrupted by insertion of loops, consisting of five to 20 segment and the complete carboxy-terminal domain.
    [Show full text]
  • D-Glyceraldehyde-3-Phosphate Dehydrogenase: Three-Dimensional Structure and Evolutionary Significance (NAD Binding/Lactate Dehydrogenase/X-Ray Crystallography)
    Proc. Nat. Acad. Sci. USA Vol. 70, No. 11, pp. 3052-3054, November 1973 D-Glyceraldehyde-3-Phosphate Dehydrogenase: Three-Dimensional Structure and Evolutionary Significance (NAD binding/lactate dehydrogenase/x-ray crystallography) MANFRED BUEHNER*, GEOFFREY C. FORD, DINO MORAS, KENNETH W. OLSEN, AND MICHAEL G. ROSSMANNt Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907 Communicated by Dr. William N. Lipscomb, July 6, 1973 ABSTRACT A 3.0-A resolution electron density map orientation of the mutually perpendicular molecular 2-fold of lobster glyceraldehyde-3-phosphate dehydrogenase axes within the unit cell had been established by Rossmann (EC 1.2.1.12) was computed. The essentially single iso- morphous replacement map was very substantially im- et al. (11) using the rotation function (12). This knowledge, proved by averaging subunits. NAD binds in an open con- along with the accurate data obtained from an Optronics formation at sites close to subunit interfaces. The coen- Film Scanner (13), enabled us to solve the difference Patter- zyme binding portion of the enzyme has almost the same son function of the K2HgI4 heavy-atom derivative for its fold as the corresponding portion of lactate dehydro- major set of four sites. This in turn genase (EC 1.1.1.27). The presence of this structure in the permitted determination of five enzymes, analyzed so far, that use nucleotide co- the other heavy-atom sites in all derivatives by difference enzymes might indicate a fundamental primordial struc- Fourier methods, to give three chemically independent sites tural element. per polypeptide chain. The 3.0-A electron density map, which was essentially D-Glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) phased by single isomorphous replacement (14), was re- catalyzes the NAD-mediated oxidative phosphorylation of oriented by means of a skew plane program (15) so that the its substrate to D-1,3-diphosphoglyceric acid.
    [Show full text]