Protein Sequence Comparison and Protein Evolution Tutorial
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Systems and Chemical Biology Approaches to Study Cell Function and Response to Toxins
Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences Presented by MSc. Yingying Jiang born in Shandong, China Oral-examination: Systems and chemical biology approaches to study cell function and response to toxins Referees: Prof. Dr. Rob Russell Prof. Dr. Stefan Wölfl CONTRIBUTIONS The chapter III of this thesis was submitted for publishing under the title “Drug mechanism predominates over toxicity mechanisms in drug induced gene expression” by Yingying Jiang, Tobias C. Fuchs, Kristina Erdeljan, Bojana Lazerevic, Philip Hewitt, Gordana Apic & Robert B. Russell. For chapter III, text phrases, selected tables, figures are based on this submitted manuscript that has been originally written by myself. i ABSTRACT Toxicity is one of the main causes of failure during drug discovery, and of withdrawal once drugs reached the market. Prediction of potential toxicities in the early stage of drug development has thus become of great interest to reduce such costly failures. Since toxicity results from chemical perturbation of biological systems, we combined biological and chemical strategies to help understand and ultimately predict drug toxicities. First, we proposed a systematic strategy to predict and understand the mechanistic interpretation of drug toxicities based on chemical fragments. Fragments frequently found in chemicals with certain toxicities were defined as structural alerts for use in prediction. Some of the predictions were supported with mechanistic interpretation by integrating fragment- chemical, chemical-protein, protein-protein interactions and gene expression data. Next, we systematically deciphered the mechanisms of drug actions and toxicities by analyzing the associations of drugs’ chemical features, biological features and their gene expression profiles from the TG-GATEs database. -
Relationship Between Sequence Homology, Genome Architecture, and Meiotic Behavior of the Sex Chromosomes in North American Voles
HIGHLIGHTED ARTICLE | INVESTIGATION Relationship Between Sequence Homology, Genome Architecture, and Meiotic Behavior of the Sex Chromosomes in North American Voles Beth L. Dumont,*,1,2 Christina L. Williams,† Bee Ling Ng,‡ Valerie Horncastle,§ Carol L. Chambers,§ Lisa A. McGraw,** David Adams,‡ Trudy F. C. Mackay,*,**,†† and Matthew Breen†,†† *Initiative in Biological Complexity, †Department of Molecular Biomedical Sciences, College of Veterinary Medicine, **Department of Biological Sciences, and ††Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 04609, ‡Cytometry Core Facility, Wellcome Sanger Institute, Hinxton, United Kingdom, CB10 1SA and §School of Forestry, Northern Arizona University, Flagstaff, Arizona 86011 ORCID ID: 0000-0003-0918-0389 (B.L.D.) ABSTRACT In most mammals, the X and Y chromosomes synapse and recombine along a conserved region of homology known as the pseudoautosomal region (PAR). These homology-driven interactions are required for meiotic progression and are essential for male fertility. Although the PAR fulfills key meiotic functions in most mammals, several exceptional species lack PAR-mediated sex chromosome associations at meiosis. Here, we leveraged the natural variation in meiotic sex chromosome programs present in North American voles (Microtus) to investigate the relationship between meiotic sex chromosome dynamics and X/Y sequence homology. To this end, we developed a novel, reference-blind computational method to analyze sparse sequencing data from flow- sorted X and Y chromosomes isolated from vole species with sex chromosomes that always (Microtus montanus), never (Microtus mogollonensis), and occasionally synapse (Microtus ochrogaster) at meiosis. Unexpectedly, we find more shared X/Y homology in the two vole species with no and sporadic X/Y synapsis compared to the species with obligate synapsis. -
Structural Basis for the Sheddase Function of Human Meprin Β Metalloproteinase at the Plasma Membrane
Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane Joan L. Arolasa, Claudia Broderb, Tamara Jeffersonb, Tibisay Guevaraa, Erwin E. Sterchic, Wolfram Boded, Walter Stöckere, Christoph Becker-Paulyb, and F. Xavier Gomis-Rütha,1 aProteolysis Laboratory, Department of Structural Biology, Molecular Biology Institute of Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona Science Park, E-08028 Barcelona, Spain; bInstitute of Biochemistry, Unit for Degradomics of the Protease Web, University of Kiel, D-24118 Kiel, Germany; cInstitute of Biochemistry and Molecular Medicine, University of Berne, CH-3012 Berne, Switzerland; dArbeitsgruppe Proteinaseforschung, Max-Planck-Institute für Biochemie, D-82152 Planegg-Martinsried, Germany; and eInstitute of Zoology, Cell and Matrix Biology, Johannes Gutenberg-University, D-55128 Mainz, Germany Edited by Brian W. Matthews, University of Oregon, Eugene, OR, and approved August 22, 2012 (received for review June 29, 2012) Ectodomain shedding at the cell surface is a major mechanism to proteolysis” step within the membrane (1). This is the case for the regulate the extracellular and circulatory concentration or the processing of Notch ligand Delta1 and of APP, both carried out by activities of signaling proteins at the plasma membrane. Human γ-secretase after action of an α/β-secretase (11), and for signal- meprin β is a 145-kDa disulfide-linked homodimeric multidomain peptide peptidase, which removes remnants of the secretory pro- type-I membrane metallopeptidase that sheds membrane-bound tein translocation from the endoplasmic membrane (13). cytokines and growth factors, thereby contributing to inflammatory Recently, human meprin β (Mβ) was found to specifically pro- diseases, angiogenesis, and tumor progression. -
Protein Family Classification with Neural Networks
Protein Family Classification with Neural Networks Timothy K. Lee Tuan Nguyen Program in Biomedical Informatics Department of Statistics Stanford University Stanford University [email protected] [email protected] Abstract Understanding protein function from amino acid sequence is a fundamental prob- lem in biology. In this project, we explore how well we can represent biological function through examination of raw sequence alone. Using a large corpus of protein sequences and their annotated protein families, we learn dense vector rep- resentations for amino acid sequences using the co-occurrence statistics of short fragments. Then, using this representation, we experiment with several neural net- work architectures to train classifiers for protein family identification. We show good performance for a multi-class prediction problem with 589 protein family classes. 1 Introduction Next-generation sequencing technologies generate large amounts of biological sequence informa- tion in the form of DNA/RNA sequences. From DNA sequences we also know the amino acid sequences of proteins, which are the fundamental molecules that perform most biological functions. The functionality of a protein is thus encoded in the amino acid sequence and understanding the sequence-function relationship is a major challenge in bioinformatics. Investigating protein func- tional often involves structural studies (crystallography) or biochemical studies, which require time consuming efforts. Protein families are defined to group together proteins that share similar function, and the aim of our project is to predict protein family from raw sequence. We focus on training infor- mative vector representations for protein sequences and investigate various neural network models for the task of predicting a protein’s family. -
Pyruvate-Phosphate Dikinase of Oxymonads and Parabasalia and the Evolution of Pyrophosphate-Dependent Glycolysis in Anaerobic Eukaryotes† Claudio H
EUKARYOTIC CELL, Jan. 2006, p. 148–154 Vol. 5, No. 1 1535-9778/06/$08.00ϩ0 doi:10.1128/EC.5.1.148–154.2006 Copyright © 2006, American Society for Microbiology. All Rights Reserved. Pyruvate-Phosphate Dikinase of Oxymonads and Parabasalia and the Evolution of Pyrophosphate-Dependent Glycolysis in Anaerobic Eukaryotes† Claudio H. Slamovits and Patrick J. Keeling* Canadian Institute for Advanced Research, Botany Department, University of British Columbia, 3529-6270 University Boulevard, Vancouver, British Columbia V6T 1Z4, Canada Received 29 September 2005/Accepted 8 November 2005 In pyrophosphate-dependent glycolysis, the ATP/ADP-dependent enzymes phosphofructokinase (PFK) and pyruvate kinase are replaced by the pyrophosphate-dependent PFK and pyruvate phosphate dikinase (PPDK), respectively. This variant of glycolysis is widespread among bacteria, but it also occurs in a few parasitic anaerobic eukaryotes such as Giardia and Entamoeba spp. We sequenced two genes for PPDK from the amitochondriate oxymonad Streblomastix strix and found evidence for PPDK in Trichomonas vaginalis and other parabasalia, where this enzyme was thought to be absent. The Streblomastix and Giardia genes may be related to one another, but those of Entamoeba and perhaps Trichomonas are distinct and more closely related to bacterial homologues. These findings suggest that pyrophosphate-dependent glycolysis is more widespread in eukaryotes than previously thought, enzymes from the pathway coexists with ATP-dependent more often than previously thought and may be spread by lateral transfer of genes for pyrophosphate-dependent enzymes from bacteria. Adaptation to anaerobic metabolism is a complex process (PPDK), respectively (for a comparison of these reactions, see involving changes to many proteins and pathways of critical reference 21). -
Gent Forms of Metalloproteinases in Hydra
Cell Research (2002); 12(3-4):163-176 http://www.cell-research.com REVIEW Structure, expression, and developmental function of early diver- gent forms of metalloproteinases in Hydra 1 2 3 4 MICHAEL P SARRAS JR , LI YAN , ALEXEY LEONTOVICH , JIN SONG ZHANG 1 Department of Anatomy and Cell Biology University of Kansas Medical Center Kansas City, Kansas 66160- 7400, USA 2 Centocor, Malvern, PA 19355, USA 3 Department of Experimental Pathology, Mayo Clinic, Rochester, MN 55904, USA 4 Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA ABSTRACT Metalloproteinases have a critical role in a broad spectrum of cellular processes ranging from the breakdown of extracellular matrix to the processing of signal transduction-related proteins. These hydro- lytic functions underlie a variety of mechanisms related to developmental processes as well as disease states. Structural analysis of metalloproteinases from both invertebrate and vertebrate species indicates that these enzymes are highly conserved and arose early during metazoan evolution. In this regard, studies from various laboratories have reported that a number of classes of metalloproteinases are found in hydra, a member of Cnidaria, the second oldest of existing animal phyla. These studies demonstrate that the hydra genome contains at least three classes of metalloproteinases to include members of the 1) astacin class, 2) matrix metalloproteinase class, and 3) neprilysin class. Functional studies indicate that these metalloproteinases play diverse and important roles in hydra morphogenesis and cell differentiation as well as specialized functions in adult polyps. This article will review the structure, expression, and function of these metalloproteinases in hydra. Key words: Hydra, metalloproteinases, development, astacin, matrix metalloproteinases, endothelin. -
Molecular Homology and Multiple-Sequence Alignment: an Analysis of Concepts and Practice
CSIRO PUBLISHING Australian Systematic Botany, 2015, 28,46–62 LAS Johnson Review http://dx.doi.org/10.1071/SB15001 Molecular homology and multiple-sequence alignment: an analysis of concepts and practice David A. Morrison A,D, Matthew J. Morgan B and Scot A. Kelchner C ASystematic Biology, Uppsala University, Norbyvägen 18D, Uppsala 75236, Sweden. BCSIRO Ecosystem Sciences, GPO Box 1700, Canberra, ACT 2601, Australia. CDepartment of Biology, Utah State University, 5305 Old Main Hill, Logan, UT 84322-5305, USA. DCorresponding author. Email: [email protected] Abstract. Sequence alignment is just as much a part of phylogenetics as is tree building, although it is often viewed solely as a necessary tool to construct trees. However, alignment for the purpose of phylogenetic inference is primarily about homology, as it is the procedure that expresses homology relationships among the characters, rather than the historical relationships of the taxa. Molecular homology is rather vaguely defined and understood, despite its importance in the molecular age. Indeed, homology has rarely been evaluated with respect to nucleotide sequence alignments, in spite of the fact that nucleotides are the only data that directly represent genotype. All other molecular data represent phenotype, just as do morphology and anatomy. Thus, efforts to improve sequence alignment for phylogenetic purposes should involve a more refined use of the homology concept at a molecular level. To this end, we present examples of molecular-data levels at which homology might be considered, and arrange them in a hierarchy. The concept that we propose has many levels, which link directly to the developmental and morphological components of homology. -
GSTM4 Is a Microsatellite-Containing EWS&Sol;FLI Target Involved in Ewing&Apos;S Sarcoma Oncogenesis and Therapeutic
Oncogene (2009) 28, 4126–4132 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc SHORT COMMUNICATION GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing’s sarcoma oncogenesis and therapeutic resistance W Luo1,2, K Gangwal1,2, S Sankar1,2, KM Boucher1, D Thomas3 and SL Lessnick1,2,4 1Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA; 2The Center for Children’s Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 3Department of Pathology, University of Michigan, Ann Arbor, MI, USA and 4Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, UT, USA Ewing’s sarcoma is a malignant bone-associated tumor of Most cases of Ewing’s sarcoma harbor recurrent children and young adults. Most cases of Ewing’s sarcoma chromosomal translocations, the most common express the EWS/FLI fusion protein. EWS/FLI functions of which encodes the EWS/FLI fusion oncoprotein as an aberrant ETS-type transcription factor and serves (Delattre et al., 1992). EWS/FLI requires both its strong as the master regulator of Ewing’s sarcoma-transformed transcriptional activation domain (derived from EWS) phenotype. We recently showed that EWS/FLI regulates and its ETS-type DNA-binding domain (derived from one of its key targets, NR0B1, through a GGAA- FLI) for oncogenic function (May et al., 1993a, b). A microsatellite in its promoter. Whether other critical variety of studies have identified a large number of EWS/FLI targets are also regulated by GGAA-micro- EWS/FLI-regulated genes (Prieur et al., 2004; Smith satellites was unknown. -
Annotation of Glycolysis and Gluconeogenesis Pathways
A metabolic insight into the Asian citrus psyllid: Annotation of glycolysis and gluconeogenesis pathways Blessy Tamayo, Kyle Kercher, Tom D’Elia, Helen Wiersma-Koch, Surya Saha, Teresa Shippy, Susan J. Brown, and Prashant Hosmani Introduction Glycolysis, as in other animals, is the major metabolic pathway that insects use to extract energy from carbohydrates [1]. This process consists of ten reactions that convert one molecule of glucose into two molecules of pyruvate within the cytosol, generating a net gain of two molecules of ATP. Simple carbohydrates are acquired through the insect diet and processed through glycolysis and the central carbohydrate metabolic steps. Comparative genomic analysis of Apis mellifera, Drosophila melanogaster, and Anopheles gambiae has revealed the presence of genes for metabolic pathways that support dietary habits dependent on sugar-rich substrates ([2]; [3]; [4]; [5]). In addition to processing sugars for energy, glycolysis also serves as a central pathway that serves as both a source of important precursors and destination for key intermediates from many metabolic pathways. Gluconeogenesis is the process through which glucose is synthesized from non- carbohydrate substrates, and is closely associated with glycolysis. Eleven enzymatic reactions occur during gluconeogenesis. Eight of the enzymes involved in the steps also catalyze the reverse reactions in glycolysis and the three remaining enzymes are specific to gluconeogenesis. 1 Gluconeogenesis generated carbohydrates are required as substrate for anaerobic glycolysis, synthesis of chitin, glycoproteins, polyols and glycoside detoxication products [1]. Gluconeogenesis is essential in insects to maintain sugar homeostasis and serves as the initial process towards the generation of glucose disaccharide trehalose, which is the main circulating sugar in the insect hemolymph ([6]; [7]). -
Whole Exome Sequencing in Families at High Risk for Hodgkin Lymphoma: Identification of a Predisposing Mutation in the KDR Gene
Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 2Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 3Ad - vanced Biomedical Computing Center, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Frederick, MD; 4Westat, Inc., Rockville MD; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; and 6Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA ©2016 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.135475 Received: August 19, 2015. Accepted: January 7, 2016. Pre-published: June 13, 2016. Correspondence: [email protected] Supplemental Author Information: NCI DCEG Cancer Sequencing Working Group: Mark H. Greene, Allan Hildesheim, Nan Hu, Maria Theresa Landi, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, Xiaohong R. Yang, Guoqin Yu NCI DCEG Cancer Genomics Research Laboratory: Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A. -
Molecular Homology and Multiple-Sequence Alignment: an Analysis of Concepts and Practice
CSIRO PUBLISHING Australian Systematic Botany, 2015, 28, 46–62 LAS Johnson Review http://dx.doi.org/10.1071/SB15001 Molecular homology and multiple-sequence alignment: an analysis of concepts and practice David A. Morrison A,D, Matthew J. Morgan B and Scot A. Kelchner C ASystematic Biology, Uppsala University, Norbyvägen 18D, Uppsala 75236, Sweden. BCSIRO Ecosystem Sciences, GPO Box 1700, Canberra, ACT 2601, Australia. CDepartment of Biology, Utah State University, 5305 Old Main Hill, Logan, UT 84322-5305, USA. DCorresponding author. Email: [email protected] Abstract. Sequence alignment is just as much a part of phylogenetics as is tree building, although it is often viewed solely as a necessary tool to construct trees. However, alignment for the purpose of phylogenetic inference is primarily about homology, as it is the procedure that expresses homology relationships among the characters, rather than the historical relationships of the taxa. Molecular homology is rather vaguely defined and understood, despite its importance in the molecular age. Indeed, homology has rarely been evaluated with respect to nucleotide sequence alignments, in spite of the fact that nucleotides are the only data that directly represent genotype. All other molecular data represent phenotype, just as do morphology and anatomy. Thus, efforts to improve sequence alignment for phylogenetic purposes should involve a more refined use of the homology concept at a molecular level. To this end, we present examples of molecular-data levels at which homology might be considered, and arrange them in a hierarchy. The concept that we propose has many levels, which link directly to the developmental and morphological components of homology. -
Rubisco Biogenesis and Assembly in Chlamydomonas Reinhardtii Wojciech Wietrzynski
Rubisco biogenesis and assembly in Chlamydomonas reinhardtii Wojciech Wietrzynski To cite this version: Wojciech Wietrzynski. Rubisco biogenesis and assembly in Chlamydomonas reinhardtii. Molecular biology. Université Pierre et Marie Curie - Paris VI, 2017. English. NNT : 2017PA066336. tel- 01770412 HAL Id: tel-01770412 https://tel.archives-ouvertes.fr/tel-01770412 Submitted on 19 Apr 2018 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. PhD Thesis of the Pierre and Marie Curie University (UPMC) Prepared in the Laboratory of Molecular and Membrane Physiology of the Chloroplast, UMR7141, CNRS/UPMC Doctoral school: Life Science Complexity, ED515 Presented by Wojciech Wietrzynski for the grade of Doctor of the Pierre and Marie Curie University Rubisco biogenesis and assembly in Chlamydomonas reinhardtii Defended on the 17th of October 2017 at the Institut of Physico-Chemical Biology in Paris, France Phd Jury: Angela Falciatore, CNRS/UPMC, president Michel Goldschmidt-Clermont, Univeristy of Geneva, reviewer Michael Schroda, University of Kaiserslautern,