Formation of Leucine Zipper Coiled Coils? (Molecular Modeling/A-Helices/Protein-Protein Interaction) ALEXANDER TROPSHA*T, J
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Dimerization Specificity of Myogenic Helix-Loop-Helix DNA-Binding Factors Directed by Nonconserved Hydrophilic Residues
Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Dimerization specificity of myogenic helix-loop-helix DNA-binding factors directed by nonconserved hydrophilic residues Masaki Shirakata, Fred K. Friedman, 1 Qin Wei, and Bruce M. Paterson Laboratory of Biochemistry, ~Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 USA The myogenic regulatory factor MyoD dimerizes with other positive and negative regulatory factors through a conserved region called the helix-loop-helix (HLH) domain. Using a non-DNA-binding MyoD mutant with a normal HLH domain as a dimerization competitor in gel mobility shift assays in conjunction with various MyoD HLH mutants, nonhydrophobic amino acids were identified in the HLH domain that contribute to dimerization specificity with El2. The assay detected subtle differences in dimerization activity among the mutant MyoD proteins that correlated with their ability to activate transcription in vivo, but this correlation was not apparent in the absence of competitor. The identification of such nonhydrophobic residues enabled us to predict the differences in dimerization affinity among the four vertebrate myogenic factors with El2. The experiments confirmed the prediction. Furthermore, a high-affinity homodimerizing analog of MyoD was designed by a single substitution at one of these residue positions. These experimental results were strengthened when they were analyzed in terms of the crystal structure for the Max bHLHZip domain homodimer. This analysis has allowed us to identify those residues that form charged residue pairs between the two HLH domains of MyoD and El2 and determine the dimerization specificity of the bHLH proteins. -
2. Proteins Have Hierarchies of Structure
27 2. Proteins have Hierarchies of Structure Protein structure is usually described at four different levels (Fig. II.2.1). The first level, called the primary structure, describes the linear sequence of the amino acids in the chain. The different primary structures correspond to the different sequences in which the amino acids are covalently linked together. The secondary structure describes two common patterns of structural repetition in proteins: the coiling up into helices of segments of the chain, and the pairing together of strands of the chain into β-sheets. The tertiary structure is the next higher level of organization, the overall arrangement of secondary structural elements. The quaternary structure describes how different polypeptide chains are assembled into complexes. Figure II.2.1. Different levels of protein structure. A protein chain’s primary structure is its amino acid sequence. Secondary structure consists of the regular organization of helices and sheets. The example shown is a schematic representation of an α helix. Tertiary structure is a polypeptide chain’s three- dimensional native conformation, which often involves compact packing of secondary structure elements. The example given in the figure is a schematic drawing of one of the four polypeptide chains (subunits) of hemoglobin, the protein that transports oxygen in the blood. α-helices along the chain are represented as cylinders. N is the amino terminus and C is the carboxyl terminus of the polypeptide chain. Quaternary structure is the arrangement of multiple polypeptide chains (subunits) to form a functional biomolecular structure. The figure shows the quaternary arrangement of four subunits to form the functional hemoglobin molecule. -
Leucine Zippers
Leucine Zippers Leucine Zippers Advanced article Toshio Hakoshima, Nara Institute of Science and Technology, Nara, Japan Article contents Introduction The leucine zipper (ZIP) motif consists of a periodic repetition of a leucine residue at every Structural Basis of ZIP seventh position and forms an a-helical conformation, which facilitates dimerization and in Occurrence of ZIP and Coiled-coil Motifs some cases higher oligomerization of proteins. In many eukaryotic gene regulatory proteins, Dimerization Specificity of ZIP the ZIP motif is flanked at its N-terminus by a basic region containing characteristic residues DNA-binding Specificity of bZIP that facilitate DNA binding. doi: 10.1038/npg.els.0005049 Introduction protein modules for protein–protein interactions. Knowing the structure and function of these motifs A structure referred to as the leucine zipper or enables us to understand the molecular recognition simply as ZIP has been proposed to explain how a system in several biological processes. class of eukaryotic gene regulatory proteins works (Landschulz et al., 1988). A segment of the mammalian CCAAT/enhancer binding protein (C/EBP) of 30 Structural Basis of ZIP amino acids shares notable sequence similarity with a segment of the cellular Myc transforming protein. The The a helix is a secondary structure element that segments have been found to contain a periodic occurs frequently in proteins. Alpha helices are repetition of a leucine residue at every seventh stabilized in proteins by being packed into the position. A periodic array of at least four leucines hydrophobic core of a protein through hydrophobic has also been noted in the sequences of the Fos and side chains. -
A Switch Between Two-, Three-, and Four-Stranded Coiled Coils in GCN4 Leucine Zipper Mutants
A Switch Between Two-, Three-, and Four-Stranded Coiled Coils in GCN4 Leucine Zipper Mutants Pehr B. Harbury; Tao Zhang; Peter S. Kim; Tom Alber Science, New Series, Vol. 262, No. 5138. (Nov. 26, 1993), pp. 1401-1407. Stable URL: http://links.jstor.org/sici?sici=0036-8075%2819931126%293%3A262%3A5138%3C1401%3AASBTTA%3E2.0.CO%3B2-H Science is currently published by American Association for the Advancement of Science. Your use of the JSTOR archive indicates your acceptance of JSTOR's Terms and Conditions of Use, available at http://www.jstor.org/about/terms.html. JSTOR's Terms and Conditions of Use provides, in part, that unless you have obtained prior permission, you may not download an entire issue of a journal or multiple copies of articles, and you may use content in the JSTOR archive only for your personal, non-commercial use. Please contact the publisher regarding any further use of this work. Publisher contact information may be obtained at http://www.jstor.org/journals/aaas.html. Each copy of any part of a JSTOR transmission must contain the same copyright notice that appears on the screen or printed page of such transmission. The JSTOR Archive is a trusted digital repository providing for long-term preservation and access to leading academic journals and scholarly literature from around the world. The Archive is supported by libraries, scholarly societies, publishers, and foundations. It is an initiative of JSTOR, a not-for-profit organization with a mission to help the scholarly community take advantage of advances in technology. For more information regarding JSTOR, please contact [email protected]. -
The Function and Evolution of C2H2 Zinc Finger Proteins and Transposons
The function and evolution of C2H2 zinc finger proteins and transposons by Laura Francesca Campitelli A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Molecular Genetics University of Toronto © Copyright by Laura Francesca Campitelli 2020 The function and evolution of C2H2 zinc finger proteins and transposons Laura Francesca Campitelli Doctor of Philosophy Department of Molecular Genetics University of Toronto 2020 Abstract Transcription factors (TFs) confer specificity to transcriptional regulation by binding specific DNA sequences and ultimately affecting the ability of RNA polymerase to transcribe a locus. The C2H2 zinc finger proteins (C2H2 ZFPs) are a TF class with the unique ability to diversify their DNA-binding specificities in a short evolutionary time. C2H2 ZFPs comprise the largest class of TFs in Mammalian genomes, including nearly half of all Human TFs (747/1,639). Positive selection on the DNA-binding specificities of C2H2 ZFPs is explained by an evolutionary arms race with endogenous retroelements (EREs; copy-and-paste transposable elements), where the C2H2 ZFPs containing a KRAB repressor domain (KZFPs; 344/747 Human C2H2 ZFPs) are thought to diversify to bind new EREs and repress deleterious transposition events. However, evidence of the gain and loss of KZFP binding sites on the ERE sequence is sparse due to poor resolution of ERE sequence evolution, despite the recent publication of binding preferences for 242/344 Human KZFPs. The goal of my doctoral work has been to characterize the Human C2H2 ZFPs, with specific interest in their evolutionary history, functional diversity, and coevolution with LINE EREs. -
Tgfβ-Regulated Gene Expression by Smads and Sp1/KLF-Like Transcription Factors in Cancer VOLKER ELLENRIEDER
ANTICANCER RESEARCH 28 : 1531-1540 (2008) Review TGFβ-regulated Gene Expression by Smads and Sp1/KLF-like Transcription Factors in Cancer VOLKER ELLENRIEDER Signal Transduction Laboratory, Internal Medicine, Department of Gastroenterology and Endocrinology, University of Marburg, Marburg, Germany Abstract. Transforming growth factor beta (TGF β) controls complex induces the canonical Smad signaling molecules which vital cellular functions through its ability to regulate gene then translocate into the nucleus to regulate transcription (2). The expression. TGFβ binding to its transmembrane receptor cellular response to TGF β can be extremely variable depending kinases initiates distinct intracellular signalling cascades on the cell type and the activation status of a cell at a given time. including the Smad signalling and transcription factors and also For instance, TGF β induces growth arrest and apoptosis in Smad-independent pathways. In normal epithelial cells, TGF β healthy epithelial cells, whereas it can also promote tumor stimulation induces a cytostatic program which includes the progression through stimulation of cell proliferation and the transcriptional repression of the c-Myc oncogene and the later induction of an epithelial-to-mesenchymal transition of tumor induction of the cell cycle inhibitors p15 INK4b and p21 Cip1 . cells (1, 3). In the last decade it has become clear that both the During carcinogenesis, however, many tumor cells lose their tumor suppressing and the tumor promoting functions of TGF β ability to respond to TGF β with growth inhibition, and instead, are primarily regulated on the level of gene expression through activate genes involved in cell proliferation, invasion and Smad-dependent and -independent mechanisms (1, 2, 4). -
Mechanism of Nucleosome Targeting by Pioneer Transcription Factors
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2019 Mechanism Of Nucleosome Targeting By Pioneer Transcription Factors Meilin Mary Fernandez Garcia University of Pennsylvania Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biochemistry Commons, and the Biophysics Commons Recommended Citation Fernandez Garcia, Meilin Mary, "Mechanism Of Nucleosome Targeting By Pioneer Transcription Factors" (2019). Publicly Accessible Penn Dissertations. 3624. https://repository.upenn.edu/edissertations/3624 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3624 For more information, please contact [email protected]. Mechanism Of Nucleosome Targeting By Pioneer Transcription Factors Abstract Transcription factors (TFs) forage the genome to instruct cell plasticity, identity, and differentiation. These developmental processes are elicited through TF engagement with chromatin. Yet, how and which TFs can engage with chromatin and thus, nucleosomes, remains largely unexplored. Pioneer TFs are TF that display a high affinity for nucleosomes. Extensive genetic and biochemical studies on the pioneer TF FOXA, a driver of fibroblast to hepatocyte reprogramming, revealed its nucleosome binding ability and chromatin targeting lead to chromatin accessibility and subsequent cooperative binding of TFs. Similarly, a number of reprogramming TFs have been suggested to have pioneering activity due to their ability to target compact chromatin and increase accessibility and enhancer formation in vivo. But whether these factors directly interact with nucleosomes remains to be assessed. Here we test the nucleosome binding ability of the cell reprogramming TFs, Oct4, Sox2, Klf4 and cMyc, that are required for the generation of induced pluripotent stem cells. In addition, we also test neuronal and macrophage reprogramming TFs. -
Mechanistic Insights Into the Effect of RUNX1/ETO Knockdown in T(8;21) AML
Mechanistic insights into the effect of RUNX1/ETO knockdown in t(8;21) AML Anna Pickin A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Institute of Biomedical Research Birmingham Centre for Genomic Biology College of Medical and Dental Sciences University of Birmingham September 2016 1 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT The mutation of transcription factor genes is a main cause for acute myeloid leukaemia. RUNX1/ETO, the product of the t(8;21) chromosomal translocation, subverts normal blood cell development by impairing myeloid differentiation. RUNX1/ETO knockdown alleviates this block, with a global reprogramming of transcription factor binding and initiation of myeloid differentiation. Co-depletion of the myeloid transcription factor C/EBPα with RUNX1/ETO suppressed this differentiation response. Furthermore, C/EBPα overexpression largely phenocopied the effect of RUNX1/ETO knockdown. Our data show that low levels of C/EBPα are critical to the maintenance of t(8;21) AML and that C/EBPα drives the response to RUNX1/ETO depletion. To examine how changes in transcription factor binding impact on the activity of cis- regulatory elements we mapped genome wide promoter-distal-element interactions in a t(8;21) AML cell line, via Capture HiC, and found that hundreds of interactions were altered by RUNX1/ETO knockdown. -
A Seven-Helix Coiled Coil
A seven-helix coiled coil Jie Liu*, Qi Zheng*, Yiqun Deng*, Chao-Sheng Cheng*, Neville R. Kallenbach†, and Min Lu*‡ *Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021; and †Department of Chemistry, New York University, New York, NY 10003 Edited by Janet M. Thornton, European Bioinformatics Institute, Cambridge, United Kingdom, and approved August 28, 2006 (received for review June 12, 2006) Coiled-coil proteins contain a characteristic seven-residue se- and d residues. Interior packing of the side chains at the a and quence repeat whose positions are designated a to g. The inter- d positions, in fact, has been shown to dominate the global acting surface between ␣-helices in a classical coiled coil is formed architecture of coiled coils (23). Polar side chains at the a and by interspersing nonpolar side chains at the a and d positions with d positions also can destabilize coiled-coil structure yet impose hydrophilic residues at the flanking e and g positions. To explore a high degree of conformational selectivity (4, 24). Moreover, how the chemical nature of these core amino acids dictates the ionic interactions between the e and g residues have been shown overall coiled-coil architecture, we replaced all eight e and g to influence the specificity of coiled-coil assembly (10–18). For residues in the GCN4 leucine zipper with nonpolar alanine side example, repulsive or attractive interactions between the e and chains. Surprisingly, the alanine-containing mutant forms a stable g side chains can control the extent of homo- versus heterodimer- ␣-helical heptamer in aqueous solution. -
EFFECTS of POSTTRANSLATIONAL MODIFICATION of TRANSCRIPTION FACTOR GLI-SIMILAR 3 by SUMOYLATION on INSULIN TRANSCRIPTION in PANCREATIC Β CELLS Tyler M
Murray State's Digital Commons Murray State Theses and Dissertations Graduate School 2017 EFFECTS OF POSTTRANSLATIONAL MODIFICATION OF TRANSCRIPTION FACTOR GLI-SIMILAR 3 BY SUMOYLATION ON INSULIN TRANSCRIPTION IN PANCREATIC β CELLS Tyler M. Hoard Murray State University Follow this and additional works at: https://digitalcommons.murraystate.edu/etd Part of the Cell Biology Commons, and the Molecular Genetics Commons Recommended Citation Hoard, Tyler M., "EFFECTS OF POSTTRANSLATIONAL MODIFICATION OF TRANSCRIPTION FACTOR GLI-SIMILAR 3 BY SUMOYLATION ON INSULIN TRANSCRIPTION IN PANCREATIC β CELLS" (2017). Murray State Theses and Dissertations. 56. https://digitalcommons.murraystate.edu/etd/56 This Thesis is brought to you for free and open access by the Graduate School at Murray State's Digital Commons. It has been accepted for inclusion in Murray State Theses and Dissertations by an authorized administrator of Murray State's Digital Commons. For more information, please contact [email protected]. EFFECTS OF SUMOYLATION OF TRANSCRIPTION FACTOR GLI-SIMILAR 3 ON INSULIN TRANSCRIPTION IN PANCREATIC β CELLS A Thesis Presented to The Faculty of the Department of Biological Sciences Murray State University Murray, Kentucky In Partial Fulfillment of the Requirements for the Degree of Master of Science in Biology By Tyler Matthew Hoard December 2017 iii Acknowledgements There are so many people to whom I am thankful for the roles that they have played in the completion of this project. I would first like to thank my thesis advisor, Dr. Gary ZeRuth. His guidance, patience, troubleshooting suggestions, and devotion to carrying out impactful research have contributed significantly to preparing me for a future in biomedical research. -
And Acidic Amino Acid-Rich Basic Leucine Zipper Proteins Modulate Peroxisome Proliferator- Activated Receptor Α (Pparα) Activity
Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator- activated receptor α (PPARα) activity Frédéric Gachona,b,1, Nicolas Leuenbergerc,2, Thierry Claudeld, Pascal Gosa, Céline Jouffeb, Fabienne Fleury Olelaa, Xavier de Mollerat du Jeue, Walter Wahlic, and Ueli Schiblera,1 aDepartment of Molecular Biology, National Center of Competence in Research “Frontiers in Genetics,” Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland; bDepartment of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland; cCenter for Integrative Genomics, National Center of Competence in Research “Frontiers in Genetics,” University of Lausanne, CH-1015 Lausanne, Switzerland; dLaboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, A-8036 Graz, Austria; and eLife Technologies, Carlsbad, CA 92008 Edited by Steven L. McKnight, University of Texas Southwestern, Dallas, TX, and approved February 4, 2011 (received for review April 7, 2010) In mammals, many aspects of metabolism are under circadian leucine zipper (PAR bZip) proteins, D-site-binding protein control. At least in part, this regulation is achieved by core-clock (DBP), thyrotroph embryonic factor (TEF), and hepatic leuke- or clock-controlled transcription factors whose abundance and/or mia factor (HLF), are examples of such output mediators (for activity oscillate during the day. The clock-controlled proline- review, see ref. 7). Mice deficient of only one or two members and acidic amino acid-rich domain basic leucine zipper proteins of the PAR bZip gene family display rather mild phenotypes, D-site-binding protein, thyrotroph embryonic factor, and hepatic suggesting that the three members execute partially redundant leukemia factor have previously been shown to participate in functions. -
Mit Family Transcriptional Factors in Immune Cell Functions Seongryong Kim Et Al
Molecules and Cells Minireview MiT Family Transcriptional Factors in Immune Cell Functions Seongryong Kim1,3, Hyun-Sup Song1,3, Jihyun Yu1, and You-Me Kim1,2,* 1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea, 2The Center for Epidemic Preparedness, KAIST, Daejeon 34141, Korea, 3These authors contributed equally to this work. *Correspondence: [email protected] https://doi.org/10.14348/molcells.2021.0067 www.molcells.org The microphthalmia-associated transcription factor family transcription factor E3 (TFE3), transcription factor EB (TFEB), (MiT family) proteins are evolutionarily conserved transcription transcription factor EC (TFEC) factors that perform many essential biological functions. In mammals, the MiT family consists of MITF (microphthalmia- INTRODUCTION associated transcription factor or melanocyte-inducing transcription factor), TFEB (transcription factor EB), TFE3 The microphthalmia-associated transcription factor fami- (transcription factor E3), and TFEC (transcription factor EC). ly (MiT family) consists of four transcription factors: MITF These transcriptional factors belong to the basic helix-loop- (microphthalmia-associated transcription factor or melano- helix-leucine zipper (bHLH-LZ) transcription factor family and cyte-inducing transcription factor), TFEB (transcription factor bind the E-box DNA motifs in the promoter regions of target EB), TFE3 (transcription factor E3), and TFEC (transcription genes to enhance transcription. The best studied functions factor EC) (Goding and Arnheiter, 2019; Napolitano and of MiT proteins include lysosome biogenesis and autophagy Ballabio, 2016; Oppezzo and Rosselli, 2021). The Mitf gene induction. In addition, they modulate cellular metabolism, encoding the first member of the MiT family, MITF, was dis- mitochondria dynamics, and various stress responses.