Plant SET Domain-Containing Proteins: Structure, Function and Regulation
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Automethylation of PRC2 Promotes H3K27 Methylation and Is Impaired in H3K27M Pediatric Glioma
Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma Chul-Hwan Lee,1,2,7 Jia-Ray Yu,1,2,7 Jeffrey Granat,1,2,7 Ricardo Saldaña-Meyer,1,2 Joshua Andrade,3 Gary LeRoy,1,2 Ying Jin,4 Peder Lund,5 James M. Stafford,1,2,6 Benjamin A. Garcia,5 Beatrix Ueberheide,3 and Danny Reinberg1,2 1Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA; 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA; 3Proteomics Laboratory, New York University School of Medicine, New York, New York 10016, USA; 4Shared Bioinformatics Core, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 5Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/ EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring inde- pendently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. -
Computational Investigation of Thiol-Based Redox Modifications in Proteins: Redox-Active Disulfides, Zn2+ Sites and Their Associations
THESIS SUBMITTED IN TOTAL FULFILLMENT OF THE REQUIREMENTS OF THE DEGREE OF DOCTOR OF PHILOSOPHY Computational investigation of thiol‐based redox modifications in proteins: redox‐active disulfides, 2+ Zn sites and their associations Application of tools of bioinformatics in health and disease Dhakshinari Vihara Kumari Hulugalle March 2013 Victor Chang Cardiac Research Institute School of Medical Sciences, Faculty of Medicine, University of New South Wales PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: HULUGALLE First name: DHAKSHINARI Other name/s: VIHARA KUMARI PhD Abbreviation for degree as given in the University calendar: School: SCHOOL OF MEDICAL SCIENCES Faculty: MEDICINE Title: Computational investigation of thiol-based redox modifications in proteins: redox-active disulfides, Zn2+ sites and their associations Abstract 350 words maximum: (PLEASE TYPE) Thiol based redox signalling is an emerging area of research in protein science. Reversible disulfide bonding and Zn2+ expulsion are two important but less explored oxidative thiol modifications associated with redox signalling. They have numerous implications in health and disease. Three computational methods have previously been developed to predict redox-active disulfides in proteins: redox pair protein (RP) method, ‘forbidden disulfides’ (FD) method and torsional energy (TE) method. These methods and other tools of bioinformatics are used in my study to investigate redox-active disulfides, Zn2+ sites and the association between FDs and Zn fingers in protein structures. The first objective of my study was to apply the RP method to predict novel proteins containing likely redox-active disulfides. Over 300 novel RP proteins were found during this study. Significant conformational changes associated with disulfide redox activity in RP protein structures were also identified. -
Engaging Chromatin: PRC2 Structure Meets Function
www.nature.com/bjc REVIEW ARTICLE Engaging chromatin: PRC2 structure meets function Paul Chammas1, Ivano Mocavini1 and Luciano Di Croce1,2,3 Polycomb repressive complex 2 (PRC2) is a key epigenetic multiprotein complex involved in the regulation of gene expression in metazoans. PRC2 is formed by a tetrameric core that endows the complex with histone methyltransferase activity, allowing it to mono-, di- and tri-methylate histone H3 on lysine 27 (H3K27me1/2/3); H3K27me3 is a hallmark of facultative heterochromatin. The core complex of PRC2 is bound by several associated factors that are responsible for modulating its targeting specificity and enzymatic activity. Depletion and/or mutation of the subunits of this complex can result in severe developmental defects, or even lethality. Furthermore, mutations of these proteins in somatic cells can be drivers of tumorigenesis, by altering the transcriptional regulation of key tumour suppressors or oncogenes. In this review, we present the latest results from structural studies that have characterised PRC2 composition and function. We compare this information with data and literature for both gain-of function and loss-of-function missense mutations in cancers to provide an overview of the impact of these mutations on PRC2 activity. British Journal of Cancer (2020) 122:315–328; https://doi.org/10.1038/s41416-019-0615-2 BACKGROUND and embryonic ectoderm development (EED) (Table 1). These Transcriptional diversity is one of the hallmarks of cellular three proteins form the minimal core that confers histone identity. It is largely regulated at the level of chromatin, where methyltransferase (HMT) activity. A fourth factor, retinoblastoma- different protein complexes act as initiators, enhancers and/or binding protein (RBBP)4/7 (also known as RBAP48/46), has a repressors of transcription. -
Structural Chemistry of Human SET Domain Protein Methyltransferases Matthieu Schapira*,1,2
Current Chemical Genomics, 2011, 5, (Suppl 1-M5) 85-94 85 Open Access Structural Chemistry of Human SET Domain Protein Methyltransferases Matthieu Schapira*,1,2 1Structural Genomics Consortium, University of Toronto, MaRS Centre, Toronto, Ontario, M5G 1L7, Canada 2 Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, Toronto, Ontario, M5S 1A8, Canada Abstract: There are about fifty SET domain protein methyltransferases (PMTs) in the human genome, that transfer a methyl group from S-adenosyl-L-methionine (SAM) to substrate lysines on histone tails or other peptides. A number of structures in complex with cofactor, substrate, or inhibitors revealed the mechanisms of substrate recognition, methylation state specificity, and chemical inhibition. Based on these structures, we review the structural chemistry of SET domain PMTs, and propose general concepts towards the development of selective inhibitors. Keywords: Methyltransferase, SET domain, structure, PMT, histone, epigenetics. INTRODUCTION activity, but sometimes recognize the methylation substrate or reaction product. For instance, it was shown that an An- Epigenetics mechanisms rely extensively on histone- kyrin repeat distinct from the catalytic domain of GLP could mediated signaling, in which chemical modifications can recognize mono- or di-methylated lysine 9 of histone 3, the make or break complex biological circuits [1, 2]. Among the very reaction product of GLP’s SET domain [16]. different histone marks, methylation of specific lysine and arginine side-chains can regulate chromatin compaction, As previously observed for histone deacetylases and his- repress or activate transcription, and control cellular differ- tone acetyltransferases, it is becoming clear that histones are entiation [3, 4]. The transfer of a methyl group from the co- not the only subtrates of some PMTs. -
Hub Domains and Intrinsically Disordered Proteins
REVIEWS αα-Hub domains and intrinsically disordered proteins: A decisive combo Received for publication, October 7, 2020, and in revised form, December 22, 2020 Published, Papers in Press, December 29, 2020, https://doi.org/10.1074/jbc.REV120.012928 Katrine Bugge1,2 , Lasse Staby1,2 , Edoardo Salladini1 , Rasmus G. Falbe-Hansen1 , Birthe B. Kragelund1,2,* , and Karen Skriver1,* From the 1REPIN and The Linderstrøm-Lang Centre for Protein Science; 2Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark Edited by Ronald Wek Hub proteins are central nodes in protein–protein interaction adaptability, multivalency, and high chemical modification networks with critical importance to all living organisms. potential (9–11). Indeed, ID appears to be a prerequisite for Recently, a new group of folded hub domains, the αα-hubs, was fidelity in signaling pathways through exploitation of the many defined based on a shared αα-hairpin supersecondary structural different mechanisms encoded in these properties (12, 13). foundation. The members PAH, RST, TAFH, NCBD, and HHD Recognition of IDRs in and by hubs depends on short linear are found in large proteins such as Sin3, RCD1, TAF4, CBP, and motifs (SLiMs), which are stretches of 2 to 12 residues with harmonin, which organize disordered transcriptional regulators only a few highly conserved positions (14, 15). It has been and membrane scaffolds in interactomes of importance to hu- proposed that the eukaryotic SLiMome consists of up to 1 man diseases and plant quality. In this review, studies of struc- million different SLiMs (16), but SLiMs active in hub in- tures, functions, and complexes across the αα-hubs are described teractions have very similar features (17). -
Atlas Journal
Atlas of Genetics and Cytogenetics in Oncology and Haematology Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Portal Teaching X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA Atlas Journal Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 12, Number 5, Sep-Oct 2008 Previous Issue / Next Issue Genes XAF1 (XIAP associated factor-1) (17p13.2). Stéphanie Plenchette, Wai Gin Fong, Robert G Korneluk. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 668-673. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/XAF1ID44095ch17p13.html WWP1 (WW domain containing E3 ubiquitin protein ligase 1) (8q21.3). Ceshi Chen. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 674-680. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/WWP1ID42993ch8q21.html TSPAN1 (tetraspanin 1) (1p34.1). David Murray, Peter Doran. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 681-683. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TSPAN1ID44178ch1p34.html TCL1B (T-cell leukemia/lymphoma 1B) (14q32.13). Herbert Eradat, Michael A Teitell. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 684-686. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/TCL1BID354ch14q32.html PVRL4 (poliovirus receptor-related 4) (1q23.3). Marc Lopez. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 687-690. [Full Text] [PDF] URL : http://atlasgeneticsoncology.org/Genes/PVRL4ID44141ch1q23.html PTTG1IP (pituitary tumor-transforming 1 interacting protein) (21q22.3). Vicki Smith, Chris McCabe. Atlas Genet Cytogenet Oncol Haematol 2008; 12 (5): 691-694. -
Structural Origins for the Product Specificity of SET Domain Protein Methyltransferases
Structural origins for the product specificity of SET domain protein methyltransferases Jean-Franc¸ois Couturea,1, Lynnette M. A. Dirkb, Joseph S. Brunzellec, Robert L. Houtzb, and Raymond C. Trievela,2 aDepartment of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109; bDepartment of Horticulture, Plant Physiology/Biochemistry/Molecular Biology Program, University of Kentucky, Lexington, KY 40546; and cDepartment of Molecular Pharmacology and Biological Chemistry, Life Sciences Collaborative Access Team, Northwestern University Center for Synchrotron Research, Argonne, IL 60439 Edited by David R. Davies, National Institutes of Health, Bethesda, MD, and approved October 30, 2008 (received for review July 11, 2008) SET domain protein lysine methyltransferases (PKMTs) regulate histone methyltransferases (Fig. S1). In lysine monomethyltrans- transcription and other cellular functions through site-specific ferases, this position is occupied by a tyrosine, whereas in most methylation of histones and other substrates. PKMTs catalyze the dimethyltransferases and trimethyltransferases, a phenylalanine formation of monomethylated, dimethylated, or trimethylated or another hydrophobic amino acid is located in this site (5–10). products, establishing an additional hierarchy with respect to These findings underpin a Phe/Tyr switch model for product methyllysine recognition in signaling. Biochemical studies of PK- specificity wherein the identity of the residue occupying the MTs have identified a conserved position within their active sites, switch position differentiates monomethyltransferases and di/ the Phe/Tyr switch, that governs their respective product specific- trimethyltransferases, with the exception of enzymes that are ities. To elucidate the mechanism underlying this switch, we have active within the context of heteromeric complexes whose sub- characterized a Phe/Tyr switch mutant of the histone H4 Lys-20 units regulate product specificity, such as ScSET1 (11) and (H4K20) methyltransferase SET8, which alters its specificity from a HsMLL (12, 13). -
Structure, Activity and Function of the NSD3 Proteinlysine
life Review Structure, Activity and Function of the NSD3 Protein Lysine Methyltransferase Philipp Rathert Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, 70569 Stuttgart, Germany; [email protected]; Tel.: +49-711-685-64388 Abstract: NSD3 is one of six H3K36-specific lysine methyltransferases in metazoans, and the methy- lation of H3K36 is associated with active transcription. NSD3 is a member of the nuclear receptor- binding SET domain (NSD) family of histone methyltransferases together with NSD1 and NSD2, which generate mono- and dimethylated lysine on histone H3. NSD3 is mutated and hyperactive in some human cancers, but the biochemical mechanisms underlying such dysregulation are barely understood. In this review, the current knowledge of NSD3 is systematically reviewed. Finally, the molecular and functional characteristics of NSD3 in different tumor types according to the current research are summarized. Keywords: NSD3; WHSC1L1; structure and function 1. Introduction In eukaryotes, DNA is assembled into a higher order nucleoprotein structure called chromatin. Besides the condensation of the DNA, chromatin poses a variety of different functions centered around the regulation of transcription, replication, DNA repair and Citation: Rathert, P. Structure, recombination. The main unit of chromatin is the nucleosome consisting of 147 base pairs Activity and Function of the NSD3 (bp) of DNA, which is wrapped around the histone octamer comprising two molecules of Protein Lysine Methyltransferase. each core histone: H2A, H2B, H3 and H4 [1]. The linker histone protein H1 is involved in Life 2021, 11, 726. https://doi.org/ packaging nucleosomes and proteins such as condensin, cohesin, CCCTC-binding factor 10.3390/life11080726 (CTCF) or Yin Yang 1 (YY1) to organize the chromatin into higher order structures such as gene loops, topologically associated domains (TADs), chromosome territories, and chro- Academic Editor: Jean Cavarelli mosomes [2–4]. -
Interaction of SET Domains with Histones and Nucleic Acid Structures in Active Chromatin
Clin Epigenet (2011) 2:17–25 DOI 10.1007/s13148-010-0015-1 CARCINOGENESIS Interaction of SET domains with histones and nucleic acid structures in active chromatin Wladyslaw A. Krajewski & Oleg L. Vassiliev Received: 15 July 2010 /Accepted: 16 November 2010 /Published online: 14 January 2011 # Springer-Verlag 2011 Abstract Changes in the normal program of gene The accumulated data suggest that many diseases and expression are the basis for a number of human diseases. metabolic disorders are caused by altered patterns of gene Epigenetic control of gene expressionisprogrammedby expression (Kaminsky et al. 2006; Perini and Tupler 2006; chromatin modifications—the inheritable “histone Maekawa and Watanabe 2007). The chromatin-templated code”—the major component of which is histone processes are controlled by a complex pattern of posttrans- methylation. This chromatin methylation code of gene lational modifications of the flexible N-terminal tails of activity is created upon cell differentiation and is further histone proteins, including methylation, acetylation, phos- controlledbythe“SET” (methyltransferase) domain phorylation, ubiquitination, etc., which comprise the inher- proteins which maintain this histone methylation pattern itable “histone code” of gene function (Marmorstein and and preserve it through rounds of cell division. The Trievel 2009), although the effects of the histone code may molecular principles of epigenetic gene maintenance are depend on the particular situation (Lee et al. 2010). essential for proper treatment and prevention of disorders Chromatin activity is largely determined by the methylation and their complications. However, the principles of status of specific lysine and arginine residues in the N epigenetic gene programming are not resolved. Here we termini of histones H3 and H4 (Li et al. -
Antibodies Products
Chapter 2 : Gentaur Products List • WDSUB1 contains 1 SAM sterile alpha motif domain 1 U Defects in DLG3 are the cause of mental retardation X • Sodium hydrogen exchangers NHEs such as SLC9A8 are box domain and 7 WD repeats The function of WDSUB1 linked type 90 MRX90 integral transmembrane proteins that exchange extracellular remains unknown • SLC25A20 is one of several closely related mitochondrial Na for intracellular H NHEs have multiple functions including • RNF217 is an E3 ubiquitin protein ligase which accepts membrane carrier proteins that shuttle substrates between intracellular pH ho ubiquitin from E2 ubiquitin conjugating enzymes in the form cytosol and the intramitochondrial matrix space It mediates • SLCO1C1 is a member of the organic anion transporter of a thioester and then directly transfers the ubiquitin to the transport of acylcarn family SLCO1C1 is a transmembrane receptor that mediates targeted substrates • The sodium iodide symporter NIS or SLC5A5 is a key the sodium independent uptake of thyroid hormones in brain • TRIM60 contains a RING finger domain a motif present in a plasma membrane protein that mediates active I uptake in tissues This protein has part variety of functionally distinct proteins and known to be thyroid lactating breast and other tissues with an • SLC35A5 belongs to the nucleotide sugar transporter involved in protein protein and protein DNA interactions The electrogenic stoichiometry of 2 Na family SLC35A subfamily It is a multi pass membrane protein encoded by thi • SLC2A9 is a member of the SLC2A -
Structure and Function of SET and MYND Domain-Containing Proteins
Int. J. Mol. Sci. 2015, 16, 1406-1428; doi:10.3390/ijms16011406 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Structure and Function of SET and MYND Domain-Containing Proteins Nicholas Spellmon 1, Joshua Holcomb 1, Laura Trescott 1, Nualpun Sirinupong 2 and Zhe Yang 1,* 1 Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 540 East Canfield Street, Detroit, MI 48201, USA; E-Mails: [email protected] (N.S.); [email protected] (J.H.); [email protected] (L.T.) 2 Nutraceuticals and Functional Food Research and Development Center, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-313-577-1294; Fax: +1-313-577-2765. Academic Editor: Charles A. Collyer Received: 5 December 2014 / Accepted: 5 January 2015 /Published: 8 January 2015 Abstract: SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control. During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle. SMYD proteins are also of therapeutic interest due to the growing list of carcinomas and cardiovascular diseases linked to SMYD overexpression or dysfunction making them a putative target for drug intervention. -
AML1-ETO Decreases ETO-2 (MTG16) Interactions with Nuclear Receptor Corepressor, an Effect That Impairs Granulocyte Differentiation
[CANCER RESEARCH 64, 4547–4554, July 1, 2004] AML1-ETO Decreases ETO-2 (MTG16) Interactions with Nuclear Receptor Corepressor, an Effect That Impairs Granulocyte Differentiation Vinzon Iban˜ez,1 Arun Sharma,1 Silvia Buonamici,1 Amit Verma,1 Sudhakar Kalakonda,3 Jianxiang Wang,4 ShriHari Kadkol,2 and Yogen Saunthararajah1 1Section of Hematology/Oncology, Department of Medicine, and 2Department of Pathology, University of Illinois, Chicago, Illinois; 3Department of Ophthalmology, University of Maryland, Baltimore, Maryland; and 4Laboratory of Hematological Malignancy, State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences ABSTRACT mology domain. NHR2 is an amphipathic helix structure that mediates homodimerization and binding of ETO to homologous family mem- The t(8;21) chromosome abnormality in acute myeloid leukemia targets bers (2). NHR3 is a coiled-coiled region that plays a role in interac- the AML1 and ETO genes to produce the leukemia fusion protein AML1- tions with N-CoR (3). NHR4 contains two MYND zinc finger motifs, ETO. Another member of the ETO family, ETO-2/MTG16, is highly which are necessary for binding to N-CoR (3–7); it is also known as expressed in murine and human hematopoietic cells, bears >75% homol- ogy to ETO, and like ETO, contains a conserved MYND domain that the MYND domain. interacts with the nuclear receptor corepressor (N-CoR). AML1-ETO ETO-2, like ETO, demonstrates corepressor function (8). This prevents granulocyte but not macrophage differentiation of murine function is likely to be mediated through the interactions of ETO-2 32Dcl3 granulocyte/macrophage progenitors. One possible mechanism with histone deacetylases 1, 2, 3, 6, and 8 and the ubiquitously is recruitment of N-CoR to aberrantly repress AML1 target genes.