G Protein-Coupled Receptor Dimerisation: Molecular Basis and Relevance to Function
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
"Protein Quaternary Structure: Subunit&Ndash;Subunit
Protein Quaternary Secondary article Structure: Subunit–Subunit Article Contents . Introduction Interactions . Quaternary Structure Assembly . Folding and Function Susan Jones, University College, London, England . Protein–Protein Recognition Sites . Concluding Remarks Janet M Thornton, University College, London, England The quaternary structure of proteins is the highest level of structural organization observed in these macromolecules. The multimeric proteins that result from quaternary structure formation involve the association of protein subunits through hydrophobic and electrostatic interactions. Protein quaternary structure has important implications for protein folding and function. Introduction from, other components. Using these definitions, the Proteins are organized into a structural hierarchy. The haemoglobin tetramer (comprised of two a and two b polypeptide chain at the primary structural level comprises polypeptide chains) is defined as an oligomer consisting of a linear, noncovalently linked amino acid residue se- two protomers, each consisting of two monomers, i.e. one a quence. Secondary structure is the level at which the linear and one b polypeptide chain. The definition of a subunit sequences aggregate to form structural motifs such as allows the term to be used for either the a-orb-monomer, helices and sheets. The tertiary structure is formed by or for the ab-protomer. The term multimer is also widely packing of the secondary structural elements into one or used in the literature and is defined here as a protein with a more compact globular domains. In many cases proteins finite number of subunits that need not be identical. are composed of only a single polypeptide chain that has The quaternary nature of some proteins was first tertiary structure as its highest level of organization, e.g. -
Gene Section Review
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review XRCC2 (X-ray repair cross complementing 2) Paul R Andreassen, Helmut Hanenberg Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA; [email protected] (PRA); Department of Pediatrics III, University Children's Hospital Essen, University Duisburg- Essen, Essen Germany; [email protected] (HH) Published in Atlas Database: November 2017 Online updated version : http://AtlasGeneticsOncology.org/Genes/XRCC2ID334ch7q36.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69759/11-2017-XRCC2ID334ch7q36.pdf DOI: 10.4267/2042/69759 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinically, the only known FA-U patient in the Abstract world exhibits severe congenital abnormalities, but XRCC2 is one of five somatic RAD51 paralogs, all had not developed, by seven years of age, the bone of which have Walker A and B ATPase motifs. marrow failure and cancer that are often seen in Each of the paralogs, including XRCC2, has a patients from other FA complementation groups. function in DNA double-strand break repair by Keywords homologous recombination (HR). However, their Fanconi anemia, Breast Cancer Susceptibility, individual roles are not as well understood as that Tumor Suppressor, Homologous Recombination, of RAD51 itself. DNA Repair, RAD51 Paralog The XRCC2 protein forms a complex (BCDX2) with three other RAD51 paralogs, RAD51B, RAD51C and RAD51D. It is believed that the Identity BCDX2 complex mediates HR downstream of Other names: FANCU BRCA2 but upstream of RAD51, as XRCC2 is HGNC (Hugo): XRCC2 involved in the assembly of RAD51 into DNA damage foci. -
Recent Advances in Drug Discovery of GPCR Allosteric Modulators
Recent Advances in Drug Discovery of GPCR Allosteric Modulators ADDEX Pharma S.A., Head of Core Chemistry Chemin Des Aulx 12, 1228 Plan-les-Ouates, Geneva, Switzerland Jean-Philippe Rocher, PhD results in a number of differentiating factors. In fact, most Introduction allosteric modulators have little or no effect on receptor function until the active site is bound by an orthosteric The importance of the allosteric regulation of cellular ligand. Allosteric modulators therefore have multiple functions has been known for decades and even the word potential advantages compared to small molecule and “allosterome,” which describes the endogenous alloste- biologic orthosteric drugs. In particular, they offer new ric regulator molecules of a cell, has been proposed 1. chemistry possibilities allowing access to well known tar- Although best described as modulators of enzymes, gets that have been considered intractable to historical advances in molecular biology and robotic HTS technolo- small molecule approaches. For example, allosteric mod- gies recently allowed the discovery of small molecule allo- ulators may soon be developed for targets which hereto- steric modulators of various biological systems, including fore have been only successfully targeted with proteins GPCR and non-GPCR targets. Today, allosteric modula- and peptides. In other words, allosteric drugs with all the tors appear to be an emerging class of orally available advantages of small molecules - brain penetration, eas- therapeutic agents that can offer a competitive advantage ier manufacturing, distribution and oral administration over classical “orthosteric” drugs. This potential stems - may soon be viewed as the best life cycle management from their ability to offer greater selectivity and differ- strategy for protein therapeutics 2. -
Biochemistry-2018-Hartman.Pdf
Article Cite This: Biochemistry 2019, 58, 1527−1538 pubs.acs.org/biochemistry Experimental Evaluation of Coevolution in a Self-Assembling Particle Emily C. Hartman,† Marco J. Lobba,† Andrew H. Favor,† Stephanie A. Robinson,† Matthew B. Francis,*,†,‡ and Danielle Tullman-Ercek*,§ † Department of Chemistry, University of California, Berkeley, California 94720-1460, United States ‡ Materials Sciences Division, Lawrence Berkeley National Laboratories, Berkeley, California 94720-1460, United States § Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, Technological Institute E136, Evanston, Illinois 60208-3120, United States *S Supporting Information ABSTRACT: Protein evolution occurs via restricted evolutionary paths that are influenced by both previous and subsequent mutations. This effect, termed epistasis, is critical in population genetics, drug resistance, and immune escape; however, the effect of epistasis on the level of protein fitness is less well characterized. We generated and characterized a 6615-member library of all two-amino acid combinations in a highly mutable loop of a virus-like particle. This particle is a model of protein self- assembly and a promising vehicle for drug delivery and imaging. In addition to characterizing the effect of all double mutants on assembly, thermostability, and acid stability, we observed many instances of epistasis, in which combinations of mutations are either more deleterious or more beneficial than expected. These results were used to generate rules governing the effects of multiple mutations on the self-assembly of the virus-like particle. rotein evolution occurs through complex pathways, often have a significant impact on biotechnology in the coming involving nonintuitive leaps between functional var- decades.23,24 To maximize this potential, it is important to P − iants.1 3 These paths include local minima and maxima, in understand how non-native functions can be hindered by which the effect of a given mutation depends entirely on the unanticipated epistatic effects. -
Biased Signaling of G Protein Coupled Receptors (Gpcrs): Molecular Determinants of GPCR/Transducer Selectivity and Therapeutic Potential
Pharmacology & Therapeutics 200 (2019) 148–178 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Biased signaling of G protein coupled receptors (GPCRs): Molecular determinants of GPCR/transducer selectivity and therapeutic potential Mohammad Seyedabadi a,b, Mohammad Hossein Ghahremani c, Paul R. Albert d,⁎ a Department of Pharmacology, School of Medicine, Bushehr University of Medical Sciences, Iran b Education Development Center, Bushehr University of Medical Sciences, Iran c Department of Toxicology–Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Iran d Ottawa Hospital Research Institute, Neuroscience, University of Ottawa, Canada article info abstract Available online 8 May 2019 G protein coupled receptors (GPCRs) convey signals across membranes via interaction with G proteins. Origi- nally, an individual GPCR was thought to signal through one G protein family, comprising cognate G proteins Keywords: that mediate canonical receptor signaling. However, several deviations from canonical signaling pathways for GPCR GPCRs have been described. It is now clear that GPCRs can engage with multiple G proteins and the line between Gprotein cognate and non-cognate signaling is increasingly blurred. Furthermore, GPCRs couple to non-G protein trans- β-arrestin ducers, including β-arrestins or other scaffold proteins, to initiate additional signaling cascades. Selectivity Biased Signaling Receptor/transducer selectivity is dictated by agonist-induced receptor conformations as well as by collateral fac- Therapeutic Potential tors. In particular, ligands stabilize distinct receptor conformations to preferentially activate certain pathways, designated ‘biased signaling’. In this regard, receptor sequence alignment and mutagenesis have helped to iden- tify key receptor domains for receptor/transducer specificity. -
Cell Penetrating Peptides, Novel Vectors for Gene Therapy
pharmaceutics Review Cell Penetrating Peptides, Novel Vectors for Gene Therapy Rebecca E. Taylor 1 and Maliha Zahid 2,* 1 Mechanical Engineering, Biomedical Engineering and Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA; [email protected] 2 Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA * Correspondence: [email protected]; Tel.: +1-412-692-8893; Fax: +1-412-692-6184 Received: 5 February 2020; Accepted: 1 March 2020; Published: 3 March 2020 Abstract: Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), first identified ~25 years ago, are small, 6–30 amino acid long, synthetic, or naturally occurring peptides, able to carry variety of cargoes across the cellular membranes in an intact, functional form. Since their initial description and characterization, the field of cell penetrating peptides as vectors has exploded. The cargoes they can deliver range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, liposomes, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes. In this review, we will focus briefly on their history, classification system, and mechanism of transduction followed by a summary of the existing literature on use of CPPs as gene delivery vectors either in the form of modified viruses, plasmid DNA, small interfering RNA, oligonucleotides, full-length genes, DNA origami or peptide nucleic acids. Keywords: cell penetrating peptides; protein transduction domains; gene therapy; small interfering RNA 1. Introduction The plasma membrane of a cell is essential to its identity and survival, but at the same time presents a barrier to intracellular delivery of potentially diagnostic or therapeutic cargoes. -
1 Advances in Therapeutic Peptides Targeting G Protein-Coupled
Advances in therapeutic peptides targeting G protein-coupled receptors Anthony P. Davenport1Ϯ Conor C.G. Scully2Ϯ, Chris de Graaf2, Alastair J. H. Brown2 and Janet J. Maguire1 1Experimental Medicine and Immunotherapeutics, Addenbrooke’s Hospital, University of Cambridge, CB2 0QQ, UK 2Sosei Heptares, Granta Park, Cambridge, CB21 6DG, UK. Ϯ Contributed equally Correspondence to Anthony P. Davenport email: [email protected] Abstract Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) — nearly fifty GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first- in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, and both to introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to bias ligands to activate specific downstream signalling pathways in order to optimise efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma-half life have been revolutionary. Here, we discuss the current status of peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties. Introduction G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of drugs in clinical use1. Although most GPCR-targeting therapeutics are small molecules2, the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful. -
Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis
cells Review Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis Hideki Tatsukawa * and Kiyotaka Hitomi Cellular Biochemistry Laboratory, Graduate School of Pharmaceutical Sciences, Nagoya University, Tokai National Higher Education and Research System, Nagoya 464-8601, Aichi, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-52-747-6808 Abstract: Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme catalyzing the crosslink- ing between Gln and Lys residues and involved in various pathophysiological events. Besides this crosslinking activity, TG2 functions as a deamidase, GTPase, isopeptidase, adapter/scaffold, protein disulfide isomerase, and kinase. It also plays a role in the regulation of hypusination and serotonylation. Through these activities, TG2 is involved in cell growth, differentiation, cell death, inflammation, tissue repair, and fibrosis. Depending on the cell type and stimulus, TG2 changes its subcellular localization and biological activity, leading to cell death or survival. In normal unstressed cells, intracellular TG2 exhibits a GTP-bound closed conformation, exerting prosurvival functions. However, upon cell stimulation with Ca2+ or other factors, TG2 adopts a Ca2+-bound open confor- mation, demonstrating a transamidase activity involved in cell death or survival. These functional discrepancies of TG2 open form might be caused by its multifunctional nature, the existence of splicing variants, the cell type and stimulus, and the genetic backgrounds and variations of the mouse models used. TG2 is also involved in the phagocytosis of dead cells by macrophages and in fibrosis during tissue repair. Here, we summarize and discuss the multifunctional and controversial Citation: Tatsukawa, H.; Hitomi, K. roles of TG2, focusing on cell death/survival and fibrosis. -
Dimerization and Domain Swapping in G-Protein-Coupled Receptors: a Computational Study Paul R
Dimerization and Domain Swapping in G-Protein-Coupled Receptors: A Computational Study Paul R. Gouldson, Ph.D., Christopher Higgs, Ph.D., Richard E. Smith, B.Sc., Mark K. Dean, B.Sc., George V. Gkoutos, M.Sc., and Christopher A. Reynolds, Ph.D. In recent years there has been an increasing number of swapped dimers and contact dimers as the models used were reports describing G protein-coupled receptor (GPCR) restricted to the helical part of the receptor. However, it is dimerization and heterodimerization. However, the evidence proposed that for the purpose of signalling, the domain on the nature of the dimers and their role in GPCR swapped dimer and the corresponding contact dimer are activation is inconclusive. Consequently, we present here a equivalent. The evolutionary trace analysis suggests that review of our computational studies on G protein-coupled every GPCR family and subfamily (for which sufficient receptor dimerization and domain swapping. The studies sequence data is available) has the potential to dimerize described include molecular dynamics simulations on through this common functional site on helices 5 and 6. The receptor monomers and dimers in the absence of ligand, in evolutionary trace results on the G protein are briefly the presence of an agonist, and in the presence of an described and these are consistent with GPCR dimerization. antagonist (or more precisely an inverse agonist). Two In addition to the functional site on helices 5 and 6, the distinct sequence-based approaches to studying protein evolutionary trace analysis identified a second functional interfaces are also described, namely correlated mutation site on helices 2 and 3. -
Systematic Characterization of Pan-Cancer Mutation Clusters
Research Collection Journal Article Systematic characterization of pan-cancer mutation clusters Author(s): Buljan, Marija; Blattmann, Peter; Aebersold, Ruedi; Boutros, Michael Publication Date: 2018-03-01 Permanent Link: https://doi.org/10.3929/ethz-b-000256182 Originally published in: Molecular Systems Biology 14(3), http://doi.org/10.15252/msb.20177974 Rights / License: Creative Commons Attribution 4.0 International This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Published online: March 23, 2018 Article Systematic characterization of pan-cancer mutation clusters Marija Buljan1,2 , Peter Blattmann1 , Ruedi Aebersold1,3,* & Michael Boutros2,4,5,** Abstract or single point mutations. Eventually, they all lead to changes in the expression levels or to altered functions of cancer driver genes and Cancer genome sequencing has shown that driver genes can often their products. Analysis of different cancer genomics datasets has be distinguished not only by the elevated mutation frequency but further underscored a high degree of heterogeneity in the mutation also by specific nucleotide positions that accumulate changes at a frequency and spectrum among different cancer types (Garraway & high rate. However, properties associated with a residue’s poten- Lander, 2013; Lawrence et al, 2013) and uncovered a long tail of tial to drive tumorigenesis when mutated have not yet been low-frequency driver mutations (Garraway & Lander, 2013). As a systematically investigated. Here, using a novel methodological corollary, in spite of the great progress in charting mutational events approach, we identify and characterize a compendium of 180 that define different cancer types, the task to distinguish driver and hotspot residues within 160 human proteins which occur with a passenger mutations in an individual genome remains a formidable significant frequency and are likely to have functionally relevant challenge. -
Pepducins As a Potential Treatment Strategy for Asthma and COPD
Thomas Jefferson University Jefferson Digital Commons Center for Translational Medicine Faculty Papers Center for Translational Medicine 6-1-2018 Pepducins as a potential treatment strategy for asthma and COPD. Reynold A. Panettieri Rutgers University - New Brunswick/Piscataway Tonio Pera Thomas Jefferson University Stephen B B. Liggett University of South Florida Jeffrey L. Benovic Thomas Jefferson University Raymond B. Penn Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/transmedfp Part of the Translational Medical Research Commons Let us know how access to this document benefits ouy Recommended Citation Panettieri, Reynold A.; Pera, Tonio; Liggett, Stephen B B.; Benovic, Jeffrey L.; and Penn, Raymond B., "Pepducins as a potential treatment strategy for asthma and COPD." (2018). Center for Translational Medicine Faculty Papers. Paper 57. https://jdc.jefferson.edu/transmedfp/57 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Center for Translational Medicine Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Curr Opin Manuscript Author Pharmacol. -
NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Colorectal
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Colorectal Version 3.2017 — October 10, 2017 NCCN.org Continue Version 3.2017, 10/10/17 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. NCCN Guidelines Version 3.2017 Panel Members NCCN Guidelines Index Table of Contents Genetic/Familial High-Risk Assessment: Colorectal Discussion * Dawn Provenzale, MD, MS/Chair ¤ Þ Michael J. Hall, MD, MS † ∆ Robert J. Mayer, MD † Þ Duke Cancer Institute Fox Chase Cancer Center Dana-Farber/Brigham and Women’s Cancer Center * Samir Gupta, MD/Vice-chair ¤ Amy L. Halverson, MD ¶ UC San Diego Moores Cancer Center Robert H. Lurie Comprehensive Cancer Reid M. Ness, MD, MPH ¤ Center of Northwestern University Vanderbilt-Ingram Cancer Center Dennis J. Ahnen, MD ¤ University of Colorado Cancer Center Stanley R. Hamilton, MD ≠ Scott E. Regenbogen, MD ¶ The University of Texas University of Michigan Travis Bray, PhD ¥ MD Anderson Cancer Center Comprehensive Cancer Center Hereditary Colon Cancer Foundation Heather Hampel, MS, CGC ∆ Niloy Jewel Samadder, MD ¤ Daniel C. Chung, MD ¤ ∆ The Ohio State University Comprehensive Huntsman Cancer Institute at the Massachusetts General Hospital Cancer Center - James Cancer Hospital University of Utah Cancer Center and Solove Research Institute Moshe Shike, MD ¤ Þ Gregory Cooper, MD ¤ Jason B. Klapman, MD ¤ Memorial Sloan Kettering Cancer Center Case Comprehensive Cancer Center/ Moffitt Cancer Center University Hospitals Seidman Cancer Thomas P. Slavin Jr, MD ∆ Center and Cleveland Clinic Taussig David W. Larson, MD, MBA¶ City of Hope Comprehensive Cancer Institute Mayo Clinic Cancer Center Cancer Center Dayna S.