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Title: Recognition of the bacterial alarmone ZMP through long-distance association of two RNA subdomains

Abstract

The bacterial alarmone 5-aminoimidazole-4-carboxamide riboside 5'-triphosphate (AICAR triphosphate or ZTP), derived from the monophosphorylated purine precursor ZMP, accumulates during folate starvation. ZTP regulates genes involved in purine and folate metabolism through a cognate riboswitch. The linker connecting this riboswitch's two subdomains varies in length by over 100 nucleotides. In this paper, we report the cocrystal structure of the Fusobacterium ulcerans riboswitch bound to ZMP, which spans the two subdomains whose interface also comprises a pseudoknot and ribose zipper. The riboswitch recognizes the carboxamide oxygen of ZMP through an unprecedented inner-sphere coordination with a Mg 2+ ion. We show that the affinity of the riboswitch for ZMP is modulated by the linker length. Notably, ZMP can simultaneously bind to the two subdomains even when they are synthesized as separate RNAs. Finally, the ZTP riboswitch demonstrates how specific small-molecule binding can drive association of distant noncoding-RNA domains to regulate gene expression.

Authors:
 [1];  [1]
  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Heart, Lung, and Blood Inst. Biochemistry and Biophysics Center
Publication Date:
Research Org.:
National Inst. of Health (NIH), Bethesda, MD (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1222002
Resource Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 9; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; RNA; SAXS; X-ray crystallography

Citation Formats

Jones, Christopher P., and Ferré-D'Amaré, Adrian R. Recognition of the bacterial alarmone ZMP through long-distance association of two RNA subdomains. United States: N. p., 2015. Web. doi:10.1038/nsmb.3073.
Jones, Christopher P., & Ferré-D'Amaré, Adrian R. Recognition of the bacterial alarmone ZMP through long-distance association of two RNA subdomains. United States. doi:10.1038/nsmb.3073.
Jones, Christopher P., and Ferré-D'Amaré, Adrian R. Mon . "Recognition of the bacterial alarmone ZMP through long-distance association of two RNA subdomains". United States. doi:10.1038/nsmb.3073. https://www.osti.gov/servlets/purl/1222002.
@article{osti_1222002,
title = {Recognition of the bacterial alarmone ZMP through long-distance association of two RNA subdomains},
author = {Jones, Christopher P. and Ferré-D'Amaré, Adrian R.},
abstractNote = {The bacterial alarmone 5-aminoimidazole-4-carboxamide riboside 5'-triphosphate (AICAR triphosphate or ZTP), derived from the monophosphorylated purine precursor ZMP, accumulates during folate starvation. ZTP regulates genes involved in purine and folate metabolism through a cognate riboswitch. The linker connecting this riboswitch's two subdomains varies in length by over 100 nucleotides. In this paper, we report the cocrystal structure of the Fusobacterium ulcerans riboswitch bound to ZMP, which spans the two subdomains whose interface also comprises a pseudoknot and ribose zipper. The riboswitch recognizes the carboxamide oxygen of ZMP through an unprecedented inner-sphere coordination with a Mg2+ ion. We show that the affinity of the riboswitch for ZMP is modulated by the linker length. Notably, ZMP can simultaneously bind to the two subdomains even when they are synthesized as separate RNAs. Finally, the ZTP riboswitch demonstrates how specific small-molecule binding can drive association of distant noncoding-RNA domains to regulate gene expression.},
doi = {10.1038/nsmb.3073},
journal = {Nature Structural & Molecular Biology},
number = 9,
volume = 22,
place = {United States},
year = {2015},
month = {8}
}

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Works referenced in this record:

Nucleic Acids, Purines, Pyrimidines (Nucleotide Synthesis)
journal, June 1959


An Ancient Riboswitch Class in Bacteria Regulates Purine Biosynthesis and One-Carbon Metabolism
journal, January 2015


Themes and variations in riboswitch structure and function
journal, October 2014

  • Peselis, Alla; Serganov, Alexander
  • Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Vol. 1839, Issue 10
  • DOI: 10.1016/j.bbagrm.2014.02.012

RNA quaternary structure and global symmetry
journal, April 2015

  • Jones, Christopher P.; Ferré-D’Amaré, Adrian R.
  • Trends in Biochemical Sciences, Vol. 40, Issue 4
  • DOI: 10.1016/j.tibs.2015.02.004

Structure and mechanism of purine-binding riboswitches
journal, July 2012


Comparative genomics reveals 104 candidate structured RNAs from bacteria, archaea, and their metagenomes
journal, January 2010


A new principle of RNA folding based on pseudoknotting
journal, January 1985

  • Pleij, Comelis W. A.; Rietveld, Krijn; Bosch, Leendert
  • Nucleic Acids Research, Vol. 13, Issue 5
  • DOI: 10.1093/nar/13.5.1717

Structure and mechanism of the T-box riboswitches: Structure and mechanism of the T-box riboswitches
journal, May 2015

  • Zhang, Jinwei; Ferré-D'Amaré, Adrian R.
  • Wiley Interdisciplinary Reviews: RNA, Vol. 6, Issue 4
  • DOI: 10.1002/wrna.1285

DNA and RNA Synthesis:  Antifolates
journal, February 2005

  • Kompis, Ivan M.; Islam, Khalid; Then, Rudolf L.
  • Chemical Reviews, Vol. 105, Issue 2
  • DOI: 10.1021/cr0301144

A General Strategy to Solve the Phase Problem in RNA Crystallography
journal, July 2007


Global RNA Fold and Molecular Recognition for a pfl Riboswitch Bound to ZMP, a Master Regulator of One-Carbon Metabolism
journal, August 2015

  • Ren, Aiming; Rajashankar, Kanagalaghatta R.; Patel, Dinshaw J.
  • Structure, Vol. 23, Issue 8
  • DOI: 10.1016/j.str.2015.05.016

Metal Ion-Mediated Nucleobase Recognition by the ZTP Riboswitch
journal, July 2015

  • Trausch, Jeremiah J.; Marcano-Velázquez, Joan G.; Matyjasik, Michal M.
  • Chemistry & Biology, Vol. 22, Issue 7
  • DOI: 10.1016/j.chembiol.2015.06.007

RNA tertiary interactions in the large ribosomal subunit: The A-minor motif
journal, April 2001

  • Nissen, P.; Ippolito, J. A.; Ban, N.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 9
  • DOI: 10.1073/pnas.081082398

RNA FOLDS: Insights from Recent Crystal Structures
journal, June 1999

  • Ferré-D'Amaré, Adrian R.; Doudna, Jennifer A.
  • Annual Review of Biophysics and Biomolecular Structure, Vol. 28, Issue 1
  • DOI: 10.1146/annurev.biophys.28.1.57

X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution
journal, August 2007

  • Putnam, Christopher D.; Hammel, Michal; Hura, Greg L.
  • Quarterly Reviews of Biophysics, Vol. 40, Issue 3
  • DOI: 10.1017/S0033583507004635

Improving small-angle X-ray scattering data for structural analyses of the RNA world
journal, January 2010


Global analysis of riboswitches by small-angle X-ray scattering and calorimetry
journal, October 2014

  • Zhang, Jinwei; Jones, Christopher P.; Ferré-D'Amaré, Adrian R.
  • Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Vol. 1839, Issue 10
  • DOI: 10.1016/j.bbagrm.2014.04.014

Ribozymes and Riboswitches: Modulation of RNA Function by Small Molecules
journal, November 2010

  • Zhang, Jinwei; Lau, Matthew W.; Ferré-D’Amaré, Adrian R.
  • Biochemistry, Vol. 49, Issue 43
  • DOI: 10.1021/bi1012645

Molecular recognition and function of riboswitches
journal, June 2012

  • Serganov, Alexander; Patel, Dinshaw J.
  • Current Opinion in Structural Biology, Vol. 22, Issue 3
  • DOI: 10.1016/j.sbi.2012.04.005

Structure of a natural guanine-responsive riboswitch complexed with the metabolite hypoxanthine
journal, November 2004

  • Batey, Robert T.; Gilbert, Sunny D.; Montange, Rebecca K.
  • Nature, Vol. 432, Issue 7015
  • DOI: 10.1038/nature03037

Structural Basis for Discriminative Regulation of Gene Expression by Adenine- and Guanine-Sensing mRNAs
journal, December 2004


Crystal structure of a c‐di‐ AMP riboswitch reveals an internally pseudo‐dimeric RNA
journal, September 2014

  • Jones, Christopher P.; Ferré‐D'Amaré, Adrian R.
  • The EMBO Journal, Vol. 33, Issue 22
  • DOI: 10.15252/embj.201489209

c-di-AMP binds the ydaO riboswitch in two pseudo-symmetry–related pockets
journal, August 2014


Structural insights into recognition of c-di-AMP by the ydaO riboswitch
journal, August 2014


Structural Basis for Molecular Discrimination by a 3′,3′-cGAMP Sensing Riboswitch
journal, April 2015


Recognition of the bacterial second messenger cyclic diguanylate by its cognate riboswitch
journal, November 2009

  • Kulshina, Nadia; Baird, Nathan J.; Ferré-D'Amaré, Adrian R.
  • Nature Structural & Molecular Biology, Vol. 16, Issue 12
  • DOI: 10.1038/nsmb.1701

Structural basis of ligand binding by a c-di-GMP riboswitch
journal, November 2009

  • Smith, Kathryn D.; Lipchock, Sarah V.; Ames, Tyler D.
  • Nature Structural & Molecular Biology, Vol. 16, Issue 12
  • DOI: 10.1038/nsmb.1702

Structural basis of differential ligand recognition by two classes of bis-(3'-5')-cyclic dimeric guanosine monophosphate-binding riboswitches
journal, April 2011

  • Smith, K. D.; Shanahan, C. A.; Moore, E. L.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 19
  • DOI: 10.1073/pnas.1018857108

Structure of the S-adenosylmethionine riboswitch regulatory mRNA element
journal, June 2006


Structure of the SAM-II riboswitch bound to S-adenosylmethionine
journal, January 2008

  • Gilbert, Sunny D.; Rambo, Robert P.; Van Tyne, Daria
  • Nature Structural & Molecular Biology, Vol. 15, Issue 2
  • DOI: 10.1038/nsmb.1371

Crystal structures of the SAM-III/SMK riboswitch reveal the SAM-dependent translation inhibition mechanism
journal, September 2008

  • Lu, Changrui; Smith, Angela M.; Fuchs, Ryan T.
  • Nature Structural & Molecular Biology, Vol. 15, Issue 10
  • DOI: 10.1038/nsmb.1494

B12 cofactors directly stabilize an mRNA regulatory switch
journal, October 2012

  • Johnson Jr, James E.; Reyes, Francis E.; Polaski, Jacob T.
  • Nature, Vol. 492, Issue 7427
  • DOI: 10.1038/nature11607

Structural insights into ligand binding and gene expression control by an adenosylcobalamin riboswitch
journal, October 2012

  • Peselis, Alla; Serganov, Alexander
  • Nature Structural & Molecular Biology, Vol. 19, Issue 11
  • DOI: 10.1038/nsmb.2405

Coenzyme recognition and gene regulation by a flavin mononucleotide riboswitch
journal, January 2009

  • Serganov, Alexander; Huang, Lili; Patel, Dinshaw J.
  • Nature, Vol. 458, Issue 7235
  • DOI: 10.1038/nature07642

The Structure of a Tetrahydrofolate-Sensing Riboswitch Reveals Two Ligand Binding Sites in a Single Aptamer
journal, October 2011


Long-range pseudoknot interactions dictate the regulatory response in the tetrahydrofolate riboswitch
journal, August 2011

  • Huang, L.; Ishibe-Murakami, S.; Patel, D. J.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 36
  • DOI: 10.1073/pnas.1111701108

Cocrystal structure of a class I preQ1 riboswitch reveals a pseudoknot recognizing an essential hypermodified nucleobase
journal, February 2009

  • Klein, Daniel J.; Edwards, Thomas E.; Ferré-D'Amaré, Adrian R.
  • Nature Structural & Molecular Biology, Vol. 16, Issue 3
  • DOI: 10.1038/nsmb.1563

Structure of a class II preQ1 riboswitch reveals ligand recognition by a new fold
journal, April 2013

  • Liberman, Joseph A.; Salim, Mohammad; Krucinska, Jolanta
  • Nature Chemical Biology, Vol. 9, Issue 6
  • DOI: 10.1038/nchembio.1231

Structural Insights into Riboswitch Control of the Biosynthesis of Queuosine, a Modified Nucleotide Found in the Anticodon of tRNA
journal, August 2010


The Structural Basis for Recognition of the PreQ 0 Metabolite by an Unusually Small Riboswitch Aptamer Domain
journal, March 2009

  • Spitale, Robert C.; Torelli, Andrew T.; Krucinska, Jolanta
  • Journal of Biological Chemistry, Vol. 284, Issue 17
  • DOI: 10.1074/jbc.C900024200

Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch
journal, May 2006

  • Serganov, Alexander; Polonskaia, Anna; Phan, Anh Tuân
  • Nature, Vol. 441, Issue 7097
  • DOI: 10.1038/nature04740

Crystal Structures of the Thi-Box Riboswitch Bound to Thiamine Pyrophosphate Analogs Reveal Adaptive RNA-Small Molecule Recognition
journal, September 2006


Structural Basis of Cooperative Ligand Binding by the Glycine Riboswitch
journal, March 2011


Structural Insights into Ligand Recognition by a Sensing Domain of the Cooperative Glycine Riboswitch
journal, December 2010


Structural insights into amino acid binding and gene control by a lysine riboswitch
journal, September 2008

  • Serganov, Alexander; Huang, Lili; Patel, Dinshaw J.
  • Nature, Vol. 455, Issue 7217
  • DOI: 10.1038/nature07326

Crystal Structure of the Lysine Riboswitch Regulatory mRNA Element
journal, July 2008

  • Garst, Andrew D.; Héroux, Annie; Rambo, Robert P.
  • Journal of Biological Chemistry, Vol. 283, Issue 33
  • DOI: 10.1074/jbc.C800120200

Sequestration of a two-component response regulator by a riboswitch-regulated noncoding RNA
journal, August 2014


A riboswitch-containing sRNA controls gene expression by sequestration of a response regulator
journal, August 2014


A trans-Acting Riboswitch Controls Expression of the Virulence Regulator PrfA in Listeria monocytogenes
journal, November 2009


Structural Basis for Specific, High-Affinity Tetracycline Binding by an In Vitro Evolved Aptamer and Artificial Riboswitch
journal, October 2008


Substructure solution with SHELXD
journal, September 2002

  • Schneider, Thomas R.; Sheldrick, George M.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 10
  • DOI: 10.1107/S0907444902011678

Substructure search procedures for macromolecular structures
journal, October 2003

  • Grosse-Kunstleve, R. W.; Adams, P. D.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 59, Issue 11
  • DOI: 10.1107/S0907444903018043

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Maximum-likelihood density modification
journal, August 2000

  • Terwilliger, Thomas C.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 56, Issue 8
  • DOI: 10.1107/S0907444900005072

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

RCrane : semi-automated RNA model building
journal, July 2012

  • Keating, Kevin S.; Pyle, Anna Marie
  • Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 8
  • DOI: 10.1107/S0907444912018549

High-Precision Isothermal Titration Calorimetry with Automated Peak-Shape Analysis
journal, June 2012

  • Keller, Sandro; Vargas, Carolyn; Zhao, Huaying
  • Analytical Chemistry, Vol. 84, Issue 11
  • DOI: 10.1021/ac3007522

In vitro approaches to analysis of transcription termination
journal, January 2009


    Works referencing / citing this record:

    Co-crystal structure of the Fusobacterium ulcerans ZTP riboswitch using an X-ray free-electron laser
    journal, June 2019

    • Jones, Christopher; Tran, Brandon; Conrad, Chelsie
    • Acta Crystallographica Section F Structural Biology Communications, Vol. 75, Issue 7
    • DOI: 10.1107/s2053230x19008549