Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

Ji, Quanjiang; Chen, Peter J.; Qin, Guangrong; Deng, Xin; Hao, Ziyang; Wawrzak, Zdzislaw; Yeo, Won -Sik; Quang, Jenny Winjing; Cho, Hoonsik; Luo, Guan -Zheng; Weng, Xiaocheng; You, Qiancheng; Luan, Chi -Hao; Yang, Xiaojing; Bae, Taeok; Yu, Kunqian; Jiang, Hualiang; He, Chuan

doi:10.1038/ncomms11000

Title: Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

Journal Article · Fri Mar 18 00:00:00 EDT 2016 · Nature Communications

DOI:https://doi.org/10.1038/ncomms11000· OSTI ID:1247346

Ji, Quanjiang ^[1]; Chen, Peter J. ^[1]; Qin, Guangrong ^[2]; Deng, Xin ^[1]; Hao, Ziyang ^[1]; Wawrzak, Zdzislaw ^[3]; Yeo, Won -Sik ^[4]; Quang, Jenny Winjing ^[5]; Cho, Hoonsik ^[4]; Luo, Guan -Zheng ^[1]; Weng, Xiaocheng ^[1]; You, Qiancheng ^[1]; Luan, Chi -Hao ^[5]; Yang, Xiaojing ^[6]; Bae, Taeok ^[4]; Yu, Kunqian ^[2]; Jiang, Hualiang ^[2]; He, Chuan ^[1]

The Univ. of Chicago, Chicago, IL (United States)
Chinese Academy of Sciences, Shanghai (China)
Northwestern Univ., Argonne, IL (United States)
Indiana Univ. School of Medicine-Northwest, Gary, IN (United States)
Northwestern Univ., Evanston, IL (United States)
Univ. of Chicago, Chicago, IL (United States)

Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase ‘WalK’ (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino-acid mutation of potential signal-transduction residues resulted in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. Lastly, the molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1247346

Journal Information:: Nature Communications, Vol. 7; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 385 works

Citation information provided by
Web of Science

References (46)

Defects in ex vivo and in vivo growth and sensitivity to osmotic stress of group A Streptococcus caused by interruption of response regulator gene vicR Liu, Mengyao; Hanks, Tracey S.; Zhang, Jinlian Microbiology, Vol. 152, Issue 4 https://doi.org/10.1099/mic.0.28706-0	journal	April 2006
Tactical Approaches to Interconverting GPCR Agonists and Antagonists Dosa, Peter I.; Amin, Elizabeth Ambrose Journal of Medicinal Chemistry, Vol. 59, Issue 3 https://doi.org/10.1021/acs.jmedchem.5b00982	journal	September 2015
Role of insertion elements and yycFG in the development of decreased susceptibility to vancomycin in Staphylococcus aureus Jansen, Andrea; Türck, Michael; Szekat, Christiane International Journal of Medical Microbiology, Vol. 297, Issue 4 https://doi.org/10.1016/j.ijmm.2007.02.002	journal	July 2007
Mechanistic Insights Revealed by the Crystal Structure of a Histidine Kinase with Signal Transducer and Sensor Domains Wang, Chen; Sang, Jiayan; Wang, Jiawei PLoS Biology, Vol. 11, Issue 2 https://doi.org/10.1371/journal.pbio.1001493	journal	February 2013
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
TopHat: discovering splice junctions with RNA-Seq Trapnell, Cole; Pachter, Lior; Salzberg, Steven L. Bioinformatics, Vol. 25, Issue 9 https://doi.org/10.1093/bioinformatics/btp120	journal	March 2009
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Allelic replacement in Staphylococcus aureus with inducible counter-selection Bae, Taeok; Schneewind, Olaf Plasmid, Vol. 55, Issue 1 https://doi.org/10.1016/j.plasmid.2005.05.005	journal	January 2006
Ligand-Binding PAS Domains in a Genomic, Cellular, and Structural Context Henry, Jonathan T.; Crosson, Sean Annual Review of Microbiology, Vol. 65, Issue 1 https://doi.org/10.1146/annurev-micro-121809-151631	journal	October 2011
An essential sensor histidine kinase controlled by transmembrane helix interactions with its auxiliary proteins Szurmant, H.; Bu, L.; Brooks, C. L. Proceedings of the National Academy of Sciences, Vol. 105, Issue 15 https://doi.org/10.1073/pnas.0800247105	journal	April 2008
An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus Chen, Peng R.; Bae, Taeok; Williams, Wade A. Nature Chemical Biology, Vol. 2, Issue 11 https://doi.org/10.1038/nchembio820	journal	September 2006
Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation Trapnell, Cole; Williams, Brian A.; Pertea, Geo Nature Biotechnology, Vol. 28, Issue 5 https://doi.org/10.1038/nbt.1621	journal	May 2010
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays Baell, Jonathan B.; Holloway, Georgina A. Journal of Medicinal Chemistry, Vol. 53, Issue 7 https://doi.org/10.1021/jm901137j	journal	April 2010
High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery Pantoliano, M. W.; Petrella, E. C.; Kwasnoski, J. D. Journal of Biomolecular Screening, Vol. 6, Issue 6 https://doi.org/10.1177/108705710100600609	journal	December 2001
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling Arnold, Konstantin; Bordoli, Lorenza; Kopp, Jürgen Bioinformatics, Vol. 22, Issue 2 https://doi.org/10.1093/bioinformatics/bti770	journal	November 2005
Two-component signal transduction as potential drug targets in pathogenic bacteria Gotoh, Yasuhiro; Eguchi, Yoko; Watanabe, Takafumi Current Opinion in Microbiology, Vol. 13, Issue 2 https://doi.org/10.1016/j.mib.2010.01.008	journal	April 2010
Quorum sensing by peptide pheromones and two‐component signal‐transduction systems in Gram‐positive bacteria Kleerebezem, Michiel; Quadri, Luis E. N.; Kuipers, Oscar P. Molecular Microbiology, Vol. 24, Issue 5 https://doi.org/10.1046/j.1365-2958.1997.4251782.x	journal	June 1997
The WalKR System Controls Major Staphylococcal Virulence Genes and Is Involved in Triggering the Host Inflammatory Response Delauné, Aurélia; Dubrac, Sarah; Blanchet, Charlène Infection and Immunity, Vol. 80, Issue 10 https://doi.org/10.1128/iai.00195-12	journal	July 2012
Autoinduction and signal transduction in the regulation of staphylococcal virulence: Regulation of staphylococcus virulence Novick, Richard P. Molecular Microbiology, Vol. 48, Issue 6 https://doi.org/10.1046/j.1365-2958.2003.03526.x	journal	May 2003
Molecular Architecture of the Regulatory Locus sae of Staphylococcus aureus and Its Impact on Expression of Virulence Factors Steinhuber, Andrea; Goerke, Christiane; Bayer, Manfred G. Journal of Bacteriology, Vol. 185, Issue 21 https://doi.org/10.1128/JB.185.21.6278-6286.2003	journal	November 2003
Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA Sun, F.; Liang, H.; Kong, X. Proceedings of the National Academy of Sciences, Vol. 109, Issue 23 https://doi.org/10.1073/pnas.1200603109	journal	May 2012
Toward the estimation of the absolute quality of individual protein structure models Benkert, Pascal; Biasini, Marco; Schwede, Torsten Bioinformatics, Vol. 27, Issue 3 https://doi.org/10.1093/bioinformatics/btq662	journal	December 2010
A matter of life and death: cell wall homeostasis and the WalKR (YycGF) essential signal transduction pathway Dubrac, Sarah; Bisicchia, Paola; Devine, Kevin M. Molecular Microbiology, Vol. 70, Issue 6 https://doi.org/10.1111/j.1365-2958.2008.06483.x	journal	December 2008
Staphylococcus aureus Infections Lowy, Franklin D. New England Journal of Medicine, Vol. 339, Issue 8 https://doi.org/10.1056/NEJM199808203390806	journal	August 1998
Capsular antibodies induce type-specific phagocytosis of capsulated Staphylococcus aureus by human polymorphonuclear leukocytes. Karakawa, W. W.; Sutton, A.; Schneerson, R. Infection and Immunity, Vol. 56, Issue 5 https://doi.org/10.1128/iai.56.5.1090-1095.1988	journal	January 1988
The MicAB Two-Component Signaling System Is Involved in Virulence of Streptococcus pneumoniae Kadioglu, Aras; Echenique, Josè; Manco, Sonia Infection and Immunity, Vol. 71, Issue 11 https://doi.org/10.1128/IAI.71.11.6676-6679.2003	journal	November 2003
A Ligand-Induced Switch in the Periplasmic Domain of Sensor Histidine Kinase CitA Sevvana, Madhumati; Vijayan, Vinesh; Zweckstetter, Markus Journal of Molecular Biology, Vol. 377, Issue 2 https://doi.org/10.1016/j.jmb.2008.01.024	journal	March 2008
Defective cell wall synthesis in Streptococcus pneumoniae R6 depleted for the essential PcsB putative murein hydrolase or the VicR (YycF) response regulator: Defective cell wall synthesis in pcsB mutants Ng, Wai-Leung; Kazmierczak, Krystyna M.; Winkler, Malcolm E. Molecular Microbiology, Vol. 53, Issue 4 https://doi.org/10.1111/j.1365-2958.2004.04196.x	journal	July 2004
Staphylococcus aureus : A Well–Armed Pathogen Archer, Gordon L. Clinical Infectious Diseases, Vol. 26, Issue 5 https://doi.org/10.1086/520289	journal	May 1998
Invasive Methicillin-Resistant <EMPH TYPE="ITAL">Staphylococcus aureus</EMPH> Infections in the United States Klevens, R. Monina JAMA, Vol. 298, Issue 15 https://doi.org/10.1001/jama.298.15.1763	journal	October 2007
Global Regulation of Gene Expression by ArlRS, a Two-Component Signal Transduction Regulatory System of Staphylococcus aureus Liang, Xudong; Zheng, Li; Landwehr, Christina Journal of Bacteriology, Vol. 187, Issue 15 https://doi.org/10.1128/JB.187.15.5486-5492.2005	journal	August 2005
YycH and YycI Interact To Regulate the Essential YycFG Two-Component System in Bacillus subtilis Szurmant, Hendrik; Mohan, Michael A.; Imus, P. Michael Journal of Bacteriology, Vol. 189, Issue 8 https://doi.org/10.1128/JB.01936-06	journal	February 2007
Antimicrobial resistance in gram-positive bacteria Rice, Louis B. American Journal of Infection Control, Vol. 34, Issue 5 https://doi.org/10.1016/j.ajic.2006.05.220	journal	June 2006
Cloning and sequencing of sarA of Staphylococcus aureus, a gene required for the expression of agr. Cheung, A. L.; Projan, S. J. Journal of Bacteriology, Vol. 176, Issue 13 https://doi.org/10.1128/jb.176.13.4168-4172.1994	journal	January 1994
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Waldiomycin, a novel WalK-histidine kinase inhibitor from Streptomyces sp. MK844-mF10 Igarashi, Masayuki; Watanabe, Takafumi; Hashida, Tomohiro The Journal of Antibiotics, Vol. 66, Issue 8 https://doi.org/10.1038/ja.2013.33	journal	May 2013
Role in Cell Permeability of an Essential Two-Component System in Staphylococcus aureus Martin, Patrick K.; Li, Tong; Sun, DongXu Journal of Bacteriology, Vol. 181, Issue 12 https://doi.org/10.1128/JB.181.12.3666-3673.1999	journal	June 1999
A New Vector for High-Throughput, Ligation-Independent Cloning Encoding a Tobacco Etch Virus Protease Cleavage Site Stols, Lucy; Gu, Minyi; Dieckman, Lynda Protein Expression and Purification, Vol. 25, Issue 1 https://doi.org/10.1006/prep.2001.1603	journal	June 2002
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
New Insights into the WalK/WalR (YycG/YycF) Essential Signal Transduction Pathway Reveal a Major Role in Controlling Cell Wall Metabolism and Biofilm Formation in Staphylococcus aureus Dubrac, S.; Boneca, I. G.; Poupel, O. Journal of Bacteriology, Vol. 189, Issue 22 https://doi.org/10.1128/JB.00645-07	journal	September 2007
Structure and Signaling Mechanism of Per-ARNT-Sim Domains Möglich, Andreas; Ayers, Rebecca A.; Moffat, Keith Structure, Vol. 17, Issue 10 https://doi.org/10.1016/j.str.2009.08.011	journal	October 2009
Crystal Structures of C ₄ -Dicarboxylate Ligand Complexes with Sensor Domains of Histidine Kinases DcuS and DctB Cheung, Jonah; Hendrickson, Wayne A. Journal of Biological Chemistry, Vol. 283, Issue 44 https://doi.org/10.1074/jbc.m805253200	journal	August 2008
Mutations and off-pathway aggregation of proteins Wetzel, Ronald Trends in Biotechnology, Vol. 12, Issue 5 https://doi.org/10.1016/0167-7799(94)90082-5	journal	May 1994
Sensor complexes regulating two-component signal transduction Szurmant, Hendrik; White, Robert A.; Hoch, James A. Current Opinion in Structural Biology, Vol. 17, Issue 6 https://doi.org/10.1016/j.sbi.2007.08.019	journal	December 2007
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Staphylococcus aureus CymR Is a New Thiol-based Oxidation-sensing Regulator of Stress Resistance and Oxidative Response Ji, Quanjiang; Zhang, Liang; Sun, Fei Journal of Biological Chemistry, Vol. 287, Issue 25 https://doi.org/10.1074/jbc.m112.359737	journal	May 2012

Cited By (4)

Streptomyces as a Prominent Resource of Future Anti-MRSA Drugs Kemung, Hefa Mangzira; Tan, Loh Teng-Hern; Khan, Tahir Mehmood Frontiers in Microbiology, Vol. 9 https://doi.org/10.3389/fmicb.2018.02221	journal	September 2018
Staphylococcus aureus virulence attenuation and immune clearance mediated by a phage lysin‐derived protein Yang, Hang; Xu, Jingjing; Li, Wuyou The EMBO Journal, Vol. 37, Issue 17 https://doi.org/10.15252/embj.201798045	journal	July 2018
The Complex Relationship between Virulence and Antibiotic Resistance Schroeder, Meredith; Brooks, Benjamin; Brooks, Amanda Genes, Vol. 8, Issue 1 https://doi.org/10.3390/genes8010039	journal	January 2017
Correspondence: Spontaneous secondary mutations confound analysis of the essential two component system WalKR in Staphylococcus aureus Monk, Ian R.; Howden, Benjamin P.; Seemann, Torsten Nature Communications https://doi.org/10.1101/058842	journal	July 2016

Similar Records

The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines

Journal Article · Thu Apr 30 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1247346

Tiwari, Nitija; López-Redondo, Marisa; Miguel-Romero, Laura; +15 more

Persister formation in Staphylococcus aureus is associated with ATP depletion

Journal Article · Mon Apr 18 00:00:00 EDT 2016 · Nature Microbiology · OSTI ID:1247346

Conlon, Brian P.; Rowe, Sarah E.; Gandt, Autumn Brown; +7 more

Transduction of methicillin resistance in Staphylococcus aureus

Journal Article · Mon Jan 01 00:00:00 EST 1973 · Pathol. Microbiol., v. 39, pp. 4-5 · OSTI ID:1247346

Wuest, J; Kayser, F H

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Title: Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus

Citation Formats

References (46)

Cited By (4)

Similar Records

Related Subjects