Critical Assessment of the Important Residues Involved in the Dimerization and Catalysis of MERS Coronavirus Main Protease
Identifieur interne : 001016 ( Pmc/Curation ); précédent : 001015; suivant : 001017Critical Assessment of the Important Residues Involved in the Dimerization and Catalysis of MERS Coronavirus Main Protease
Auteurs : Bo-Lin Ho ; Shu-Chun Cheng ; Lin Shi ; Ting-Yun Wang ; Kuan-I Ho ; Chi-Yuan ChouSource :
- PLoS ONE [ 1932-6203 ] ; 2015.
Abstract
A highly pathogenic human coronavirus (CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged in Jeddah and other places in Saudi Arabia, and has quickly spread to European and Asian countries since September 2012. Up to the 1st October 2015 it has infected at least 1593 people with a global fatality rate of about 35%. Studies to understand the virus are necessary and urgent. In the present study, MERS-CoV main protease (Mpro) is expressed; the dimerization of the protein and its relationship to catalysis are investigated.
The crystal structure of MERS-CoV Mpro indicates that it shares a similar scaffold to that of other coronaviral Mpro and consists of chymotrypsin-like domains I and II and a helical domain III of five helices. Analytical ultracentrifugation analysis demonstrated that MERS-CoV Mpro undergoes a monomer to dimer conversion in the presence of a peptide substrate. Glu169 is a key residue and plays a dual role in both dimerization and catalysis. The mutagenesis of other residues found on the dimerization interface indicate that dimerization of MERS-CoV Mpro is required for its catalytic activity. One mutation, M298R, resulted in a stable dimer with a higher level of proteolytic activity than the wild-type enzyme.
MERS-CoV Mpro shows substrate-induced dimerization and potent proteolytic activity. A critical assessment of the residues important to these processes provides insights into the correlation between dimerization and catalysis within the coronaviral Mpro family.
Url:
DOI: 10.1371/journal.pone.0144865
PubMed: 26658006
PubMed Central: 4682845
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Critical Assessment of the Important Residues Involved in the Dimerization and Catalysis of MERS Coronavirus Main Protease</title><author><name sortKey="Ho, Bo Lin" sort="Ho, Bo Lin" uniqKey="Ho B" first="Bo-Lin" last="Ho">Bo-Lin Ho</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Cheng, Shu Chun" sort="Cheng, Shu Chun" uniqKey="Cheng S" first="Shu-Chun" last="Cheng">Shu-Chun Cheng</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Shi, Lin" sort="Shi, Lin" uniqKey="Shi L" first="Lin" last="Shi">Lin Shi</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Wang, Ting Yun" sort="Wang, Ting Yun" uniqKey="Wang T" first="Ting-Yun" last="Wang">Ting-Yun Wang</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Ho, Kuan I" sort="Ho, Kuan I" uniqKey="Ho K" first="Kuan-I" last="Ho">Kuan-I Ho</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Chou, Chi Yuan" sort="Chou, Chi Yuan" uniqKey="Chou C" first="Chi-Yuan" last="Chou">Chi-Yuan Chou</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26658006</idno><idno type="pmc">4682845</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682845</idno><idno type="RBID">PMC:4682845</idno><idno type="doi">10.1371/journal.pone.0144865</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">001016</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001016</idno><idno type="wicri:Area/Pmc/Curation">001016</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001016</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Critical Assessment of the Important Residues Involved in the Dimerization and Catalysis of MERS Coronavirus Main Protease</title><author><name sortKey="Ho, Bo Lin" sort="Ho, Bo Lin" uniqKey="Ho B" first="Bo-Lin" last="Ho">Bo-Lin Ho</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Cheng, Shu Chun" sort="Cheng, Shu Chun" uniqKey="Cheng S" first="Shu-Chun" last="Cheng">Shu-Chun Cheng</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Shi, Lin" sort="Shi, Lin" uniqKey="Shi L" first="Lin" last="Shi">Lin Shi</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Wang, Ting Yun" sort="Wang, Ting Yun" uniqKey="Wang T" first="Ting-Yun" last="Wang">Ting-Yun Wang</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Ho, Kuan I" sort="Ho, Kuan I" uniqKey="Ho K" first="Kuan-I" last="Ho">Kuan-I Ho</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Chou, Chi Yuan" sort="Chou, Chi Yuan" uniqKey="Chou C" first="Chi-Yuan" last="Chou">Chi-Yuan Chou</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>A highly pathogenic human coronavirus (CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged in Jeddah and other places in Saudi Arabia, and has quickly spread to European and Asian countries since September 2012. Up to the 1<sup>st</sup> October 2015 it has infected at least 1593 people with a global fatality rate of about 35%. Studies to understand the virus are necessary and urgent. In the present study, MERS-CoV main protease (M<sup>pro</sup>) is expressed; the dimerization of the protein and its relationship to catalysis are investigated.</p></sec><sec id="sec002"><title>Methods and Results</title><p>The crystal structure of MERS-CoV M<sup>pro</sup> indicates that it shares a similar scaffold to that of other coronaviral M<sup>pro</sup> and consists of chymotrypsin-like domains I and II and a helical domain III of five helices. Analytical ultracentrifugation analysis demonstrated that MERS-CoV M<sup>pro</sup> undergoes a monomer to dimer conversion in the presence of a peptide substrate. Glu169 is a key residue and plays a dual role in both dimerization and catalysis. The mutagenesis of other residues found on the dimerization interface indicate that dimerization of MERS-CoV M<sup>pro</sup> is required for its catalytic activity. One mutation, M298R, resulted in a stable dimer with a higher level of proteolytic activity than the wild-type enzyme.</p></sec><sec id="sec003"><title>Conclusions</title><p>MERS-CoV M<sup>pro</sup> shows substrate-induced dimerization and potent proteolytic activity. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26658006</article-id><article-id pub-id-type="pmc">4682845</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0144865</article-id><article-id pub-id-type="publisher-id">PONE-D-15-31990</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Critical Assessment of the Important Residues Involved in the Dimerization and Catalysis of MERS Coronavirus Main Protease</article-title><alt-title alt-title-type="running-head">Dimerization and Catalysis of MERS-CoV Main Protease</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ho</surname><given-names>Bo-Lin</given-names></name><xref ref-type="aff" rid="aff001"></xref></contrib><contrib contrib-type="author"><name><surname>Cheng</surname><given-names>Shu-Chun</given-names></name><xref ref-type="aff" rid="aff001"></xref></contrib><contrib contrib-type="author"><name><surname>Shi</surname><given-names>Lin</given-names></name><xref ref-type="aff" rid="aff001"></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Ting-Yun</given-names></name><xref ref-type="aff" rid="aff001"></xref></contrib><contrib contrib-type="author"><name><surname>Ho</surname><given-names>Kuan-I</given-names></name><xref ref-type="aff" rid="aff001"></xref></contrib><contrib contrib-type="author"><name><surname>Chou</surname><given-names>Chi-Yuan</given-names></name><xref rid="cor001" ref-type="corresp">*</xref><xref ref-type="aff" rid="aff001"></xref></contrib></contrib-group><aff id="aff001"><addr-line>Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Korolev</surname><given-names>Sergey</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Saint Louis University, UNITED STATES</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: CYC. Performed the experiments: BLH SCC LS TYW KIH. Analyzed the data: BLH TYW. Contributed reagents/materials/analysis tools: SCC. Wrote the paper: CYC.</p></fn><corresp id="cor001">* E-mail: <email>cychou@ym.edu.tw</email></corresp></author-notes><pub-date pub-type="epub"><day>14</day><month>12</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>10</volume><issue>12</issue><elocation-id>e0144865</elocation-id><history><date date-type="received"><day>31</day><month>7</month><year>2015</year></date><date date-type="accepted"><day>23</day><month>11</month><year>2015</year></date></history><permissions><copyright-statement>© 2015 Ho et al</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Ho et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="pone.0144865.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>A highly pathogenic human coronavirus (CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged in Jeddah and other places in Saudi Arabia, and has quickly spread to European and Asian countries since September 2012. Up to the 1<sup>st</sup> October 2015 it has infected at least 1593 people with a global fatality rate of about 35%. Studies to understand the virus are necessary and urgent. In the present study, MERS-CoV main protease (M<sup>pro</sup>) is expressed; the dimerization of the protein and its relationship to catalysis are investigated.</p></sec><sec id="sec002"><title>Methods and Results</title><p>The crystal structure of MERS-CoV M<sup>pro</sup> indicates that it shares a similar scaffold to that of other coronaviral M<sup>pro</sup> and consists of chymotrypsin-like domains I and II and a helical domain III of five helices. Analytical ultracentrifugation analysis demonstrated that MERS-CoV M<sup>pro</sup> undergoes a monomer to dimer conversion in the presence of a peptide substrate. Glu169 is a key residue and plays a dual role in both dimerization and catalysis. The mutagenesis of other residues found on the dimerization interface indicate that dimerization of MERS-CoV M<sup>pro</sup> is required for its catalytic activity. One mutation, M298R, resulted in a stable dimer with a higher level of proteolytic activity than the wild-type enzyme.</p></sec><sec id="sec003"><title>Conclusions</title><p>MERS-CoV M<sup>pro</sup> shows substrate-induced dimerization and potent proteolytic activity. A critical assessment of the residues important to these processes provides insights into the correlation between dimerization and catalysis within the coronaviral M<sup>pro</sup> family.</p></sec></abstract><funding-group><funding-statement>This research was supported by grants from Ministry of Science and Technology, Taiwan (103-2320-B-010-025 and 104-2320-B-010-034) to CYC. We also thank National Yang-Ming University for its financial support (Aim for Top University Plan from Ministry of Education). Portions of this research were carried out at the National Synchrotron Radiation Research Center, a national user facility supported by the Ministry of Science and Technology of Taiwan, ROC. The Synchrotron Radiation Protein Crystallography Facility is supported by the National Core Facility Program for Biotechnology.</funding-statement></funding-group><counts><fig-count count="6"></fig-count><table-count count="2"></table-count><page-count count="18"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper and its Supporting Information files.</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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