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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">GSK3β Phosphorylates Newly Identified Site in the Pro-Ala Rich Region of Cardiac Myosin Binding Protein C and Alters Cross-Bridge Cycling Kinetics in Human</title><author><name sortKey="Kuster, Diederik W D" sort="Kuster, Diederik W D" uniqKey="Kuster D" first="Diederik W. D." last="Kuster">Diederik W. D. Kuster</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Sequeira, Vasco" sort="Sequeira, Vasco" uniqKey="Sequeira V" first="Vasco" last="Sequeira">Vasco Sequeira</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Najafi, Aref" sort="Najafi, Aref" uniqKey="Najafi A" first="Aref" last="Najafi">Aref Najafi</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Boontje, Nicky M" sort="Boontje, Nicky M" uniqKey="Boontje N" first="Nicky M." last="Boontje">Nicky M. Boontje</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Wijnker, Paul J M" sort="Wijnker, Paul J M" uniqKey="Wijnker P" first="Paul J. M." last="Wijnker">Paul J. M. Wijnker</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Witjas Paalberends, E Rosalie" sort="Witjas Paalberends, E Rosalie" uniqKey="Witjas Paalberends E" first="E. Rosalie" last="Witjas-Paalberends">E. Rosalie Witjas-Paalberends</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Marston, Steven B" sort="Marston, Steven B" uniqKey="Marston S" first="Steven B." last="Marston">Steven B. Marston</name><affiliation><nlm:aff id="A2">Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Dos Remedios, Cristobal G" sort="Dos Remedios, Cristobal G" uniqKey="Dos Remedios C" first="Cristobal G." last="Dos Remedios">Cristobal G. Dos Remedios</name><affiliation><nlm:aff id="A3">Muscle Research Unit, Bosch Institute, University of Sydney, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Carrier, Lucie" sort="Carrier, Lucie" uniqKey="Carrier L" first="Lucie" last="Carrier">Lucie Carrier</name><affiliation><nlm:aff id="A4">Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Inserm U974, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">UMR-S974, CNRS UMR7215, Institut de Myologie, IFR14,University Pierre et Marie Curie-Paris, 75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Demmers, Jeroen A A" sort="Demmers, Jeroen A A" uniqKey="Demmers J" first="Jeroen A. A." last="Demmers">Jeroen A. A. Demmers</name><affiliation><nlm:aff id="A7">Proteomics Centre, Erasmus University Medical Centre, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Redwood, Charles" sort="Redwood, Charles" uniqKey="Redwood C" first="Charles" last="Redwood">Charles Redwood</name><affiliation><nlm:aff id="A8">Department of Cardiovascular Medicine, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Sadayappan, Sakthivel" sort="Sadayappan, Sakthivel" uniqKey="Sadayappan S" first="Sakthivel" last="Sadayappan">Sakthivel Sadayappan</name><affiliation><nlm:aff id="A9">Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Van Der Velden, Jolanda" sort="Van Der Velden, Jolanda" uniqKey="Van Der Velden J" first="Jolanda" last="Van Der Velden">Jolanda Van Der Velden</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23277198</idno><idno type="pmc">3595322</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595322</idno><idno type="RBID">PMC:3595322</idno><idno type="doi">10.1161/CIRCRESAHA.112.275602</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001C62</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001C62</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">GSK3β Phosphorylates Newly Identified Site in the Pro-Ala Rich Region of Cardiac Myosin Binding Protein C and Alters Cross-Bridge Cycling Kinetics in Human</title><author><name sortKey="Kuster, Diederik W D" sort="Kuster, Diederik W D" uniqKey="Kuster D" first="Diederik W. D." last="Kuster">Diederik W. D. Kuster</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Sequeira, Vasco" sort="Sequeira, Vasco" uniqKey="Sequeira V" first="Vasco" last="Sequeira">Vasco Sequeira</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Najafi, Aref" sort="Najafi, Aref" uniqKey="Najafi A" first="Aref" last="Najafi">Aref Najafi</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Boontje, Nicky M" sort="Boontje, Nicky M" uniqKey="Boontje N" first="Nicky M." last="Boontje">Nicky M. Boontje</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Wijnker, Paul J M" sort="Wijnker, Paul J M" uniqKey="Wijnker P" first="Paul J. M." last="Wijnker">Paul J. M. Wijnker</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Witjas Paalberends, E Rosalie" sort="Witjas Paalberends, E Rosalie" uniqKey="Witjas Paalberends E" first="E. Rosalie" last="Witjas-Paalberends">E. Rosalie Witjas-Paalberends</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Marston, Steven B" sort="Marston, Steven B" uniqKey="Marston S" first="Steven B." last="Marston">Steven B. Marston</name><affiliation><nlm:aff id="A2">Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK</nlm:aff></affiliation></author><author><name sortKey="Dos Remedios, Cristobal G" sort="Dos Remedios, Cristobal G" uniqKey="Dos Remedios C" first="Cristobal G." last="Dos Remedios">Cristobal G. Dos Remedios</name><affiliation><nlm:aff id="A3">Muscle Research Unit, Bosch Institute, University of Sydney, Sydney, Australia</nlm:aff></affiliation></author><author><name sortKey="Carrier, Lucie" sort="Carrier, Lucie" uniqKey="Carrier L" first="Lucie" last="Carrier">Lucie Carrier</name><affiliation><nlm:aff id="A4">Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Inserm U974, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A6">UMR-S974, CNRS UMR7215, Institut de Myologie, IFR14,University Pierre et Marie Curie-Paris, 75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Demmers, Jeroen A A" sort="Demmers, Jeroen A A" uniqKey="Demmers J" first="Jeroen A. A." last="Demmers">Jeroen A. A. Demmers</name><affiliation><nlm:aff id="A7">Proteomics Centre, Erasmus University Medical Centre, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Redwood, Charles" sort="Redwood, Charles" uniqKey="Redwood C" first="Charles" last="Redwood">Charles Redwood</name><affiliation><nlm:aff id="A8">Department of Cardiovascular Medicine, University of Oxford, Oxford, UK</nlm:aff></affiliation></author><author><name sortKey="Sadayappan, Sakthivel" sort="Sadayappan, Sakthivel" uniqKey="Sadayappan S" first="Sakthivel" last="Sadayappan">Sakthivel Sadayappan</name><affiliation><nlm:aff id="A9">Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL</nlm:aff></affiliation></author><author><name sortKey="Van Der Velden, Jolanda" sort="Van Der Velden, Jolanda" uniqKey="Van Der Velden J" first="Jolanda" last="Van Der Velden">Jolanda Van Der Velden</name><affiliation><nlm:aff id="A1">Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author></analytic><series><title level="j">Circulation research</title><idno type="ISSN">0009-7330</idno><idno type="eISSN">1524-4571</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Rationale</title><p id="P1">Cardiac myosin binding protein C (cMyBP-C) regulates cross-bridge cycling kinetics and thereby fine-tunes the rate of cardiac muscle contraction and relaxation. Its effects on cardiac kinetics are modified by phosphorylation. Three phosphorylation sites (Ser275, Ser284, Ser304) have been identified <italic>in vivo</italic>, all located in the cardiac-specific M-domain of cMyBP-C. However recent work has shown that up to four phosphate groups are present in human cMyBP-C.</p></sec><sec id="S2"><title>Objective</title><p id="P2">To identify and characterize additional phosphorylation sites in human cMyBP-C.</p></sec><sec id="S3"><title>Methods and results</title><p id="P3">Cardiac MyBP-C was semi-purified from human heart tissue. Tandem mass-spectrometry analysis identified a novel phosphorylation site on serine 133 in the proline-alanine (Pro-Ala) rich linker sequence between the C0 and C1 domains of cMyBP-C. Unlike the known sites, Ser133 was not a target of protein kinase A. <italic>In silico</italic> kinase prediction revealed glycogen synthase kinase 3β (GSK3β) as the most likely kinase to phosphorylate Ser133. <italic>In vitro</italic> incubation of the C0C2 fragment of cMyBP-C with GSK3β showed phosphorylation on Ser133. In addition, GSK3β phosphorylated Ser304, although the degree of phosphorylation was less compared to PKA-induced phosphorylation at Ser304. GSK3β treatment of single membrane-permeabilized human cardiomyocytes significantly enhanced the maximal rate of tension redevelopment.</p></sec><sec id="S4"><title>Conclusion</title><p id="P4">GSK3β phosphorylates cMyBP-C on a novel site, which is positioned in the Pro-Ala rich region and increases kinetics of force development, suggesting a non-canonical role for GSK3β at the sarcomere level. Phosphorylation of Ser133 in the linker domain of cMyBP-C may be a novel mechanism to regulate sarcomere kinetics.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0047103</journal-id><journal-id journal-id-type="pubmed-jr-id">2974</journal-id><journal-id journal-id-type="nlm-ta">Circ Res</journal-id><journal-id journal-id-type="iso-abbrev">Circ. Res.</journal-id><journal-title-group><journal-title>Circulation research</journal-title></journal-title-group><issn pub-type="ppub">0009-7330</issn><issn pub-type="epub">1524-4571</issn></journal-meta><article-meta><article-id pub-id-type="pmid">23277198</article-id><article-id pub-id-type="pmc">3595322</article-id><article-id pub-id-type="doi">10.1161/CIRCRESAHA.112.275602</article-id><article-id pub-id-type="manuscript">NIHMS441708</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>GSK3β Phosphorylates Newly Identified Site in the Pro-Ala Rich Region of Cardiac Myosin Binding Protein C and Alters Cross-Bridge Cycling Kinetics in Human</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kuster</surname><given-names>Diederik W.D.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Sequeira</surname><given-names>Vasco</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Najafi</surname><given-names>Aref</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Boontje</surname><given-names>Nicky M.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wijnker</surname><given-names>Paul J.M.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Witjas-Paalberends</surname><given-names>E. Rosalie</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Marston</surname><given-names>Steven B.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>dos Remedios</surname><given-names>Cristobal G.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Carrier</surname><given-names>Lucie</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Demmers</surname><given-names>Jeroen A.A.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Redwood</surname><given-names>Charles</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Sadayappan</surname><given-names>Sakthivel</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>van der Velden</surname><given-names>Jolanda</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label>Dept of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands</aff><aff id="A2"><label>2</label>Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK</aff><aff id="A3"><label>3</label>Muscle Research Unit, Bosch Institute, University of Sydney, Sydney, Australia</aff><aff id="A4"><label>4</label>Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany</aff><aff id="A5"><label>5</label>Inserm U974, 75013 Paris, France</aff><aff id="A6"><label>6</label>UMR-S974, CNRS UMR7215, Institut de Myologie, IFR14,University Pierre et Marie Curie-Paris, 75013 Paris, France</aff><aff id="A7"><label>7</label>Proteomics Centre, Erasmus University Medical Centre, Rotterdam, The Netherlands</aff><aff id="A8"><label>8</label>Department of Cardiovascular Medicine, University of Oxford, Oxford, UK</aff><aff id="A9"><label>9</label>Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL</aff><author-notes><corresp id="cor1"><bold>Address correspondence to:</bold> Dr. Diederik W.D. Kuster, Cell and Molecular Physiology, Health Science Division, Loyola University of Chicago, 2160 First Avenue, Building 102, Room 4637, Maywood, IL 60153, Tel: (708)-2169064, Fax: (708)-2166308, <email>dkuster@lumc.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>22</day><month>2</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>31</day><month>12</month><year>2012</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>2</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>2</month><year>2014</year></pub-date><volume>112</volume><issue>4</issue><fpage>633</fpage><lpage>639</lpage><abstract><sec id="S1"><title>Rationale</title><p id="P1">Cardiac myosin binding protein C (cMyBP-C) regulates cross-bridge cycling kinetics and thereby fine-tunes the rate of cardiac muscle contraction and relaxation. Its effects on cardiac kinetics are modified by phosphorylation. Three phosphorylation sites (Ser275, Ser284, Ser304) have been identified <italic>in vivo</italic>, all located in the cardiac-specific M-domain of cMyBP-C. However recent work has shown that up to four phosphate groups are present in human cMyBP-C.</p></sec><sec id="S2"><title>Objective</title><p id="P2">To identify and characterize additional phosphorylation sites in human cMyBP-C.</p></sec><sec id="S3"><title>Methods and results</title><p id="P3">Cardiac MyBP-C was semi-purified from human heart tissue. Tandem mass-spectrometry analysis identified a novel phosphorylation site on serine 133 in the proline-alanine (Pro-Ala) rich linker sequence between the C0 and C1 domains of cMyBP-C. Unlike the known sites, Ser133 was not a target of protein kinase A. <italic>In silico</italic> kinase prediction revealed glycogen synthase kinase 3β (GSK3β) as the most likely kinase to phosphorylate Ser133. <italic>In vitro</italic> incubation of the C0C2 fragment of cMyBP-C with GSK3β showed phosphorylation on Ser133. In addition, GSK3β phosphorylated Ser304, although the degree of phosphorylation was less compared to PKA-induced phosphorylation at Ser304. GSK3β treatment of single membrane-permeabilized human cardiomyocytes significantly enhanced the maximal rate of tension redevelopment.</p></sec><sec id="S4"><title>Conclusion</title><p id="P4">GSK3β phosphorylates cMyBP-C on a novel site, which is positioned in the Pro-Ala rich region and increases kinetics of force development, suggesting a non-canonical role for GSK3β at the sarcomere level. Phosphorylation of Ser133 in the linker domain of cMyBP-C may be a novel mechanism to regulate sarcomere kinetics.</p></sec></abstract><kwd-group><kwd>Cardiac myosin binding protein-C</kwd><kwd>phosphorylation</kwd><kwd>GSK3β</kwd><kwd>heart failure</kwd><kwd>contractile proteins</kwd><kwd>hypertrophy/remodeling</kwd><kwd>myocardial contractility</kwd></kwd-group><funding-group><award-group><funding-source country="United States">National Heart, Lung, and Blood Institute : NHLBI</funding-source><award-id>R01 HL105826 || HL</award-id></award-group><award-group><funding-source country="United States">National Heart, Lung, and Blood Institute : NHLBI</funding-source><award-id>K02 HL114749 || HL</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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