A Novel Mutant Cardiac Troponin C Disrupts Molecular Motions Critical for Calcium Binding Affinity and Cardiomyocyte Contractility
Troponin C (TnC) belongs to the superfamily of EF-hand (helix–loop–helix) Ca 2+-binding proteins and is an essential component of the regulatory thin filament complex. In a patient diagnosed with idiopathic dilated cardiomyopathy, we identified two novel missense mutations localized in the regulator...
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| Veröffentlicht in: | Biophysical journal 2008-05, Vol.94 (9), p.3577-3589 |
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| creator | Lim, Chee Chew Yang, Haijun Yang, Mingfeng Wang, Chien-Kao Shi, Jianru Berg, Eric A. Pimentel, David R. Gwathmey, Judith K. Hajjar, Roger J. Helmes, Michiel Costello, Catherine E. Huo, Shuanghong Liao, Ronglih |
| description | Troponin C (TnC) belongs to the superfamily of EF-hand (helix–loop–helix) Ca
2+-binding proteins and is an essential component of the regulatory thin filament complex. In a patient diagnosed with idiopathic dilated cardiomyopathy, we identified two novel missense mutations localized in the regulatory Ca
2+-binding Site II of TnC, TnC
(E59D,D75Y). Expression of recombinant TnC
(E59D,D75Y) in isolated rat cardiomyocytes induced a marked decrease in contractility despite normal intracellular calcium homeostasis in intact cardiomyocytes and resulted in impaired myofilament calcium responsiveness in Triton-permeabilized cardiomyocytes. Expression of the individual mutants in cardiomyocytes showed that TnC
D75Y was able to recapitulate the TnC
(E59D,D75Y) phenotype, whereas TnC
E59D was functionally benign. Force-pCa relationships in TnC
(E59D,D75Y) reconstituted rabbit psoas fibers and fluorescence spectroscopy of TnC
(E59D,D75Y) labeled with 2-[(4′-iodoacetamide)-aniline]naphthalene-6-sulfonic acid showed a decrease in myofilament Ca
2+ sensitivity and Ca
2+ binding affinity, respectively. Furthermore, computational analysis of TnC showed the Ca
2+-binding pocket as an active region of concerted motions, which are decreased markedly by mutation D75Y. We conclude that D75Y interferes with proper concerted motions within the regulatory Ca
2+-binding pocket of TnC that hinders the relay of the thin filament calcium signal, thereby providing a primary stimulus for impaired cardiomyocyte contractility. This in turn may trigger pathways leading to aberrant ventricular remodeling and ultimately a dilated cardiomyopathy phenotype. |
| doi_str_mv | 10.1529/biophysj.107.112896 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2292379</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S000634950870434X</els_id><sourcerecordid>864417583</sourcerecordid><originalsourceid>FETCH-LOGICAL-c582t-2068f56166548215f3ca6ff2c87ab110d08e0d521d4a498a253b3f5a5e4f69ce3</originalsourceid><addsrcrecordid>eNp9ksuOFCEUhitG47SjT2BiiAtddQsUUNRCk7a8JjO6GdeEpmDmdKqgBKqT2vrkMun2upgVhPP9_7lwquopwRvCaftqB2G6WdJ-Q3CzIYTKVtyrVoQzusZYivvVCmMs1jVr-Vn1KKU9xoRyTB5WZ0RSQjGRq-rHFn0JBzugyzlrn1GnYw_aoKsYpuDBow69gxTnKSd0GQZr5kHHcssQfEJdhAxGD8iFWKSDgXlEb8H34K_R1jnwkBekfX_0DeMSzJIt6oLPUZsMQ4k_rh44PST75HSeV98-vL_qPq0vvn783G0v1oZLmtcUC-m4IEJwVsrnrjZaOEeNbPSOENxjaXHPKemZZq3UlNe72nHNLXOiNbY-r94cfad5N9re2NsaBjVFGHVcVNCg_o14uFHX4aAobWndtMXg5ckghu-zTVmNkIwdBu1tmJOSgjHScFkX8sWdZIOZZJizAj7_D9yHOfoyBlVaFLJtWlGg-giZGFKK1v2umWB1uwrq1yqUh0YdV6Gonv3d7h_N6e8L8PoI2DL0A9iokgHrje0hWpNVH-DOBD8BecDI1Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>215689796</pqid></control><display><type>article</type><title>A Novel Mutant Cardiac Troponin C Disrupts Molecular Motions Critical for Calcium Binding Affinity and Cardiomyocyte Contractility</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>Elsevier ScienceDirect Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Lim, Chee Chew ; Yang, Haijun ; Yang, Mingfeng ; Wang, Chien-Kao ; Shi, Jianru ; Berg, Eric A. ; Pimentel, David R. ; Gwathmey, Judith K. ; Hajjar, Roger J. ; Helmes, Michiel ; Costello, Catherine E. ; Huo, Shuanghong ; Liao, Ronglih</creator><creatorcontrib>Lim, Chee Chew ; Yang, Haijun ; Yang, Mingfeng ; Wang, Chien-Kao ; Shi, Jianru ; Berg, Eric A. ; Pimentel, David R. ; Gwathmey, Judith K. ; Hajjar, Roger J. ; Helmes, Michiel ; Costello, Catherine E. ; Huo, Shuanghong ; Liao, Ronglih</creatorcontrib><description>Troponin C (TnC) belongs to the superfamily of EF-hand (helix–loop–helix) Ca
2+-binding proteins and is an essential component of the regulatory thin filament complex. In a patient diagnosed with idiopathic dilated cardiomyopathy, we identified two novel missense mutations localized in the regulatory Ca
2+-binding Site II of TnC, TnC
(E59D,D75Y). Expression of recombinant TnC
(E59D,D75Y) in isolated rat cardiomyocytes induced a marked decrease in contractility despite normal intracellular calcium homeostasis in intact cardiomyocytes and resulted in impaired myofilament calcium responsiveness in Triton-permeabilized cardiomyocytes. Expression of the individual mutants in cardiomyocytes showed that TnC
D75Y was able to recapitulate the TnC
(E59D,D75Y) phenotype, whereas TnC
E59D was functionally benign. Force-pCa relationships in TnC
(E59D,D75Y) reconstituted rabbit psoas fibers and fluorescence spectroscopy of TnC
(E59D,D75Y) labeled with 2-[(4′-iodoacetamide)-aniline]naphthalene-6-sulfonic acid showed a decrease in myofilament Ca
2+ sensitivity and Ca
2+ binding affinity, respectively. Furthermore, computational analysis of TnC showed the Ca
2+-binding pocket as an active region of concerted motions, which are decreased markedly by mutation D75Y. We conclude that D75Y interferes with proper concerted motions within the regulatory Ca
2+-binding pocket of TnC that hinders the relay of the thin filament calcium signal, thereby providing a primary stimulus for impaired cardiomyocyte contractility. This in turn may trigger pathways leading to aberrant ventricular remodeling and ultimately a dilated cardiomyopathy phenotype.</description><identifier>ISSN: 0006-3495</identifier><identifier>EISSN: 1542-0086</identifier><identifier>DOI: 10.1529/biophysj.107.112896</identifier><identifier>PMID: 18212018</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Actin Cytoskeleton - genetics ; Actin Cytoskeleton - metabolism ; Animals ; Binding sites ; Calcium ; Calcium - metabolism ; Cardiac arrhythmia ; Cell Membrane Permeability ; Gene Expression Regulation ; Humans ; Molecular biology ; Movement - physiology ; Muscle and Contractility ; Mutation, Missense ; Myocardial Contraction - genetics ; Myocardial Contraction - physiology ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - metabolism ; Protein Binding ; Proteins ; Psoas Muscles - cytology ; Psoas Muscles - metabolism ; Rabbits ; Sarcomeres - genetics ; Sarcomeres - metabolism ; Spectrum analysis ; Substrate Specificity ; Troponin C - chemistry ; Troponin C - genetics ; Troponin C - metabolism</subject><ispartof>Biophysical journal, 2008-05, Vol.94 (9), p.3577-3589</ispartof><rights>2008 The Biophysical Society</rights><rights>Copyright Biophysical Society May 1, 2008</rights><rights>Copyright © 2008, Biophysical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c582t-2068f56166548215f3ca6ff2c87ab110d08e0d521d4a498a253b3f5a5e4f69ce3</citedby><cites>FETCH-LOGICAL-c582t-2068f56166548215f3ca6ff2c87ab110d08e0d521d4a498a253b3f5a5e4f69ce3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292379/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S000634950870434X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,3536,27903,27904,53769,53771,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18212018$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lim, Chee Chew</creatorcontrib><creatorcontrib>Yang, Haijun</creatorcontrib><creatorcontrib>Yang, Mingfeng</creatorcontrib><creatorcontrib>Wang, Chien-Kao</creatorcontrib><creatorcontrib>Shi, Jianru</creatorcontrib><creatorcontrib>Berg, Eric A.</creatorcontrib><creatorcontrib>Pimentel, David R.</creatorcontrib><creatorcontrib>Gwathmey, Judith K.</creatorcontrib><creatorcontrib>Hajjar, Roger J.</creatorcontrib><creatorcontrib>Helmes, Michiel</creatorcontrib><creatorcontrib>Costello, Catherine E.</creatorcontrib><creatorcontrib>Huo, Shuanghong</creatorcontrib><creatorcontrib>Liao, Ronglih</creatorcontrib><title>A Novel Mutant Cardiac Troponin C Disrupts Molecular Motions Critical for Calcium Binding Affinity and Cardiomyocyte Contractility</title><title>Biophysical journal</title><addtitle>Biophys J</addtitle><description>Troponin C (TnC) belongs to the superfamily of EF-hand (helix–loop–helix) Ca
2+-binding proteins and is an essential component of the regulatory thin filament complex. In a patient diagnosed with idiopathic dilated cardiomyopathy, we identified two novel missense mutations localized in the regulatory Ca
2+-binding Site II of TnC, TnC
(E59D,D75Y). Expression of recombinant TnC
(E59D,D75Y) in isolated rat cardiomyocytes induced a marked decrease in contractility despite normal intracellular calcium homeostasis in intact cardiomyocytes and resulted in impaired myofilament calcium responsiveness in Triton-permeabilized cardiomyocytes. Expression of the individual mutants in cardiomyocytes showed that TnC
D75Y was able to recapitulate the TnC
(E59D,D75Y) phenotype, whereas TnC
E59D was functionally benign. Force-pCa relationships in TnC
(E59D,D75Y) reconstituted rabbit psoas fibers and fluorescence spectroscopy of TnC
(E59D,D75Y) labeled with 2-[(4′-iodoacetamide)-aniline]naphthalene-6-sulfonic acid showed a decrease in myofilament Ca
2+ sensitivity and Ca
2+ binding affinity, respectively. Furthermore, computational analysis of TnC showed the Ca
2+-binding pocket as an active region of concerted motions, which are decreased markedly by mutation D75Y. We conclude that D75Y interferes with proper concerted motions within the regulatory Ca
2+-binding pocket of TnC that hinders the relay of the thin filament calcium signal, thereby providing a primary stimulus for impaired cardiomyocyte contractility. This in turn may trigger pathways leading to aberrant ventricular remodeling and ultimately a dilated cardiomyopathy phenotype.</description><subject>Actin Cytoskeleton - genetics</subject><subject>Actin Cytoskeleton - metabolism</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Calcium</subject><subject>Calcium - metabolism</subject><subject>Cardiac arrhythmia</subject><subject>Cell Membrane Permeability</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Molecular biology</subject><subject>Movement - physiology</subject><subject>Muscle and Contractility</subject><subject>Mutation, Missense</subject><subject>Myocardial Contraction - genetics</subject><subject>Myocardial Contraction - physiology</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Psoas Muscles - cytology</subject><subject>Psoas Muscles - metabolism</subject><subject>Rabbits</subject><subject>Sarcomeres - genetics</subject><subject>Sarcomeres - metabolism</subject><subject>Spectrum analysis</subject><subject>Substrate Specificity</subject><subject>Troponin C - chemistry</subject><subject>Troponin C - genetics</subject><subject>Troponin C - metabolism</subject><issn>0006-3495</issn><issn>1542-0086</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9ksuOFCEUhitG47SjT2BiiAtddQsUUNRCk7a8JjO6GdeEpmDmdKqgBKqT2vrkMun2upgVhPP9_7lwquopwRvCaftqB2G6WdJ-Q3CzIYTKVtyrVoQzusZYivvVCmMs1jVr-Vn1KKU9xoRyTB5WZ0RSQjGRq-rHFn0JBzugyzlrn1GnYw_aoKsYpuDBow69gxTnKSd0GQZr5kHHcssQfEJdhAxGD8iFWKSDgXlEb8H34K_R1jnwkBekfX_0DeMSzJIt6oLPUZsMQ4k_rh44PST75HSeV98-vL_qPq0vvn783G0v1oZLmtcUC-m4IEJwVsrnrjZaOEeNbPSOENxjaXHPKemZZq3UlNe72nHNLXOiNbY-r94cfad5N9re2NsaBjVFGHVcVNCg_o14uFHX4aAobWndtMXg5ckghu-zTVmNkIwdBu1tmJOSgjHScFkX8sWdZIOZZJizAj7_D9yHOfoyBlVaFLJtWlGg-giZGFKK1v2umWB1uwrq1yqUh0YdV6Gonv3d7h_N6e8L8PoI2DL0A9iokgHrje0hWpNVH-DOBD8BecDI1Q</recordid><startdate>20080501</startdate><enddate>20080501</enddate><creator>Lim, Chee Chew</creator><creator>Yang, Haijun</creator><creator>Yang, Mingfeng</creator><creator>Wang, Chien-Kao</creator><creator>Shi, Jianru</creator><creator>Berg, Eric A.</creator><creator>Pimentel, David R.</creator><creator>Gwathmey, Judith K.</creator><creator>Hajjar, Roger J.</creator><creator>Helmes, Michiel</creator><creator>Costello, Catherine E.</creator><creator>Huo, Shuanghong</creator><creator>Liao, Ronglih</creator><general>Elsevier Inc</general><general>Biophysical Society</general><general>The Biophysical Society</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080501</creationdate><title>A Novel Mutant Cardiac Troponin C Disrupts Molecular Motions Critical for Calcium Binding Affinity and Cardiomyocyte Contractility</title><author>Lim, Chee Chew ; Yang, Haijun ; Yang, Mingfeng ; Wang, Chien-Kao ; Shi, Jianru ; Berg, Eric A. ; Pimentel, David R. ; Gwathmey, Judith K. ; Hajjar, Roger J. ; Helmes, Michiel ; Costello, Catherine E. ; Huo, Shuanghong ; Liao, Ronglih</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c582t-2068f56166548215f3ca6ff2c87ab110d08e0d521d4a498a253b3f5a5e4f69ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Actin Cytoskeleton - genetics</topic><topic>Actin Cytoskeleton - metabolism</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Calcium</topic><topic>Calcium - metabolism</topic><topic>Cardiac arrhythmia</topic><topic>Cell Membrane Permeability</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Molecular biology</topic><topic>Movement - physiology</topic><topic>Muscle and Contractility</topic><topic>Mutation, Missense</topic><topic>Myocardial Contraction - genetics</topic><topic>Myocardial Contraction - physiology</topic><topic>Myocytes, Cardiac - cytology</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Psoas Muscles - cytology</topic><topic>Psoas Muscles - metabolism</topic><topic>Rabbits</topic><topic>Sarcomeres - genetics</topic><topic>Sarcomeres - metabolism</topic><topic>Spectrum analysis</topic><topic>Substrate Specificity</topic><topic>Troponin C - chemistry</topic><topic>Troponin C - genetics</topic><topic>Troponin C - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lim, Chee Chew</creatorcontrib><creatorcontrib>Yang, Haijun</creatorcontrib><creatorcontrib>Yang, Mingfeng</creatorcontrib><creatorcontrib>Wang, Chien-Kao</creatorcontrib><creatorcontrib>Shi, Jianru</creatorcontrib><creatorcontrib>Berg, Eric A.</creatorcontrib><creatorcontrib>Pimentel, David R.</creatorcontrib><creatorcontrib>Gwathmey, Judith K.</creatorcontrib><creatorcontrib>Hajjar, Roger J.</creatorcontrib><creatorcontrib>Helmes, Michiel</creatorcontrib><creatorcontrib>Costello, Catherine E.</creatorcontrib><creatorcontrib>Huo, Shuanghong</creatorcontrib><creatorcontrib>Liao, Ronglih</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biophysical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lim, Chee Chew</au><au>Yang, Haijun</au><au>Yang, Mingfeng</au><au>Wang, Chien-Kao</au><au>Shi, Jianru</au><au>Berg, Eric A.</au><au>Pimentel, David R.</au><au>Gwathmey, Judith K.</au><au>Hajjar, Roger J.</au><au>Helmes, Michiel</au><au>Costello, Catherine E.</au><au>Huo, Shuanghong</au><au>Liao, Ronglih</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Mutant Cardiac Troponin C Disrupts Molecular Motions Critical for Calcium Binding Affinity and Cardiomyocyte Contractility</atitle><jtitle>Biophysical journal</jtitle><addtitle>Biophys J</addtitle><date>2008-05-01</date><risdate>2008</risdate><volume>94</volume><issue>9</issue><spage>3577</spage><epage>3589</epage><pages>3577-3589</pages><issn>0006-3495</issn><eissn>1542-0086</eissn><abstract>Troponin C (TnC) belongs to the superfamily of EF-hand (helix–loop–helix) Ca
2+-binding proteins and is an essential component of the regulatory thin filament complex. In a patient diagnosed with idiopathic dilated cardiomyopathy, we identified two novel missense mutations localized in the regulatory Ca
2+-binding Site II of TnC, TnC
(E59D,D75Y). Expression of recombinant TnC
(E59D,D75Y) in isolated rat cardiomyocytes induced a marked decrease in contractility despite normal intracellular calcium homeostasis in intact cardiomyocytes and resulted in impaired myofilament calcium responsiveness in Triton-permeabilized cardiomyocytes. Expression of the individual mutants in cardiomyocytes showed that TnC
D75Y was able to recapitulate the TnC
(E59D,D75Y) phenotype, whereas TnC
E59D was functionally benign. Force-pCa relationships in TnC
(E59D,D75Y) reconstituted rabbit psoas fibers and fluorescence spectroscopy of TnC
(E59D,D75Y) labeled with 2-[(4′-iodoacetamide)-aniline]naphthalene-6-sulfonic acid showed a decrease in myofilament Ca
2+ sensitivity and Ca
2+ binding affinity, respectively. Furthermore, computational analysis of TnC showed the Ca
2+-binding pocket as an active region of concerted motions, which are decreased markedly by mutation D75Y. We conclude that D75Y interferes with proper concerted motions within the regulatory Ca
2+-binding pocket of TnC that hinders the relay of the thin filament calcium signal, thereby providing a primary stimulus for impaired cardiomyocyte contractility. This in turn may trigger pathways leading to aberrant ventricular remodeling and ultimately a dilated cardiomyopathy phenotype.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18212018</pmid><doi>10.1529/biophysj.107.112896</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0006-3495 |
| ispartof | Biophysical journal, 2008-05, Vol.94 (9), p.3577-3589 |
| issn | 0006-3495 1542-0086 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2292379 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Actin Cytoskeleton - genetics Actin Cytoskeleton - metabolism Animals Binding sites Calcium Calcium - metabolism Cardiac arrhythmia Cell Membrane Permeability Gene Expression Regulation Humans Molecular biology Movement - physiology Muscle and Contractility Mutation, Missense Myocardial Contraction - genetics Myocardial Contraction - physiology Myocytes, Cardiac - cytology Myocytes, Cardiac - metabolism Protein Binding Proteins Psoas Muscles - cytology Psoas Muscles - metabolism Rabbits Sarcomeres - genetics Sarcomeres - metabolism Spectrum analysis Substrate Specificity Troponin C - chemistry Troponin C - genetics Troponin C - metabolism |
| title | A Novel Mutant Cardiac Troponin C Disrupts Molecular Motions Critical for Calcium Binding Affinity and Cardiomyocyte Contractility |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T22%3A02%3A58IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Novel%20Mutant%20Cardiac%20Troponin%20C%20Disrupts%20Molecular%20Motions%20Critical%20for%20Calcium%20Binding%20Affinity%20and%20Cardiomyocyte%20Contractility&rft.jtitle=Biophysical%20journal&rft.au=Lim,%20Chee%20Chew&rft.date=2008-05-01&rft.volume=94&rft.issue=9&rft.spage=3577&rft.epage=3589&rft.pages=3577-3589&rft.issn=0006-3495&rft.eissn=1542-0086&rft_id=info:doi/10.1529/biophysj.107.112896&rft_dat=%3Cproquest_pubme%3E864417583%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=215689796&rft_id=info:pmid/18212018&rft_els_id=S000634950870434X&rfr_iscdi=true |