{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:40:53Z","timestamp":1792658453620,"version":"4.5.0"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"31","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,7,30]]},"abstract":"<jats:p>Cardiovascular disorders are the leading cause of morbidity and mortality in the developed world, and hypertrophic cardiomyopathy (HCM) is among the most frequently occurring inherited cardiac disorders. HCM is caused by mutations in the genes encoding the fundamental force-generating machinery of the cardiac muscle, including \u03b2-cardiac myosin. Here, we present a biomechanical analysis of the HCM-causing mutation, R453C, in the context of human \u03b2-cardiac myosin. We found that this mutation causes a \u223c30% decrease in the maximum ATPase of the human \u03b2-cardiac subfragment 1, the motor domain of myosin, and a similar percent decrease in the in vitro velocity. The major change in the R453C human \u03b2-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type, with no appreciable change in the stroke size, as observed with a dual-beam optical trap. These results predict that the overall force of the ensemble of myosin molecules in the muscle should be higher in the R453C mutant compared with wild type. Loaded in vitro motility assay confirms that the net force in the ensemble is indeed increased. Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle.<\/jats:p>","DOI":"10.1073\/pnas.1309493110","type":"journal-article","created":{"date-parts":[[2013,6,25]],"date-time":"2013-06-25T00:20:05Z","timestamp":1372119605000},"page":"12607-12612","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":178,"title":["Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human \u03b2-cardiac myosin motor function"],"prefix":"10.1073","volume":"110","author":[{"given":"Ruth F.","family":"Sommese","sequence":"first","affiliation":[{"name":"Departments of aBiochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongmin","family":"Sung","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry,"},{"name":"Department of Applied Physics, Stanford University, Stanford, CA 94305; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman","family":"Nag","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Sutton","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Deacon","sequence":"additional","affiliation":[{"name":"BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Choe","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry,"},{"name":"Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie A.","family":"Leinwand","sequence":"additional","affiliation":[{"name":"BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Ruppel","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry,"},{"name":"Pediatrics (Cardiology), and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Spudich","sequence":"additional","affiliation":[{"name":"Departments of aBiochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,6,24]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.4.785"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/CRD.0b013e318178e525"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201101100"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90274-I"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2011.159"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223842"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018613907574"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.7.737"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800554200"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.450668"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0913527107"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119115"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01015.2003"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00128.2007"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(90)90287-V"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2003.11.011"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi001701b"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/cm.20441"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/cm.970220407"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1923.sp002115"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1060"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600458"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116530"},{"key":"e_1_3_3_24_2","first-page":"1394","volume-title":"Braunwald\u2019s Heart Disease: A Textbook of Cardiovascular Medicine","author":"Wynne JBE","year":"1992","unstructured":"JBE Wynne, The cardiomyopathies and myocarditis: Toxic, chemical and physical damage to the heart. 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