The effect of the dilated cardiomyopathy-causing Glu40Lys TPM1 mutation on actin-myosin interactions during the ATPase cycle |
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Authors: | Borovikov Yurii S Avrova Stanislava V Karpicheva Olga E Robinson Paul Redwood Charles S |
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Institution: | aLaboratory of Mechanisms of Cell Motility, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Avenue, St. Petersburg 194064, Russia;bDepartment of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom |
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Abstract: | Dilated cardiomyopathy (DCM), characterized by cardiac dilatation and contractile dysfunction, is a major cause of heart failure. DCM can result from mutations in the gene encoding cardiac α-tropomyosin (TM). In order to understand how the dilated cardiomyopathy-causing Glu40Lys mutation in TM affects actomyosin interactions, thin filaments have been reconstituted in muscle ghost fibers by incorporation of labeled Cys707 of myosin subfragment-1 and Cys374 of actin with fluorescent probe 1.5-IAEDANS and α-tropomyosin (wild-type or Glu40Lys mutant). For the first time, the effect of these α-tropomyosins on the mobility and rotation of subdomain-1 of actin and the SH1 helix of myosin subfragment-1 during the ATP hydrolysis cycle have been demonstrated directly by polarized fluorimetry. The Glu40Lys mutant TM inhibited these movements at the transition from AM∗∗·ADP·Pi to AM state, indicating a decrease of the proportion of the strong-binding sub-states in the actomyosin population. These structural changes are likely to underlie the contractile deficit observed in human dilated cardiomyopathy. |
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Keywords: | Abbreviations: DCM dilated cardiomyopathy S1 myosin subfragment 1 1 5-IAEDANS N-iodoacetyl-N&prime -(5-sulfo-1-naphtylo)ethylenediamine TM tropomyosin TN troponin |
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