title: The effect of the dilated cardiomyopathy-causing Glu40Lys TPM1 mutation on actin-myosin interactions during the ATPase cycle.
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.
authors: Laboratory of Mechanisms of Cell Motility, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Avenue, St. Petersburg 194064, Russia. boroviko@mail.cytspb.rssi.ru
authors: Yurii S
authors: YS
authors: Borovikov
authors: Stanislava V
authors: SV
authors: Avrova
authors: Olga E
authors: OE
authors: Karpicheva
authors: Paul
authors: P
authors: Robinson
authors: Charles S
authors: CS
authors: Redwood
mesh_terms: D000199:Actins / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism*; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D009218:Myosins / Q000378:metabolism*; D014335:Tropomyosin / Q000235:genetics*
chemical_list: D000199:Actins; C490775:TPM1 protein, human; D014335:Tropomyosin; D018698:Glutamic Acid; D000251:Adenosine Triphosphatases; D009218:Myosins; D008239:Lysine