The effect of the dilated cardiomyopathy-causing Glu40Lys TPM1 mutation on actin-myosin interactions during the ATPase cycle

Journal article

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. © 2011 Elsevier Inc.

Authors: Borovikov, Y; Avrova, S; Karpicheva, O; Robinson, P; Redwood, C

• Journal: Biochemical and Biophysical Research Communications
• Volume: 411
• Issue: 3
• Pages: 496-500
• Publication date: 2011-08-05
• DOI: 10.1016/j.bbrc.2011.06.138
• EISSN: 1090-2104
• ISSN: 0006-291X
• Language: English
• Keywords: Ghost muscle fibers; α-Tropomyosin; Polarized fluorescence; ATPase cycle; Dilated cardiomyopathy