Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 19, Pages 13471-13477Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M509561200
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Funding
- NHLBI NIH HHS [R37 HL 22231, P01 HL 62426] Funding Source: Medline
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To understand the molecular mechanisms whereby cardiomyopathy-related cardiac troponin I ( cTnI) mutations affect myofilament activity, we have investigated the Ca2+ binding properties of various assemblies of the regulatory components that contain one of the cardiomyopahty- related mutant cTnI. Acto- S1 ATPase activities in reconstituted systems were also determined. We investigated R145G and R145W mutations from the inhibitory region and D190H and R192H mutations from the second actin- tropomyosin-binding site. Each of the four mutations sensitized the acto- S1 ATPase to Ca2+. Whereas the mutations from the inhibitory region increased the basal level of ATPase activity, those from the second actin- tropomyosin- binding site did not. The effects on the Ca2+ binding properties of the troponin ternary complex and the troponin-tropomyosin complex with one of four mutations were either desensitization or no effect compared with those with wild- type cTnI. All of the mutations, however, affected the Ca2+ sensitivities of the reconstituted thin filaments in the same direction as the acto- S1 ATPase activity. Also the thin filaments with one of the mutant cTnIs bound Ca2+ with less cooperativity compared with those with wild- type cTnI. These data indicate that the mutations found in the inhibitory region and those from the second actin-tropomyosin site shift the equilibrium of the states of the thin filaments differently. Moreover, the increased Ca2+ bound to myofilaments containing the mutant cTnIs may be an important factor in triggered arrhythmias associated with the cardiomyopathy.
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