Drastic Ca2+ sensitization of myofilament associated with a small structural change in troponin I in inherited restrictive cardiomyopathy

Yumoto, Fumiaki; Lu, Qun; Morimoto, Sachio; Tanaka, Hiroyuki; Kono, Naoko; Nagata, Koji; Ojima, Takao; Takahashi-Yanaga, Fumi; Miwa, Yoshiro; Sasaguri, Toshiyuki; Nishita, Kiyoyoshi; Tanokura, Masaru; Ohtsuki, Iwao

doi:10.1016/j.bbrc.2005.10.116

Cited by 75 publications

(60 citation statements)

References 41 publications

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“…Reconstituted troponin complexes with RCM cTnI were unable to properly inhibit actomyosin ATPase (Gomes et al, 2005). Replacing endogenous cTnIs with the RCM cTnIs, in skinned cardiac fibers revealed elevated levels of basal force production (Gomes et al, 2005;Yumoto et al, 2005). Furthermore, relative to wild-type, the RCM cTnI mutations significantly increased the Ca 2ϩ sensitivity of force development in skinned cardiac fibers.…”

Section: Discussionmentioning

confidence: 99%

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

Cammarato

Dambacher

Knowles

et al. 2008

MBoC

116

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Striated muscle myosin is a multidomain ATP-dependent molecular motor. Alterations to various domains affect the chemomechanical properties of the motor, and they are associated with skeletal and cardiac myopathies. The myosin transducer domain is located near the nucleotide-binding site. Here, we helped define the role of the transducer by using an integrative approach to study how Drosophila melanogaster transducer mutations D45 and Mhc 5 affect myosin function and skeletal and cardiac muscle structure and performance. We found D45 (A261T) myosin has depressed ATPase activity and in vitro actin motility, whereas Mhc 5 (G200D) myosin has these properties enhanced. Depressed D45 myosin activity protects against age-associated dysfunction in metabolically demanding skeletal muscles. In contrast, enhanced Mhc 5 myosin function allows normal skeletal myofibril assembly, but it induces degradation of the myofibrillar apparatus, probably as a result of contractile disinhibition. Analysis of beating hearts demonstrates depressed motor function evokes a dilatory response, similar to that seen with vertebrate dilated cardiomyopathy myosin mutations, and it disrupts contractile rhythmicity. Enhanced myosin performance generates a phenotype apparently analogous to that of human restrictive cardiomyopathy, possibly indicating myosin-based origins for the disease. The D45 and Mhc 5 mutations illustrate the transducer's role in influencing the chemomechanical properties of myosin and produce unique pathologies in distinct muscles. Our data suggest Drosophila is a valuable system for identifying and modeling mutations analogous to those associated with specific human muscle disorders. INTRODUCTIONThe myosin molecular motor of striated muscle is a hexameric molecule composed of two myosin heavy chains (MHCs) and four light chains. The N-terminal globular motor domain is a product inhibited ATPase comprised of several communicating domains and functional units (reviewed by Holmes, 1999, 2005;. Alterations to the various domains dramatically affect the biochemical and mechanical properties of the motor in vitro, and mutations that diminish or enhance the molecular performance of myosin in vivo are associated with the pathogenesis of both skeletal and cardiac myopathies (reviewed by Sellers, 1999;Redowicz, 2002;Oldfors et al., 2004;Chang and Potter, 2005;Laing and Nowak, 2005;Tardiff, 2005;Oldfors, 2007). Central to an understanding of myosinbased myopathies is a fundamental appreciation for how depressed or enhanced molecular motor function differentially affects diverse striated muscles.Among the communicating functional units of myosin is the recently described transducer region (Coureux et al., 2004). Myosin V crystal structures reveal the transducer's central location within the motor domain near the nucleotide binding site. The transducer includes the last three strands of a seven-stranded ␤-sheet, which undergoes distortion essential for rearrangements within the nucleotide pocket during the ATPase cycle, and the loops an...

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Section: Discussionmentioning

confidence: 99%

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

Cammarato

Dambacher

Knowles

et al. 2008

MBoC

116

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“…On the other hand, the side chain of Arg-192 is not directly involved in the interaction with actin, which is consistent with our observation that R192H mutation did not cause a large increase of Ca 2ϩ binding affinity of the thin filaments. Recently Yumoto et al (71) reported that one of the RCM-related mutations found in the C-terminal mobile domain of cTnI (K178E) induced a subtle localized structural perturbation around the mutated residue in an isolated C-terminal part of cTnI (residues 129 -210). A reversal of the charged state of this position could cause a decreased affinity for actin without disrupting a mobile domain structure significantly.…”

Section: Discussionmentioning

confidence: 99%

Increased Ca2+ Affinity of Cardiac Thin Filaments Reconstituted with Cardiomyopathy-related Mutant Cardiac Troponin I

Kobayashi

Solaro

2006

Journal of Biological Chemistry

115

128

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To understand the molecular mechanisms whereby cardiomyopathy-related cardiac troponin I (cTnI) mutations affect myofilament activity, we have investigated the Ca 2؉ 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-tropomyosinbinding site. Each of the four mutations sensitized the acto-S1 ATPase to Ca 2؉ . 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 Ca 2؉ 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 Ca 2؉ 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 Ca 2؉ 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 actintropomyosin site shift the equilibrium of the states of the thin filaments differently. Moreover, the increased Ca 2؉ bound to myofilaments containing the mutant cTnIs may be an important factor in triggered arrhythmias associated with the cardiomyopathy.In experiments reported here, we have investigated the functional significance of mutations of cardiac troponin I (cTnI) 2 linked to cardiomyopathy. The Ca 2ϩ -dependent interaction of TnI with actin and TnC is one of the most important events in the regulation of striated muscle contraction. Ca 2ϩ binding to troponin C (TnC) triggers a series of conformational transitions among thin filament proteins that activate the thin filament (for review, see Refs. 1-4). A current model for the regulatory mechanism of muscle contraction, originally derived from biochemical analysis, involves three states of the thin filament:blocked (B-state), closed (C-state), and open (M-state) (5-7). The three states have been defined to reflect different interactions between actin and the myosin head. The B-state, which the majority of the thin filaments occupy when the cytoplasmic [Ca 2ϩ ] is low and Ca 2ϩ is not bound to the regulatory site(s) on Tn (5,8,9), is stabilized by the interaction between TnI and actin. With Ca 2ϩ binding to the regulatory site(s) of TnC, a hydrophobic patch is exposed in the N-terminal regulatory site of TnC (10, 11). In the case of cardiac TnC (cTnC), this structural change requires cTnI (12-14). The newly exposed hydrophobic patch interacts with the regulatory region of TnI (12, 15-17) and the C-terminal half of the TnI molecule moves away from actin (18 -22). In the C-state, non-force-generating cross-bridges bind weakly to actin...

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“…These shared domains suggest that the location of the mutation is important to the functional outcome, but they do not address the phenotypic divergence seen at the organ level. Biochemical reconstitution studies showed that RCM-linked mutations in cTnI hypersensitize the myofilaments to Ca 2ϩ relative to the already sensitized HCM counterparts (277,445,998). Acute gene transfer experiments demonstrated that RCM-linked mutant R193H cTnI myocytes are hypersensitive to Ca 2ϩ (158).…”

Section: Gene Transfer Of Tni Isoformsmentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Drastic Ca2+ sensitization of myofilament associated with a small structural change in troponin I in inherited restrictive cardiomyopathy

Cited by 75 publications

References 41 publications

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

Myosin Transducer Mutations Differentially Affect Motor Function, Myofibril Structure, and the Performance of Skeletal and Cardiac Muscles

Increased Ca2+ Affinity of Cardiac Thin Filaments Reconstituted with Cardiomyopathy-related Mutant Cardiac Troponin I

Designing Heart Performance by Gene Transfer

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