Structural Basis for Ca2+-regulated Muscle Relaxation at Interaction Sites of Troponin with Actin and Tropomyosin

Murakami, Kenji; Yumoto, Fumiaki; Ohki, Shinya; Yasunaga, Takuo; Tanokura, Masaru; Wakabayashi, T.

doi:10.1016/j.jmb.2005.06.067

Cited by 101 publications

(138 citation statements)

References 97 publications

(115 reference statements)

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“…Although the specific structural features of this extension cannot be deduced from the low-resolution neutron models, the novel finding of this structural change in sTnI has laid a foundation for further high-resolution studies. 15,[63][64][65] All optimized SANS-derived models point to a similar shape for sTnC, that of a fully extended dumbbell shape in both Ca 21 -free and Ca 21 -bound states, consistent with previous interpretations 48,49 as opposed to the somewhat more compact conformation observed in the cTn crystal structure 60 and SANS models for cTn. 50,51 In the SANS-derived model for sTn, the N-terminal domain of Ca 21 -bound sTnC rotates more than 1008 away from the position seen in the crystal structure.…”

Section: Probing the Structures Of Muscle Regulatory Proteins 509supporting

confidence: 84%

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

Jeffries

Trewhella

2011

Biopolymers

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Small‐angle X‐ray and neutron scattering with contrast variation have made important contributions in advancing our understanding of muscle regulatory protein structures in the context of the dynamic molecular processes governing muscle action. The contributions of the scattering investigations have depended upon the results of key crystallographic, NMR, and electron microscopy experiments that have provided detailed structural information that has aided in the interpretation of the scattering data. This review will cover the advances made using small‐angle scattering techniques, in combination with the results from these complementary techniques, in probing the structures of troponin and myosin binding protein C. A focus of the troponin work has been to understand the isoform differences between the skeletal and cardiac isoforms of this major calcium receptor in muscle. In the case of myosin binding protein C, significant data are accumulating, indicating that this protein may act to modulate the primary calcium signals from troponin, and interest in its biological role has grown because of linkages between gene mutations in the cardiac isoform and serious heart disease. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 505–516, 2011.

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Section: Probing the Structures Of Muscle Regulatory Proteins 509supporting

confidence: 84%

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

Jeffries

Trewhella

2011

Biopolymers

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“…From sequence comparisons with profilin, which interacts with the same of region of actin as TnI, and the crystal structure of the actin-profilin complex, Tung et al suggested that the inhibitory region may form a β-hairpin conformation when actin bound [30]. The atomic model for the interaction between the mobile domain, which includes the second actin binding site and actinTm filament, was proposed based on the NMR structure of the mobile domain determined by Murakami et al [31]. Yet ESR experiments with reconstituted thin filaments indicate that most of the mobile domain remains flexible even in the absence of Ca 2+ [32].…”

Section: Molecular Mechanisms Of Ctni Function In Ca2+ and Crossbridgmentioning

confidence: 99%

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Solaro

Rosevear

Kobayashi

2008

Biochemical and Biophysical Research Communications

105

119

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We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I. KeywordsCardiac; Sarcomeres; Adrenergic stimulation; Mechanics; Kinases; Phosphatases In the time since the troponin discovery and naming by the laboratory of Setsuro Ebashi [1], there has been a constant stream of evidence indicating the substantial role of modifications in cardiac troponin (cTn) as a critical control element in the body's response to physiological stressors such as the hemodynamic demands of exercise. It is now widely recognized that regulatory processes at the level of the sarcomeres and the hetero-trimeric Tn complex involve not only the reception of Ca 2+ by cTnC, but also transduction of this Ca-binding signal by cTnI and cTnT [2,3]. Multiple interactions of cTnI and cTnT with actin and tropomyosin (Tm) control the number and kinetics of interactions of cross-bridges with the thin filament. Our focus here on cTnI serves to highlight the significant impact of modifications in the function of Tn in working cardiac myocytes and in the integrated physiological responses to exercise, which we have reviewed previously [4,5]. Evidence summarized below indicates that phosphorylation of cTnI by adrenergic signaling cascades is an indispensable control mechanism in matching cardiac output to venous return and myocyte dynamics to heart rate. Specific modifications in troponin I affect the dynamics and intensity of the heart beatElucidation of the function of an N-terminal extension of ~30 amino acids with sites (Ser-23, Ser-24) of phosphorylation by protein kinase A (PKA), not present in the fast skeletal (fsTnI) or slow skeletal isoforms (ssTnI), provided the first evidence that cTnI may have a special role * Corresponding

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“…Loss of Ca 2+ causes the rigid central helix of sTnC to collapse and to release the inhibitory region of sTnI [42]. A recent study has shown that sTnI in the sTnC·sTnI·sTnT2 ternary complex constitutes a mobile actin binding domain that tumbles independently of the core domain and that this tumbling is more restricted through the closer contact with the core domain at high Ca 2+ concentrations [43]. This study also proposed a structure for the mobile domain that consists of two helices connected by a β-bulge [43].…”

Section: Introductionmentioning

confidence: 99%

“…A recent study has shown that sTnI in the sTnC·sTnI·sTnT2 ternary complex constitutes a mobile actin binding domain that tumbles independently of the core domain and that this tumbling is more restricted through the closer contact with the core domain at high Ca 2+ concentrations [43]. This study also proposed a structure for the mobile domain that consists of two helices connected by a β-bulge [43]. Based on the cardiac core domain structure, Takeda et al [35] proposed a "drag and release" model for cTnC-cTnI interaction.…”

Section: Introductionmentioning

confidence: 99%

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Robertson

Sykes

2008

Biochemical and Biophysical Research Communications

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Over the forty years since its discovery, many studies have focused on understanding the role of troponin as a myofilament based molecular switch in regulating the Ca 2+ -dependent activation of striated muscle contraction. Recently, studies have explored the role of cardiac troponin as a target for cardiotonic agents. These drugs are clinically useful for treating heart failure, a condition in which the heart is no longer able to pump enough blood to other organs. These agents act via a mechanism that modulates the Ca 2+ -sensitivity of troponin; such a mode of action is therapeutically desirable because intracellular Ca 2+ concentration is not perturbed, preserving the regulation of other Ca 2+ -based signaling pathways. This review describes molecular details of the interaction of cardiac troponin with a variety of cardiotonic drugs. We present recent structural work that has identified the docking sites of several cardiotonic drugs in the troponin C -troponin I interface and discuss their relevance in the design of troponin based drugs for the treatment of heart disease.

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Structural Basis for Ca2+-regulated Muscle Relaxation at Interaction Sites of Troponin with Actin and Tropomyosin

Cited by 101 publications

References 97 publications

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

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