Solution Structure of Human Cardiac Troponin C in Complex with the Green Tea Polyphenol, (−)-Epigallocatechin 3-Gallate

Robertson, Ian M.; Li, Monica X.; Sykes, Brian D.

doi:10.1074/jbc.m109.021352

Cited by 60 publications

(93 citation statements)

References 58 publications

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“…The polyphenolic compounds EGCg 160 and resveratrol 161 were also found to bind to cCTnC, but not cNTnC. While EGCg is found in green tea, resveratrol is found in red wine.…”

Section: Compounds That Bind To the Structural Domain Cctncmentioning

confidence: 94%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

Self Cite

106

105

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In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

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“…The polyphenolic compounds EGCg 160 and resveratrol 161 were also found to bind to cCTnC, but not cNTnC. While EGCg is found in green tea, resveratrol is found in red wine.…”

Section: Compounds That Bind To the Structural Domain Cctncmentioning

confidence: 94%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

Self Cite

106

105

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“…A great concern about biological agents is their non-toxicity and their good bioavailability but there are few Ca 2+ desensitizers possessing such qualities. The catechin, (-)-epigallocatechin-3-gallate (EGCg) has been newly found to possess Ca 2+ desensitizing abilities via its interaction with cTnC [14,15]. This compound is the most abundant catechin in green tea and is credited for the numerous health benefits attributed to green tea consumption.…”

Section: ) Reverse Diastolic Dysfunction By Chemical Ca 2+ Desensitimentioning

confidence: 99%

“…This compound is the most abundant catechin in green tea and is credited for the numerous health benefits attributed to green tea consumption. EGCg desensitizes myofilament to Ca 2+ by forming a ternary complex with the C-terminal domain of troponin C and the anchoring region of cTnI [15]. The affinity of TnC to Ca 2+ is reduced as a result which facilitates cardiac relaxation.…”

Section: ) Reverse Diastolic Dysfunction By Chemical Ca 2+ Desensitimentioning

confidence: 99%

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

Xu¹,

Tian²,

Huang³

2014

JAMR

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Abstract-Troponin, a contractile protein of the thin filament of striated muscle, consists of three subunits: troponin C (TnC), troponin T (TnT), and troponin I (TnI). Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. The physiological effect of cTnI, as an inhibitory subunit of troponin complex, is to prevent the interaction between myosin heavy chain heads and actins, i.e. the cross-bridge formation, and to ensure a proper relaxation of cardiac myofilaments. In pathological conditions, the deficiency of cTnI or mutations in cTnI especially in the C-terminus of cTnI is associated with diastolic dysfunction caused by myofibril hypersensitivity to Ca 2+ . Our laboratory has generated cTnI knockout mouse model to investigate the cellular and molecular function of cTnI and created cTnI mutant disease mouse models to explore the pathophysiology caused by cTnI mutations in the heart. Here, we present our recent studies on physiological function of cTnI in the heart and the pathological consequences caused by the cTnI mutations in the diseased heart using the transgenic mouse models. The mechanisms underlying diastolic dysfunction and heart failure caused by cTnI mutations are explored in cell-based assays and in transgenic animal models. These studies provide us with useful information in searching for therapeutic strategies and target-oriented medication for the treatment of diastolic dysfunction and heart failure.

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“…Whereas several small-molecule Ca 2ϩ sensitizers have been developed for the treatment of heart failure, little attention has been paid to myofilament Ca 2ϩ desensitizers. EGCG and resveratrol have been suggested to bind to cTnC and decrease Ca 2ϩ sensitivity (19,26,28). EGCG was recently shown to improve diastolic dysfunction in HCM and RCM mouse models, suggesting that desensitization of the myofilament is therapeutically relevant (10,32,35).…”

Section: Discussionmentioning

confidence: 99%

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca²⁺-sensitive myofilaments

Thompson

Martindale

Metzger

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Thompson BR, Martindale J, Metzger JM. Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca 2ϩ -sensitive myofilaments. Am J Physiol Heart Circ Physiol 311: H36 -H43, 2016. First published May 13, 2016 doi:10.1152/ajpheart.00981.2015.-The sarcomere is the functional unit of the heart. Alterations in sarcomere activation lead to disease states such as hypertrophic and restrictive cardiomyopathy (HCM/ RCM). Mutations in many of the sarcomeric genes are causal for HCM/RCM. In most cases, these mutations result in increased Ca 2ϩ sensitivity of the sarcomere, giving rise to altered systolic and diastolic function. There is emerging evidence that small-molecule sarcomere neutralization is a potential therapeutic strategy for HCM/ RCM. To pursue proof-of-concept, W7 was used here because of its well-known Ca 2ϩ desensitizer biochemical effects at the level of cardiac troponin C. Acute treatment of adult cardiac myocytes with W7 caused a dose-dependent (1-10 M) decrease in contractility in a Ca 2ϩ -independent manner. Alkalosis was used as an in vitro experimental model of acquired heightened Ca 2ϩ sensitivity, resulting in increased live cell contractility and decreased baseline sarcomere length, which were rapidly corrected with W7. As an inherited cardiomyopathy model, R193H cardiac troponin I (cTnI) transgenic myocytes showed significant decreased baseline sarcomere length and slowed relaxation that were rapidly and dose-dependently corrected by W7. Langendorff whole heart pacing stress showed that R193H cTnI transgenic hearts had elevated end-diastolic pressures at all pacing frequencies compared with hearts from nontransgenic mice. Acute treatment with W7 rapidly restored end-diastolic pressures to normal values in R193H cTnI hearts, supporting a sarcomere intrinsic mechanism of dysfunction. The known off-target effects of W7 notwithstanding, these results provide further proof-of-concept that small-molecule-based sarcomere neutralization is a potential approach to remediate hyper-Ca 2ϩ -sensitive sarcomere function.

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Solution Structure of Human Cardiac Troponin C in Complex with the Green Tea Polyphenol, (−)-Epigallocatechin 3-Gallate

Cited by 60 publications

References 58 publications

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca²⁺-sensitive myofilaments

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Solution Structure of Human Cardiac Troponin C in Complex with the Green Tea Polyphenol, (−)-Epigallocatechin 3-Gallate

Cited by 60 publications

References 58 publications

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments

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Product

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About

Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca²⁺-sensitive myofilaments