Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility

Cheng, Yuanhua; Regnier, Michael

doi:10.1016/j.abb.2016.02.004

Cited by 40 publications

(36 citation statements)

References 212 publications

(232 reference statements)

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“…The other three HCM substitutions, P80S, D86A, and K97N, did not significantly alter maximum ATPase activity. These trends are consistent with observations reported by other groups (30)(31)(32)(33).…”

Section: Resultssupporting

confidence: 93%

Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region

Gangadharan

Sunitha

Mukherjee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Point mutations in genes encoding sarcomeric proteins are the leading cause of inherited primary cardiomyopathies. Among them are mutations in the gene that encodes cardiac troponin T (TnT). These mutations are clustered in the tropomyosin (Tm) binding region of TnT, TNT1 (residues 80-180). To understand the mechanistic changes caused by pathogenic mutations in the TNT1 region, six hypertrophic cardiomyopathy (HCM) and two dilated cardiomyopathy (DCM) mutants were studied by biochemical approaches. Binding assays in the absence and presence of actin revealed changes in the affinity of some, but not all, TnT mutants for Tm relative to WT TnT. HCM mutants were hypersensitive and DCM mutants were hyposensitive to Ca in regulated actomyosin ATPase activities. To gain better insight into the disease mechanism, we modeled the structure of TNT1 and its interactions with Tm. The stability predictions made by the model correlated well with the affinity changes observed in vitro of TnT mutants for Tm. The changes in Ca sensitivity showed a strong correlation with the changes in binding affinity. We suggest the primary reason by which these mutations between residues 92 and 144 cause cardiomyopathy is by changing the affinity of TnT for Tm within the TNT1 region.

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Section: Resultssupporting

confidence: 93%

Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region

Gangadharan

Sunitha

Mukherjee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…hs-cTnT is a speci c regulatory protein, and cTnI is a speci c contractile protein on myocardial bres. When the myocardial cell membrane is intact, neither hs-cTnT nor cTnI can penetrate the cell membrane into the peripheral blood circulation, so hs-cTnT and cTnI cannot be detected in the peripheral blood of healthy people [5] . cTnI, a non-enzymatic serum marker with high speci city and sensitivity, is one of the most commonly used markers for detecting myocardial injury.…”

Section: Discussionmentioning

confidence: 99%

“…According to the de nition, slight myocardial injury can be detected by cTn in the early postoperative period [4] . cTn exists only in cardiomyocytes and is a complex composed of troponin T (cTnT), troponin I (cTnI) and troponin C (cTnC) [5] . hs-cTnT is a unique regulatory protein located on cardiac bres.…”

Section: Introductionmentioning

confidence: 99%

Two Different Troponin Isoforms for Detecting Early Myocardial Injury after Curative Resection of Oesophageal Cancer

Tang

Zhang

et al. 2020

Preprint

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Abstract Background: The objective of this study was to explore the consistency and correlation of two troponin (cTn) subtypes, troponin I (cTnI) and high-sensitivity troponin T (hs-cTnT), which can be used to judge early myocardial injury after curative resection of oesophageal cancer.Methods: This study is a secondary analysis of data obtained from a previous randomized controlled trial on postoperative myocardial injury in 70 patients undergoing elective curative resection of oesophageal cancer who were randomly assigned to undergo aggressive body temperature management (nasopharyngeal temperature 36.61±0.18°C) or standard body temperature management (35.80±0.18°C, n = 35 in each arm). The serum cTnI and hs-cTnT levels were measured in each patient at the 4 time points: before the operation and 6 h~12 h, 24 h and 48 h after the operation. The diagnostic criteria of myocardial injury followed the third edition ESC/ACCF definition of myocardial infarction. The primary outcomes included the following: (1) the incidence of myocardial injury and the relationship between hs-cTnT and cTn and (2) the consistency and correlation of the two cTn subtypes.Results: A total of 280 pairs of cTn samples were tested. The incidence of postoperative day 2 myocardial injury was 8.6% (3/35) among patients receiving aggressive body temperature management and 31.4% (11/35) among patients receiving standard body temperature management (P<0.05). Among 3 patients who experienced myocardial injury in the aggressive body temperature management group, 2 met the diagnostic criteria for cTnI and hs-cTnT and only 1 met the diagnostic criteria for hs-cTnT. Among the 11 patients who experienced myocardial injury in the standard body temperature management group, 7 met the diagnostic criteria for cTnI and hs-cTnT and only 3 met the diagnostic criteria for hs-cTnT; only 1 met the diagnostic criteria for cTnI. The bias of cTnI and hs-cTnT was -8.82±31.91 ng/L. The consistency limit was -71.37~53.73 ng/L. The proportion within the scope of the consistency of its corresponding boundary was 98.57%. The correlation coefficient of cTnI and hs-cTnT was 0.845 (P<0.05).Conclusions: In the evaluation of postoperative myocardial injury in patients undergoing curative resection of oesophageal cancer, cTnI and hs-cTnT exhibit high consistency and a good correlation. The combination of cTnI and hs-cTnT can improve the detection rate of myocardial injury, thus providing a better reference than a single measure alone for reducing the risk of perioperative myocardial injury in patients.Trial registration: ChiCTR-INR-17011621. Registered June 10, 2017

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“…The contacts between the intrinsically disordered segments and the troponin core are interesting since they are involved in the mechanism of regulation by troponin (Cheng and Regnier, 2016). In order for the opening of the hydrophobic cleft upon Ca 2+ binding to occur, TnC must interact with the TnI switch peptide (148–154).…”

Section: Insights For Troponin Regulatory Mechanismmentioning

confidence: 99%

The Importance of Intrinsically Disordered Segments of Cardiac Troponin in Modulating Function by Phosphorylation and Disease-Causing Mutations

Papadaki

Marston

2016

Front. Physiol.

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Troponin plays a central role in regulation of muscle contraction. It is the Ca2+ switch of striated muscles including the heart and in the cardiac muscle it is physiologically modulated by PKA-dependent phosphorylation at Ser22 and 23. Many cardiomyopathy-related mutations affect Ca2+ regulation and/or disrupt the relationship between Ca2+ binding and phosphorylation. Unlike the mechanism of heart activation, the modulation of Ca2+-sensitivity by phosphorylation of the cardiac specific N-terminal segment of TnI (1–30) is structurally subtle and has proven hard to investigate. The crystal structure of cardiac troponin describes only the relatively stable core of the molecule and the crucial mobile parts of the molecule are missing including TnI C-terminal region, TnI (1–30), TnI (134–149) (“inhibitory” peptide) and the C-terminal 28 amino acids of TnT that are intrinsically disordered. Recent studies have been performed to answer this matter by building structural models of cardiac troponin in phosphorylated and dephosphorylated states based on peptide NMR studies. Now these have been updated by more recent concepts derived from molecular dynamic simulations treating troponin as a dynamic structure. The emerging model confirms the stable core structure of troponin and the mobile structure of the intrinsically disordered segments. We will discuss how we can describe these segments in terms of dynamic transitions between a small number of states, with the probability distributions being altered by phosphorylation and by HCM or DCM-related mutations that can explain how Ca2+-sensitivity is modulated by phosphorylation and the effects of mutations.

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Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility

Cited by 40 publications

References 212 publications

Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region

Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region

Two Different Troponin Isoforms for Detecting Early Myocardial Injury after Curative Resection of Oesophageal Cancer

The Importance of Intrinsically Disordered Segments of Cardiac Troponin in Modulating Function by Phosphorylation and Disease-Causing Mutations

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