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Biochemistry. Biokhimiia Dec 2013Troponin complex is a component of skeletal and cardiac muscle thin filaments. It consists of three subunits - troponin I, T, and C, and it plays a crucial role in... (Review)
Review
Troponin complex is a component of skeletal and cardiac muscle thin filaments. It consists of three subunits - troponin I, T, and C, and it plays a crucial role in muscle activity, connecting changes in intracellular Ca2+ concentration with generation of contraction. In spite of more than 40 years of studies, many aspects of troponin functioning are still not completely understood, and several models describing the mechanism of muscle contraction exist. Being a key factor in the regulation of cardiac muscle contraction, troponin complex is utilized in medicine as a target for some cardiotonic drugs used in the treatment of heart failure. A number of mutations in troponin subunits are associated with development of different types of cardiomyopathy. Moreover, for the last 25 years cardiac isoforms of troponin I and T have been widely used for immunochemical diagnostics of pathologies associated with cardiomyocyte death (myocardial infarction, myocardial trauma, and others). This review summarizes the existing evidence on the structure and function of troponin complex subunits, their role in the regulation of cardiac muscle contraction, and their clinical applications.
Topics: Animals; Heart Diseases; Humans; Myocardium; Troponin C; Troponin I; Troponin T
PubMed: 24490734
DOI: 10.1134/S0006297913130063 -
Archives of Biochemistry and Biophysics Mar 2019The cardiac contraction-relaxation cycle is controlled by a sophisticated set of machinery. Of particular interest, is the revelation that allosteric networks transmit... (Review)
Review
The cardiac contraction-relaxation cycle is controlled by a sophisticated set of machinery. Of particular interest, is the revelation that allosteric networks transmit effects of binding at one site to influence troponin complex dynamics and structural-mediated signaling in often distal, functional sites in the myofilament. Our recent observations provide compelling evidence that allostery can explain the function of large-scale macromolecular events. Here we elaborate on our recent findings of interdomain communication within troponin C, using cutting-edge structural biology approaches, and highlight the importance of unveiling the unknown, distant communication networks within this system to obtain more comprehensive knowledge of how allostery impacts cardiac physiology and disease.
Topics: Allosteric Regulation; Amino Acid Sequence; Animals; Humans; Protein Binding; Structure-Activity Relationship; Troponin C; Troponin I
PubMed: 30584890
DOI: 10.1016/j.abb.2018.12.026 -
Journal of Muscle Research and Cell... Mar 2020The molecular mechanism by which Ca binding and phosphorylation regulate muscle contraction through Troponin is not yet fully understood. Revealing the differences... (Review)
Review
The molecular mechanism by which Ca binding and phosphorylation regulate muscle contraction through Troponin is not yet fully understood. Revealing the differences between the relaxed and active structure of cTn, as well as the conformational changes that follow phosphorylation has remained a challenge for structural biologists over the years. Here we review the current understanding of how Ca, phosphorylation and disease-causing mutations affect the structure and dynamics of troponin to regulate the thin filament based on electron microscopy, X-ray diffraction, NMR and molecular dynamics methodologies.
Topics: Calcium; Humans; Muscle Contraction; Troponin I
PubMed: 31030382
DOI: 10.1007/s10974-019-09513-1 -
Molecules (Basel, Switzerland) Aug 2021Cardiovascular diseases are considered one of the major causes of human death globally. Myocardial infarction (MI), characterized by a diminished flow of blood to the... (Review)
Review
Cardiovascular diseases are considered one of the major causes of human death globally. Myocardial infarction (MI), characterized by a diminished flow of blood to the heart, presents the highest rate of morbidity and mortality among all other cardiovascular diseases. These fatal effects have triggered the need for early diagnosis of appropriate biomarkers so that countermeasures can be taken. Cardiac troponin, the central key element of muscle regulation and contraction, is the most specific biomarker for cardiac injury and is considered the "gold standard". Due to its high specificity, the measurement of cardiac troponin levels has become the predominant indicator of MI. Various forms of diagnostic methods have been developed so far, including chemiluminescence, fluorescence immunoassay, enzyme-linked immunosorbent assay, surface plasmon resonance, electrical detection, and colorimetric protein assays. However, fluorescence-based immunoassays are considered fast, accurate and most sensitive of all in the determination of cardiac troponins post-MI. This review represents the strategies, methods and levels of detection involved in the reported fluorescence-based immunoassays for the detection of cardiac troponin I.
Topics: Biomarkers; Fluorescence; Humans; Immunoassay; Myocardial Infarction; Troponin I
PubMed: 34443402
DOI: 10.3390/molecules26164812 -
Oncotarget Aug 2016Human tumors of various tissue origins show an intriguing over-expression of genes not considered oncogenes, such as that encoding Troponin-I (TnI), a well-known muscle...
Human tumors of various tissue origins show an intriguing over-expression of genes not considered oncogenes, such as that encoding Troponin-I (TnI), a well-known muscle protein. Out of the three TnI genes known in humans, the slow form, TNNI1, is affected the most. Drosophila has only one TnI gene, wupA. Here, we studied excess- and loss-of function of wupA in Drosophila, and assayed TNNI1 down regulation in human tumors growing in mice. Drosophila TnI excess-of-function increases proliferation and potentiates oncogenic mutations in Ras, Notch and Lgl genes. By contrast, TnI loss-of-function reduces proliferation and antagonizes the overgrowth due to these oncogenic mutations. Troponin-I defective cells undergo Flower- and Sparc-dependent cell competition. TnI can localize to the nucleus and its excess elicits transcriptional up-regulation of InR, Rap1 and Dilp8, which is consistent with the increased cell proliferation. Human tumor cell lines treated with a human Troponin-I peptide arrest in G0/G1. In addition, proliferation of non-small-cell lung carcinoma xenografts in mice is restrained by TNNI1 down-regulation. Thus, Troponin-I reveals a novel function in cell proliferation that may be of therapeutic interest in certain types of cancer.
Topics: A549 Cells; Animals; Animals, Genetically Modified; Drosophila Proteins; Drosophila melanogaster; Female; Gene Expression; Humans; Lung Neoplasms; Male; Mice, Nude; RNA Interference; RNAi Therapeutics; Troponin I; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 27437768
DOI: 10.18632/oncotarget.10616 -
Archives of Biochemistry and Biophysics May 2019The troponin complex plays a central role in regulating the contraction and relaxation of striated muscles. Among the three protein subunits of troponin, the calcium... (Review)
Review
The troponin complex plays a central role in regulating the contraction and relaxation of striated muscles. Among the three protein subunits of troponin, the calcium receptor subunit, TnC, belongs to the calmodulin family of calcium signaling proteins whereas the inhibitory subunit, TnI, and tropomyosin-binding/thin filament-anchoring subunit, TnT, are striated muscle-specific regulatory proteins. TnI and TnT emerged early in bilateral symmetric invertebrate animals and have co-evolved during the 500-700 million years of muscle evolution. To understand the divergence as well as conservation of the structures of TnI and TnT in invertebrate and vertebrate organisms adds novel insights into the structure-function relationship of troponin and the muscle type isoforms of TnI and TnT. Based on the significant growth of genomic database of multiple species in the past decade, this focused review studied the primary structure features of invertebrate troponin subunits in comparisons with the vertebrate counterparts. The evolutionary data demonstrate valuable information for a better understanding of the thin filament regulation of striated muscle contractility in health and diseases.
Topics: Animals; Biological Evolution; Invertebrates; Muscle Contraction; Muscle, Striated; Troponin I; Troponin T
PubMed: 30928296
DOI: 10.1016/j.abb.2019.03.013 -
Journal of Molecular Biology Jul 2016The troponin complex is a molecular switch that ties shifting intracellular calcium concentration to association and dissociation of actin and myosin, effectively... (Review)
Review
The troponin complex is a molecular switch that ties shifting intracellular calcium concentration to association and dissociation of actin and myosin, effectively allowing excitation-contraction coupling in striated muscle. Although there is a long history of muscle biophysics and structural biology, many of the mechanistic details that enable troponin's function remain incompletely understood. This review summarizes the current structural understanding of the troponin complex on the muscle thin filament, focusing on conformational changes in flexible regions of the troponin I subunit. In particular, we focus on order-disorder transitions in the C-terminal domain of troponin I, which have important implications in cardiac disease and could also have potential as a model system for the study of coupled binding and folding.
Topics: Actin Cytoskeleton; Animals; Calcium; Heart; Humans; Muscle, Skeletal; Protein Binding; Protein Folding; Troponin I
PubMed: 27395017
DOI: 10.1016/j.jmb.2016.06.022 -
American Journal of Physiology. Heart... Jul 2022Troponin released from irreversibly injured myocytes is the gold standard biomarker for the rapid identification of an acute coronary syndrome. In acute myocardial... (Review)
Review
Troponin released from irreversibly injured myocytes is the gold standard biomarker for the rapid identification of an acute coronary syndrome. In acute myocardial infarction, necrotic cell death is characterized by sarcolemmal disruption in response to a critical level of energy depletion after more than 15 min of ischemia. Although troponin I and T are highly specific for cardiomyocyte death, high-sensitivity assays have demonstrated that measurable circulating levels of troponin are present in many normal subjects. In addition, transient as well as chronic elevations have been demonstrated in many disease states not clearly associated with myocardial ischemia. The latter observations have given rise to the clinical concept of myocardial injury. This review will summarize evidence supporting the notion that circulating troponin levels parallel the extent of myocyte apoptosis in normal ventricular remodeling and in pathophysiological conditions not associated with infarction or necrosis. It will review the evidence that myocyte apoptosis can be accelerated by diastolic strain from elevated ventricular preload and systolic strain from dyskinesis after brief episodes of ischemia too short to cause a critical level of myocyte energy depletion. We then show how chronic, low rates of myocyte apoptosis from endogenous myocyte turnover, repetitive ischemia, or repetitive elevations in left ventricular diastolic pressure can lead to significant myocyte loss in the absence of neurohormonal stimulation. Finally, we posit that the differential response to strain-induced injury in heart failure may determine whether progressive myocyte loss and heart failure with reduced ejection fraction or interstitial fibrosis and heart failure with preserved ejection fraction become the heart failure phenotype.
Topics: Heart Failure; Humans; Myocardial Infarction; Myocytes, Cardiac; Necrosis; Troponin I; Ventricular Remodeling
PubMed: 35559722
DOI: 10.1152/ajpheart.00093.2022 -
Gene Jan 2016Troponin I (TnI) is the inhibitory subunit of the troponin complex in the sarcomeric thin filament of striated muscle and plays a central role in the calcium regulation... (Review)
Review
Troponin I (TnI) is the inhibitory subunit of the troponin complex in the sarcomeric thin filament of striated muscle and plays a central role in the calcium regulation of contraction and relaxation. Vertebrate TnI has evolved into three isoforms encoded by three homologous genes: TNNI1 for slow skeletal muscle TnI, TNNI2 for fast skeletal muscle TnI and TNNI3 for cardiac TnI, which are expressed under muscle type-specific and developmental regulations. To summarize the current knowledge on the TnI isoform genes and products, this review focuses on the evolution, gene regulation, posttranslational modifications, and structure-function relationship of TnI isoform proteins. Their physiological and medical significances are also discussed.
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Gene Expression Regulation; Humans; MAP Kinase Kinase Kinases; Molecular Sequence Data; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Sequence Homology, Amino Acid; Structure-Activity Relationship; Troponin I
PubMed: 26526134
DOI: 10.1016/j.gene.2015.10.052 -
Journal of the American College of... Apr 2018
Topics: Humans; Muscular Diseases; Troponin I; Troponin T
PubMed: 29622162
DOI: 10.1016/j.jacc.2018.01.068