{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNNC1, which encodes cardiac troponin C (cTnC), is the central Ca²⁺‐sensing component of the troponin complex in the cardiac thin filament. Binding of Ca²⁺ to the low‑affinity N‑terminal regulatory domain of cTnC induces a conformational “opening” that exposes a hydrophobic patch, thereby permitting interaction with troponin I. This interaction relieves the inhibitory constraints on actin and initiates the cascade of protein–protein interactions that ultimately enable myocardial contraction. Structural and spectroscopic studies have detailed these dynamic allosteric transitions, establishing cTnC as a molecular switch critical for coupling intracellular Ca²⁺ fluctuations to cardiac muscle activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in TNNC1 can perturb these tightly regulated Ca²⁺‐dependent processes, thereby contributing to cardiomyopathic phenotypes. Several studies have identified single amino acid substitutions—including variants such as L29Q, G159D, and others—that either enhance or diminish Ca²⁺ sensitivity and modify the kinetics of force generation. Such mutations frequently alter the binding affinity between cTnC and troponin I, interfere with β‑adrenergic modulation, and disrupt the equilibrium of cross‑bridge cycling, ultimately leading to either hypertrophic, dilated, or restrictive cardiomyopathy. These observations highlight the delicate balance in cTnC’s role in regulating myocardial contractility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its fundamental role in Ca²⁺ sensing, TNNC1 serves as a pivotal hub that integrates post‑translational modifications and pharmacological modulation to fine‑tune myofilament activity. Alterations in the cTnC–troponin I interaction—whether through phosphorylation, ligand binding, or even rationally engineered mutations—can recalibrate the Ca²⁺ responsiveness of the thin filament, thereby affecting contractile kinetics and force production. Such mechanistic insights have underscored the potential of targeting cTnC dynamics for diagnostic purposes and for the development of therapeutic strategies to restore proper cardiac function in the setting of disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Darrin A Lindhout, Brian D Sykes "}, {"type": "b", "children": [{"type": "t", "text": "Structure and dynamics of the C-domain of human cardiac troponin C in complex with the inhibitory region of human cardiac troponin I."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M302497200"}], "href": "https://doi.org/10.1074/jbc.M302497200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12732641"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12732641"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Shoji Ueki, Motoyoshi Nakamura, Tomotaka Komori, et al. 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Structure and functions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (Mosc) (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1134/S0006297913130063"}], "href": "https://doi.org/10.1134/S0006297913130063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24490734"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24490734"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Monica X Li, Peter M Hwang "}, {"type": "b", "children": [{"type": "t", "text": "Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2015.07.074"}], "href": "https://doi.org/10.1016/j.gene.2015.07.074"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26232335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26232335"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Anja Schmidtmann, Christopher Lindow, Sylvie Villard, et al. 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