Troponin: biology, molecular mechanisms, and multidimensional clinical applications

Figures

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  Fig. 1. The figure shows the cardiac troponin complex. a Cardiac troponins I and C are displayed in light gray, while cardiac troponin T helix H1 is highlighted in red and helix H2 in yellow. Troponin T is composed of three major domains: the N-terminal domain, the linker region, and the C-terminal domain. Based on fragmentation studies, it is also divided into the T1 and T2 fragments, corresponding to the N-terminal and C-terminal domains, respectively. The N-terminal domain begins with a hypervariable region and includes a tropomyosin-binding site. The linker region connects the N-terminal and C-terminal domains. The C-terminal domain consists of helices H1 and H2, as well as the C-terminal peptide. In this model, only helices H1 and H2 are shown. Helix H2 interacts with troponins I and C. b Cardiac troponins T and C are displayed in light gray, while the domains of cardiac troponin I are highlighted. The IT arm domain is shown in red, the inhibitory peptide in yellow, and the switch peptide in green. Troponin I consists of six structural regions: the N-terminal cardiac-specific extension, the N-terminal region, the IT arm, the inhibitory peptide, the switch peptide, and the C-terminal…

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  Fig. 2. We employed bioinformatic tools to further elucidate nuclear localization sequences (NLSs) and leucine zipper domains (LZD) in structure of troponin complex subunits. We used PSORT II web based subcellular localization prediction tool, to look for NLSs and Clustal Omega tool for multiple sequence alignment of troponin isoforms. All sequences were downloaded from Uniprot database. a TNNT3 non-canonical LZD sequence is highlighted in green. Canonical LZD motifs of TNNT2 and isoforms 2 and 3 of TNNT1 are highlighted in yellow. Leucines (L) and phenylalanine (F) are marked by squares. Presence of non-canonical LZD motif in mouse TNNT3 was proposed and supported by changes in apoptosis induced by mutation in the proposed LZD sequence. The human TNNT3 also has a predicted non-canonical LZD sequence that differs from the mouse ortholog only by two substitutions: tyrosine to histidine at position 13 and threonine to isoleucine at position 17. Other troponin T isoforms sequences include predicted cannonical LZD motif. Isoform 1 of TNNT1 is not included in the picture, because it does not include canonical LZD motif. It is plausible that it contains non-cannonical LZD. b PSORT II…

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  Fig. 3. Several troponin isoforms are involved in the regulation of gene expression. TNNI2 binds to the nuclear receptor ERRα via its LXXLL motif and functions as a co-activator. The TNNI2-ERRα complex binds to ERREs and regulates the expression of ERRα downstream targets. Because ERRα target genes are co-activator-specific and those regulated specifically by TNNI2 have not been described, dashed lines are used to connect this complex to several known functions of ERRα. TNNI3 associates with the transcription factor YY1, which recruits cofactors (co-activators and co-repressors) that modulate its activity. Both TNNI3 and YY1 bind to the CCAT motif. The TNNI3-YY1 complex binds to the promoter of the ATP2A2 gene and upregulates its expression. ATP2A2 encodes SERCA2, which is essential for the reuptake of calcium into the sarcoplasmic reticulum following muscle contraction. The TNNI3-YY1 complex also binds to a CCAT motif in the promoter of the FOS gene, resulting in increased c-Fos expression. Although c-Fos has multiple functions, it also promotes the expression of the key autophagy regulator ATG5. Through this mechanism, TNNI3 enhances autophagy. TNNT3 increases the expression of RRM2B…

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  Fig. 4. Summary of the effects of troponin isoforms on mitochondria. TNNI3 interacts with the d subunit of mitochondrial F₁F₀-ATP synthase. This interaction requires the N-terminal region of TNNI3, which binds to the peripheral stalk of the F₁F₀-ATP synthase complex. Increased TNNI3 binding reduces ATP synthase activity while enhancing its ATP hydrolase activity and ATP degradation. These changes disrupt mitochondrial energy metabolism and promote cellular damage. Elevated TNNI3 levels also increase the permeability of the mPTP, thereby promoting apoptosis. TNNI3 R193H mutant variant interacts with HDAC1 and enhances its binding to the promoter region of the PDE4D gene. This leads to reduced histone acetylation and repression of PDE4D expression. Expression of the TNNI3 R193H is also associated with decreased levels of proteins involved in mitochondrial metabolism, including ND5, LRPPRC, and PGC-1α. The mechanism by which TNNI3 R193H causes these changes remains unknown. The same mutation is also associated with mitochondrial structural damage, including vacuolization, disrupted cristae, and signs of mitophagy. Abbreviations: mPTP: mitochondrial permeability transition pore, HDAC1:…

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  Fig. 5. Troponin isoforms are involved in the regulation of EMT in cancer cells. Specifically, TNNC1 promotes EMT in ovarian cancer cells, whereas TNNT1 promotes EMT in colorectal carcinoma, lung squamous cell carcinoma and lung adenocarcinoma cells. EMT is regulated by several signaling pathways, including integrin, TGF-β, receptor tyrosine kinases, and Wnt signaling pathways. TNNC1 expression is associated with the phosphorylation of Akt and GSK-3β. Akt phosphorylates GSK-3β at serine 9, leading to its inactivation. In its active unphosphorylated state, GSK-3β suppresses EMT by phosphorylating transcription factors such as Snail and Slug, thereby targeting them for proteasomal degradation. GSK-3β is also inhibited by LRP6, a co-receptor in the Wnt/β-catenin signaling pathway. TNNT1 expression is associated with increased levels of several EMT-related proteins, including the transcription factor Snail. TNNT1 is presumed to promote this increase in Snail levels by affecting GSK-3β activity; however, the mechanism by which TNNT1 inhibits GSK-3β has not yet been elucidated with potential involvement of Wnt cascade being proposed.Abbreviations:EMT: epithelial-mesenchymal transition, TGF-β:…

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  Fig. 6. Outstanding questions regarding the non-classical functions of troponin. This figure provides an overview of the most important unanswered questions, the answers to which would substantially advance our understanding of troponin's cellular roles under both physiological and pathological conditions. Abbreviations: NLS: nuclear localization signal, LZD: leucine zipper domain