Tropomyosin is in a reduced state in rat cardiac muscle
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Tropomyosin
Cardiac muscle
In both cardiac and skeletal muscles, contraction begins when Ca2+ binds to a regulatory site or sites in the N-lobe of troponin (Tn) C. Ca2+ binding to TnC induces sequential protein–protein interactions between TnC and TnI, TnI and TnT, and TnI–TnT and tropomyosin (Tm). As a result, Tm moves along actin (A) molecules exposing the sites for myosin S1 to attach thus leading to contraction. Recent protein biochemical, protein crystal structural, and cell physiology studies have advanced our understanding of the structure and function of myofilament proteins, especially the thin filament proteins (reviewed in Gordon et al. 2000; Kobayashi & Solaro, 2005). It has been demonstrated that for each seven actin monomers, there is one Tm and one Tn (7: 1: 1, A: Tm: Tn), which makes up one regulatory unit (RU). This structural arrangement forms the basis for cooperative interactions not only between Tn–Tm along the thin filament within the unit but also cooperative interactions between near-neighbouring regulatory units when cross-bridges are formed. In fact, it has been hypothesized that 12–14 actin monomers are controlled by one Tn. This hypothesis has recently been supported by Regnier et al. (2002) who have shown that in skeletal muscle, Ca2+-triggered activation of thin filament spread beyond the regulatory unit up to 10–12 actins which compose one functional unit (FU). What about cardiac muscle activation? The sequential events after Ca2+ binding to TnC are very similar in both types of muscles. However, several lines of evidence may indicate that cardiac muscle activates in a unique fashion. (1) The Ca2+ transient during systole may not be long enough to fully activate the thin filament. (2) Cardiac muscle must have a greater sarcomere length dependence of force development due to the narrow range of sarcomere lengths the heart normally works. (3) Cardiac muscle is more responsive to neuro/hormonal stimulation. In this issue of The Journal of Physiology, Gillis et al. (2007) have demonstrated that a cardiac FU in thin filament activation is limited within a RU in that Tn activates ≤ 7 actins upon Ca2+ activation, and that the behaviour of the cardiac FU depends on bound cross-bridges within the RU and is relatively independent of near-neighbour FUs (i.e. greater local control of activation). Although the molecular mechanism for the local control of thin filament activation is not precisely known, these findings indeed highlight the fact that different isoforms of regulatory proteins may be responsible for the differences in thin filament activation between cardiac and fast skeletal muscles. For example, as discussed by Gillis et al. structural and kinetic differences in Ca2+ binding to cTnC, cTnI–cTnC interactions between fast skeletal and cardiac isoforms, as well as more flexible Tm in cardiac muscle could contribute to the differences in RUs between skeletal and cardiac muscle. The findings that cardiac muscle activation is more limited within the RU and has a greater reliance on crossbridge attachment, thus allowing greater and finer local control of activation and force generation, has important implications for pathophysiological states. For example, hypertrophic and dilated cardiomyopathies can be caused by mutations in genes which encode thick or thin filament proteins (Morita et al. 2005). These mutant proteins impact on Ca2+ sensitivity, sarcomere length dependence and also cross-bridge behaviour of the cardiac muscle. Post-translational modifications also impact on thin filament proteins in disease states including degradation and oxidation of myofilament proteins in ischaemia/reperfusion injury which are functionally significant. Finally, cardiac muscle activation is influenced by neuro/hormonal modulation via protein kinase signalling pathways. In heart failure, altered phosphorylation of myofilament proteins may alter cross-bridge dynamics and decrease force production. Precisely how of each of the myofilament proteins contribute to the limited near-neighbour interactions and greater cross-bridge attachment control of activation in cardiac muscle is not known and should be the focus of future investigations. Understanding the molecular properties of these regulatory proteins will no doubt help us to better appreciate the nature of cardiac contraction at both whole organ and cellular level in health and disease.
Tropomyosin
Myofilament
Cardiac muscle
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Tropomyosin
Cardiac muscle
Myofilament
Troponin complex
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Tropomyosin
Bivalent (engine)
Troponin C
Troponin complex
Cardiac muscle
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Significance Muscle contraction is required for critical physiological functions. It relies on the interaction of myosin motors with the thin filament (TF), which is regulated through a translocation of tropomyosin on the surface of F-actin by the troponin complex in response to Ca 2+ . The lack of high-resolution structure of the TF under relaxing (low-Ca 2+ ) and activating (high-Ca 2+ ) conditions impairs our understanding of the mechanism of cardiac muscle regulation. Here we report high-resolution structures of the native cardiac TF under relaxing and activating conditions. Our data lead to a model for cardiac TF regulation by Ca 2+ levels that is an important step in understanding how the components of cardiac muscle work in concert to maintain healthy heart functions.
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The functional significance of the molecular swivel at the head-to-tail overlapping ends of contiguous tropomyosin (Tm) dimers in striated muscle is unknown. Contractile measurements were made in muscle fibers from transgenic (TG) mouse hearts that expressed a mutant α-Tm (TmH276N). We also reconstituted mouse cardiac troponin T (McTnT) N-terminal deletion mutants, McTnT1–44Δ and McTnT45–74Δ, into muscle fibers from TmH276N. For controls, we used the wild-type (WT) McTnT because altered effects could be correlated with the mutant forms of McTnT. TmH276N slowed crossbridge (XB) detachment rate (g) by 19%. McTnT1-44Δ attenuated Ca2+-activated maximal tension against TmWT (36%) and TmH276N (38%), but sped g only against TmH276N by 35%. The rate of tension redevelopment decreased (17%) only in McTnT1–44Δ + TmH276N fibers. McTnT45–74Δ attenuated tension (19%) and myofilament Ca2+ sensitivity (pCa50=5.93 vs. 6.00 in the control fibers) against TmH276N, but not against TmWT background. Thus, altered XB cycling kinetics decreased the fraction of strongly bound XBs in McTnT1-44Δ + TmH276N fibers, whereas diminished thin-filament cooperativity attenuated tension in McTnT45-74Δ + TmH276N fibers. In summary, our study is the first to show that the interplay between the N terminus of cTnT and the overlapping ends of contiguous Tm effectuates different states of Tm on the actin filament. —Mamidi, R., Michael, J. J., Muthuchamy, M., Chandra, M., Interplay between the overlapping ends of tropomyosin and the N terminus of cardiac troponin T affects tropomyosin states on actin. FASEB J. 27, 3848–3859 (2013). www.fasebj.org
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Tropomyosin
Cardiac muscle
Myofilament
Troponin complex
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The cardiac thin filament regulates actomyosin interactions through calcium-dependent alterations in the dynamics of cardiac troponin and tropomyosin. Over the past several decades, many details of the structure and function of the cardiac thin filament and its components have been elucidated. We propose a dynamic, complete model of the thin filament that encompasses known structures of cardiac troponin, tropomyosin, and actin and show that it is able to capture key experimental findings. By performing molecular dynamics simulations under two conditions, one with calcium bound and the other without calcium bound to site II of cardiac troponin C (cTnC), we found that subtle changes in structure and protein contacts within cardiac troponin resulted in sweeping changes throughout the complex that alter tropomyosin (Tm) dynamics and cardiac troponin--actin interactions. Significant calcium-dependent changes in dynamics occur throughout the cardiac troponin complex, resulting from the combination of the following: structural changes in the N-lobe of cTnC at and adjacent to sites I and II and the link between them; secondary structural changes of the cardiac troponin I (cTnI) switch peptide, of the mobile domain, and in the vicinity of residue 25 of the N-terminus; secondary structural changes in the cardiac troponin T (cTnT) linker and Tm-binding regions; and small changes in cTnC-cTnI and cTnT-Tm contacts. As a result of these changes, we observe large changes in the dynamics of the following regions: the N-lobe of cTnC, the mobile domain of cTnI, the I-T arm, the cTnT linker, and overlapping Tm. Our model demonstrates a comprehensive mechanism for calcium activation of the cardiac thin filament consistent with previous, independent experimental findings. This model provides a valuable tool for research into the normal physiology of cardiac myofilaments and a template for studying cardiac thin filament mutations that cause human cardiomyopathies.
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Tropomyosin (Tm) is the key regulatory com- ponent of the thin-filament and plays a central role in the cardiac muscle's cooperative activation mechanism. Many mutations of cardiac Tm are related to hypertrophic car- diomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC). Using the thin- filament extraction/reconstitution technique, we are able to incorporate various Tm mutants and protein isoforms into a muscle fiber environment to study their roles in Ca 2? regulation, cross-bridge kinetics, and force generation. The thin-filament reconstitution technique poses several advantages compared to other in vitro and in vivo methods: (1) Tm mutants and isoforms are placed into the real muscle fiber environment to exhibit their effect on a level much higher than simple protein complexes; (2) only the primary and immediate effects of Tm mutants are studied in the thin-filament reconstituted myocardium; (3) lethal mutants of Tm can be studied without causing a problem; and (4) inexpensive. In transgenic models, various sec- ondary effects (myocyte disarray, ECM fibrosis, altered protein phosphorylation levels, etc.) also affect the per- formance of the myocardium, making it very difficult to isolate the primary effect of the mutation. Our studies on Tm have demonstrated that: (1) Tm positively enhances the hydrophobic interaction between actin and myosin in the ''closed state'', which in turn enhances the isometric ten- sion; (2) Tm's seven periodical repeats carry distinct functions, with the 3rd period being essential for the ten- sion enhancement; (3) Tm mutants lead to HCM by impairing the relaxation on one hand, and lead to DCM by over inhibition of the AM interaction on the other hand. Ca 2? sensitivity is affected by inorganic phosphate, ionic strength, and phosphorylation of constituent proteins; hence it may not be the primary cause of the pathogenesis. Here, we review our current knowledge regarding Tm's effect on the actomyosin interaction and the early molec- ular pathogenesis of Tm mutation related to HCM, DCM, and LVNC.
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