High-resolution cryo-EM structure of the junction region of the native cardiac thin filament in relaxed state

Risi, Cristina; Belknap, Betty; White, Howard D.; Dryden, Kelly A.; Pinto, José R.; Chase, P. Bryant; Galkin, Vitold E.

doi:10.1093/pnasnexus/pgac298

Cited by 19 publications

(29 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Presently, the prevailing pathomechanism ascribed to thin-filament mutations (cardiac troponins and tropomyosin) associated with HCM involves the disruption of tropomyosin's ability to block myosin-binding sites on actin. [43][44][45] When this blockade is disrupted, myosinbinding sites become more accessible, thereby facilitating the formation of force-producing crossbridges. 36 In HCM, the destabilization of tropomyosin's blockade of actin can be further facilitated by the reduced phosphorylation of myofilament proteins, such as cTnI (cardiac troponin I), by PKA (protein kinase A).…”

Section: Influence Of Thin-filament Hcm-causing Mutations On Actin-ta...mentioning

confidence: 99%

“…As Ca 2+ concentration rises, tropomyosin moves, exposing most of the actin’s myosin-binding sites. 45,46,52 However, myosin is relatively weakly bound to actin (in the myosin-ADP-Pi state), and the myofilament remains inactive. 53 Myofilament activation occurs with the formation of strongly bound force-producing crossbridges (in the myosin-ADP state).…”

Section: Adp’s Influence In Shifting the Equilibrium Toward The Drx S...mentioning

confidence: 99%

See 1 more Smart Citation

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect

Sequeira,

Maack,

Reil

et al. 2024

Circulation Research

View full text Add to dashboard Cite

The Anrep effect is an adaptive response that increases left ventricular contractility following an acute rise in afterload. Although the mechanistic origin remains undefined, recent findings suggest a two-phase activation of resting myosin for contraction, involving strain-sensitive and posttranslational phases. We propose that this mobilization represents a transition among the relaxed states of myosin—specifically, from the super-relaxed (SRX) to the disordered-relaxed (DRX)—with DRX myosin ready to participate in force generation. This hypothesis offers a unified explanation that connects myosin’s SRX-DRX equilibrium and the Anrep effect as parts of a singular phenomenon. We underscore the significance of this equilibrium in modulating contractility, primarily studied in the context of hypertrophic cardiomyopathy, the most common inherited cardiomyopathy associated with diastolic dysfunction, hypercontractility, and left ventricular hypertrophy. As we posit that the cellular basis of the Anrep effect relies on a two-phased transition of myosin from the SRX to the contraction-ready DRX configuration, any dysregulation in this equilibrium may result in the pathological manifestation of the Anrep phenomenon. For instance, in hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect. These valuable insights call for additional research to uncover a clinical Anrep fingerprint in pathological states. Here, we demonstrate through noninvasive echocardiographic pressure-volume measurements that this fingerprint is evident in 12 patients with hypertrophic obstructive cardiomyopathy before septal myocardial ablation. This unique signature is characterized by enhanced contractility, indicated by a leftward shift and steepening of the end-systolic pressure-volume relationship, and a prolonged systolic ejection time adjusted for heart rate, which reverses post-procedure. The clinical application of this concept has potential implications beyond hypertrophic cardiomyopathy, extending to other genetic cardiomyopathies and even noncongenital heart diseases with complex etiologies across a broad spectrum of left ventricular ejection fractions.

show abstract

Section: Influence Of Thin-filament Hcm-causing Mutations On Actin-ta...mentioning

confidence: 99%

Section: Adp’s Influence In Shifting the Equilibrium Toward The Drx S...mentioning

confidence: 99%

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect

Sequeira,

Maack,

Reil

et al. 2024

Circulation Research

View full text Add to dashboard Cite

show abstract

“…According to structural models of the F-actin-Tpm complex, only residues D20 and E181 form electrostatic contacts with a cluster of charged residues on actin comprising K326 and K328. 18,30 Results of this work provide mechanistic insights into the muscle disease phenotypes linked to mutations in TPM2. We found that, in consistency with the clinical phenotypes, mutations in first and second halves of the actin-binding periods of Tpm2.2 can either strengthen or weaken the inhibitory potential of Tpm2.2 by affecting the position of Tpm2.2 on the filament and changing kinetics of ATP turnover and product release by myosin head.…”

Section: Introductionmentioning

confidence: 99%

“…All four selected substitutions are in the “f” positions of the heptad repeat, which are exposed outside the coiled coil and are potentially available for Tpm2.2 interactions with binding partners (Figure 1B). According to structural models of the F‐actin‐Tpm complex, only residues D20 and E181 form electrostatic contacts with a cluster of charged residues on actin comprising K326 and K328 18,30 …”

Section: Introductionmentioning

confidence: 99%

Mechanochemical consequences of myopathy‐linked mutations in Tpm2.2 on striated muscle contractility

Küçükdogru,

Franz,

Worch

et al. 2023

The FASEB Journal

View full text Add to dashboard Cite

Tropomyosin (Tpm) is an actin‐binding protein central to muscle contraction regulation. The Tpm sequence consists of periodic repeats corresponding to seven actin‐binding sites, further divided in two functionally distinct halves. To clarify the importance of the first and second halves of the actin‐binding periods in regulating the interaction of myosin with actin, we introduced hypercontractile mutations D20H, E181K located in the N‐terminal halves of periods 1 and 5 and hypocontractile mutations E41K, N202K located in the C‐terminal halves of periods 1 and 5 of the skeletal muscle Tpm isoform Tpm2.2. Wild‐type and mutant Tpms displayed similar actin‐binding properties, however, as revealed by FRET experiments, the hypercontractile mutations affected the binding geometry and orientation of Tpm2.2 on actin, causing a stimulation of myosin motor performance. Contrary, the hypocontractile mutations led to an inhibition of both, actin activation of the myosin ATPase and motor activity, that was more pronounced than with wild‐type Tpm2.2. Single ATP turnover kinetic experiments indicate that the introduced mutations have opposite effects on product release kinetics. While the hypercontractile Tpm2.2 mutants accelerated product release, the hypocontractile mutants decelerated product release from myosin, thus having either an activating or inhibitory influence on myosin motor performance, which agrees with the muscle disease phenotypes caused by these mutations.

show abstract

“…1 A , green and yellow ribbons); ii) orienting the cTn core domain relative to the direction of the thin filament; and iii) stabilizing the tropomyosin head-to-tail region ( Fig. 1 A , black bracket) ( 3 – 10 ). Structural studies demonstrated that the loop region of TnT1 interacts with the actin backbone of the cardiac thin filament via ionic bonds ( Fig.…”

mentioning

confidence: 99%

Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function

Landim-Vieira

Song

et al. 2023

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

Self Cite

View full text Add to dashboard Cite

Missense variant Ile79Asn in human cardiac troponin T (cTnT-I79N) has been associated with hypertrophic cardiomyopathy and sudden cardiac arrest in juveniles. cTnT-I79N is located in the cTnT N-terminal (TnT1) loop region and is known for its pathological and prognostic relevance. A recent structural study revealed that I79 is part of a hydrophobic interface between the TnT1 loop and actin, which stabilizes the relaxed (OFF) state of the cardiac thin filament. Given the importance of understanding the role of TnT1 loop region in Ca 2+ regulation of the cardiac thin filament along with the underlying mechanisms of cTnT-I79N-linked pathogenesis, we investigated the effects of cTnT-I79N on cardiac myofilament function. Transgenic I79N (Tg-I79N) muscle bundles displayed increased myofilament Ca 2+ sensitivity, smaller myofilament lattice spacing, and slower crossbridge kinetics. These findings can be attributed to destabilization of the cardiac thin filament’s relaxed state resulting in an increased number of crossbridges during Ca 2+ activation. Additionally, in the low Ca 2+ -relaxed state (pCa8), we showed that more myosin heads are in the disordered-relaxed state (DRX) that are more likely to interact with actin in cTnT-I79N muscle bundles. Dysregulation of the myosin super-relaxed state (SRX) and the SRX/DRX equilibrium in cTnT-I79N muscle bundles likely result in increased mobility of myosin heads at pCa8, enhanced actomyosin interactions as evidenced by increased active force at low Ca 2+ , and increased sinusoidal stiffness. These findings point to a mechanism whereby cTnT-I79N weakens the interaction of the TnT1 loop with the actin filament, which in turn destabilizes the relaxed state of the cardiac thin filament.

show abstract

High-resolution cryo-EM structure of the junction region of the native cardiac thin filament in relaxed state

Cited by 19 publications

References 81 publications

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect

Mechanochemical consequences of myopathy‐linked mutations in Tpm2.2 on striated muscle contractility

Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function

Contact Info

Product

Resources

About