The evolutionarily conserved C-terminal peptide of troponin I is an independently configured regulatory structure to function as a myofilament Ca2+-desensitizer

Wong, Sienna; Feng, Han‐Zhong; Jin, Jian Ping

doi:10.1016/j.yjmcc.2019.09.002

Cited by 13 publications

(28 citation statements)

References 43 publications

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“…Our results show that HcTnI-C27 binds aTm with an affinity in the order of low micromolar (~10 µM). This finding is in agreement with the previous report that the HcTnI-C27 peptide is capable of competing at low micromolar concentration with intact bovine cardiac TnI for binding to aTm whereas the HcTnI-C27-H mutant peptide showed a decreased effect in the competitive binding assay (12). Supporting this notion, our fluorescence measurements in the present study show that the Tm-binding affinity of HcTnI-C27-H was lower than that of the wild-type peptide (Fig.…”

Section: C27 Peptide Binds Atm With Micromolar Affinitysupporting

confidence: 94%

“…To establish the functional significance of the structural data, contractility studies showed that the addition of HcTnI-C27 peptide reproduced the Ca 2+desensitization effect with a right-shift of the force-pCa curve in skinned mouse cardiac muscle strips (Fig. 9A) as reported previously (12). The effect was greater at longer sarcomere length of 2.3 μm than that at sarcomere length of 2.0 μm (Fig.…”

Section: Impaired Effect Of the Myopathic Mutant Peptide Hctni-c27-h supporting

confidence: 76%

“…We have previously shown that it is a Ca 2+ -regulated exposed allosteric structure in reconstituted troponin complex and binds tropomyosin at low Ca 2+ -state, indicating a role in the inhibitory function of TnI during muscle relaxation ( 11 ). Independent of the TnI backbone, isolated C27 peptide folds into a native conformation recognized by an anti-TnI C-terminus monoclonal antibody (mAb) TnI-1 ( 6 ) in physiological solution and retains binding affinity for Tm ( 12 ). The mAb TnI-1 recognized epitope in the C-terminal end peptide of TnI is conserved in all vertebrate TnI sequenced to date.…”

mentioning

confidence: 99%

“…The mAb TnI-1 recognized epitope in the C-terminal end peptide of TnI is conserved in all vertebrate TnI sequenced to date. A restrictive cardiomyopathy mutation (Arg192His) in the C-terminal end segment of cardiac TnI ( 13 ) diminishes the bindings to mAb TnI-1 and Tm ( 12 ).…”

mentioning

confidence: 99%

“…When added to skinned cardiac muscle strips, the C27 peptide of human cardiac TnI (HcTnI-C27) causes reduction of myofilament Ca 2+ -sensitivity especially at the activated state without decreasing the maximum force production ( 12 ). The data indicate that the C-terminal end segment of TnI is a regulatory element of troponin, which retains the native configuration and physiological effect on myofilament Ca 2+ -desensitization in the form of free peptide.…”

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confidence: 99%

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The muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect

Hornos

Feng

Rizzuti

et al. 2021

Journal of Biological Chemistry

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The conserved C-terminal end segment of troponin I (TnI) plays a critical role in regulating muscle relaxation. This function is retained in the isolated C-terminal 27 amino acid peptide (residues 184–210) of human cardiac TnI (HcTnI-C27): When added to skinned muscle fibers, HcTnI-C27 reduces the Ca 2+ -sensitivity of activated myofibrils and facilitates relaxation without decreasing the maximum force production. However, the underlying mechanism of HcTnI-C27 function is unknown. We studied the conformational preferences of HcTnI-C27 and a myopathic mutant, Arg192His, (HcTnI-C27-H). Both peptides were mainly disordered in aqueous solution with a nascent helix involving residues from Trp191 to Ile195, as shown by NMR analysis and molecular dynamics simulations. The population of nascent helix was smaller in HcTnI-C27-H than in HcTnI-C27, as shown by circular dichroism (CD) titrations. Fluorescence and isothermal titration calorimetry (ITC) showed that both peptides bound tropomyosin (αTm), with a detectably higher affinity (∼10 μM) of HcTnI-C27 than that of HcTnI-C27-H (∼15 μM), consistent with an impaired Ca 2+ -desensitization effect of the mutant peptide on skinned muscle strips. Upon binding to αTm, HcTnI-C27 acquired a weakly stable helix-like conformation involving residues near Trp191, as shown by transferred nuclear Overhauser effect spectroscopy and hydrogen/deuterium exchange experiments. With the potent Ca 2+ -desensitization effect of HcTnI-C27 on skinned cardiac muscle from a mouse model of hypertrophic cardiomyopathy, the data support that the C-terminal end domain of TnI can function as an isolated peptide with the intrinsic capacity of binding tropomyosin, providing a promising therapeutic approach to selectively improve diastolic function of the heart.

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Section: C27 Peptide Binds Atm With Micromolar Affinitysupporting

confidence: 94%

Section: Impaired Effect Of the Myopathic Mutant Peptide Hctni-c27-h supporting

confidence: 76%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect

Hornos

Feng

Rizzuti

et al. 2021

Journal of Biological Chemistry

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Potential impacts of the cardiac troponin I mobile domain on myofilament activation and relaxation

Creso

Campbell

2021

Journal of Molecular and Cellular Cardiology

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Troponin-I–induced tropomyosin pivoting defines thin-filament function in relaxed and active muscle

Lehman

Rynkiewicz

2023

Journal of General Physiology

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Regulation of the crossbridge cycle that drives muscle contraction involves a reconfiguration of the troponin–tropomyosin complex on actin filaments. By comparing atomic models of troponin–tropomyosin fitted to cryo-EM structures of inhibited and Ca2+-activated thin filaments, we find that tropomyosin pivots rather than rolls or slides across actin as generally thought. We propose that pivoting can account for the Ca2+ activation that initiates muscle contraction and then relaxation influenced by troponin-I (TnI). Tropomyosin is well-known to occupy either of three meta-stable configurations on actin, regulating access of myosin motorheads to their actin-binding sites and thus the crossbridge cycle. At low Ca2+ concentrations, tropomyosin is trapped by TnI in an inhibitory B-state that sterically blocks myosin binding to actin, leading to muscle relaxation. Ca2+ binding to TnC draws TnI away from tropomyosin, while tropomyosin moves to a C-state location over actin. This partially relieves the steric inhibition and allows weak binding of myosin heads to actin, which then transition to strong actin-bound configurations, fully activating the thin filament. Nevertheless, the reconfiguration that accompanies the initial Ca2+-sensitive B-state/C-state shift in troponin–tropomyosin on actin remains uncertain and at best is described by moderate-resolution cryo-EM reconstructions. Our recent computational studies indicate that intermolecular residue-to-residue salt-bridge linkage between actin and tropomyosin is indistinguishable in B- and C-state thin filament configurations. We show here that tropomyosin can pivot about relatively fixed points on actin to accompany B-state/C-state structural transitions. We argue that at low Ca2+ concentrations C-terminal TnI domains attract tropomyosin, causing it to bend and then pivot toward the TnI, thus blocking myosin binding and contraction.

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The evolutionarily conserved C-terminal peptide of troponin I is an independently configured regulatory structure to function as a myofilament Ca2+-desensitizer

Cited by 13 publications

References 43 publications

The muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect

The muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect

Potential impacts of the cardiac troponin I mobile domain on myofilament activation and relaxation

Troponin-I–induced tropomyosin pivoting defines thin-filament function in relaxed and active muscle

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