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

Hornos, Felipe; Feng, Han‐Zhong; Rizzuti, Bruno; Palomino‐Schätzlein, Martina; Wieczorek, David F.; Neira, José L.; Jin, Jian‐Ping

doi:10.1074/jbc.ra120.016012

Cited by 5 publications

(7 citation statements)

References 76 publications

(123 reference statements)

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“…We previously demonstrated that the C-terminal end 27 AA (C27) segment of TnI recognized by mAb TnI-1 binds Tm (Zhang, Akhter et al 2011). The cTnI-C27 epitope structure was preserved in both isolated C27 peptide of TnI and in intact cTnI as detectable by mAb TnI-1 (Wong, Feng et al 2019) and functions as an activated state myofilament Ca 2+ desensitizer (Wong, Feng et al 2019, Hornos, Feng et al 2021). Therefore, we further tested whether the TnI-1 epitope structure resumed in the C-terminal end segment of cTnT also binds Tm.…”

Section: Resultsmentioning

confidence: 99%

“…The mAb TnI-1 recognized C-terminal end segment of TnI is a Ca 2+ -regulated allosteric Tm-binding structure in the troponin complex (Zhang, Akhter et al 2011). The C-terminal end 27 amino acids segment of cardiac TnI (cTnI-C27) binds Tm in the form of free peptide with functional effect on reducing the Ca 2+ sensitivity of activated cardiac muscle strips (Wong, Feng et al 2019, Hornos, Feng et al 2021.…”

Section: Introductionmentioning

confidence: 99%

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The Conserved C-terminal End Segment of Troponin T Is A New Tropomyosin-Binding Site Modulating the Kinetics of Cardiac Muscle

Cao

Feng

Jin

2023

Preprint

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Evolved from duplication of a troponin I (TnI)-like ancestor gene, troponin T (TnT) and TnI are two subunits of the troponin complex that regulates the contraction and relaxation of striated muscles. Proteolytic deletion of the evolutionarily added N-terminal variable region of TnT in adaptation to acute myocardial stress restores a conformation like that of the C-terminal end segment of TnI, a tropomyosin (Tm)-binding and inhibitory structure, with an effect on reducing the contractile velocity of cardiac muscle to prolong ejection time and sustain the stroke volume. To investigate the underlying mechanism of this adaptive conditional function of TnT that is known to have two Tm-binding sites, our study localized a conformationally modulated new Tm-binding site in the highly conserved 14 amino acid C-terminal end segment of TnT. Localized surface plasmon resonance data showed that a hypertrophic cardiomyopathy mutation R278C within the C-terminal end segment of TnT alters the tropomyosin binding with direct responses to physiological concentrations of Ca2+. The functions are retained in the form of free peptide with an inhibitory regulatory effect on the contractile and relaxation kinetics of skinned cardiac muscle. In addition to revealing the underlying mechanisms of cTnT-ND adaptation and cardiac TnT C-terminal myopathic mutations, the new findings provide novel insights into the structure-function relationship of TnT in the kinetics of striated muscle contraction and relaxation with broad physiological and pathophysiological implications.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Conserved C-terminal End Segment of Troponin T Is A New Tropomyosin-Binding Site Modulating the Kinetics of Cardiac Muscle

Cao

Feng

Jin

2023

Preprint

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“…Studies in aging-induced and cardiac disorder-induced diastolic abnormalities indicate the potential for therapeutic applications of our findings. The effects of cTnI-ND provide information for targeting the sarcomere with small molecules or peptides such as that derived the COOH-terminus of cTnI [34]. The success in the use of small molecules for inhibition of the hypercontractility in the clinical course of advanced HCM [35] indicates the importance of detection of new targets to address the diverse responses to triggering mutations in HCM [36].…”

Section: Discussionmentioning

confidence: 99%

NH2-Terminal Cleavage of Cardiac Troponin I Signals Adaptive Response to Cardiac Stressors

Warren

Hałas

Feng

et al. 2021

Journal of Cellular Signaling

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Cardiac sarcomeres express a variant of troponin I (cTnI) that contains a unique N-terminal extension of ~30 amino acids with regulatory phosphorylation sites. The extension is important in the control of myofilament response to Ca 2+ , which contributes to the neuro-humoral regulation of the dynamics of cardiac contraction and relaxation. Hearts of various species including humans express a stress-induced truncated variant of cardiac troponin I (cTnI-ND) missing the first ~30 amino acids and functionally mimicking the phosphorylated state of cTnI. Studies have demonstrated that upregulation of cTnI-ND potentially represents a homeostatic mechanism as well as an adaptive response in pathophysiology including ischemia/reperfusion injury, beta adrenergic maladaptive activation, and aging. We present evidence showing that cTnI-ND can modify the trigger for hypertrophic cardiomyopathy (HCM) by reducing the Ca 2+ sensitivity of myofilaments from hearts with an E180G mutation in α-tropomyosin. Induction of this truncation may represent a therapeutic approach to modifying Ca 2+ -responses in hearts with hypercontractility or heat failure with preserved ejection fraction.

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“…Thermal denaturation midpoints of the isolated importin species or of the corresponding complexes were determined as described elsewhere [ 44 ]. Thermal denaturations were used because, if there is binding, the thermal denaturation midpoint of the complex with NLS-Myc should increase when compared with that of either isolated Impα3 or ΔImpα3 [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

Deciphering the Binding of the Nuclear Localization Sequence of Myc Protein to the Nuclear Carrier Importin α3

Rizzuti

Iovanna

Neira

2022

IJMS

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The oncoprotein Myc is a transcription factor regulating global gene expression and modulating cell proliferation, apoptosis, and metabolism. Myc has a nuclear localization sequence (NLS) comprising residues Pro320 to Asp328, to allow for nuclear translocation. We designed a peptide comprising such region and the flanking residues (Ala310-Asn339), NLS-Myc, to study, in vitro and in silico, the ability to bind importin α3 (Impα3) and its truncated species (ΔImpα3) depleted of the importin binding domain (IBB), by using fluorescence, circular dichroism (CD), biolayer interferometry (BLI), nuclear magnetic resonance (NMR), and molecular simulations. NLS-Myc interacted with both importin species, with affinity constants of ~0.5 µM (for Impα3) and ~60 nM (for ΔImpα3), as measured by BLI. The molecular simulations predicted that the anchoring of NLS-Myc took place in the major binding site of Impα3 for the NLS of cargo proteins. Besides clarifying the conformational behavior of the isolated NLS of Myc in solution, our results identified some unique properties in the binding of this localization sequence to the nuclear carrier Impα3, such as a difference in the kinetics of its release mechanism depending on the presence or absence of the IBB domain.

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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

Cited by 5 publications

References 76 publications

The Conserved C-terminal End Segment of Troponin T Is A New Tropomyosin-Binding Site Modulating the Kinetics of Cardiac Muscle

The Conserved C-terminal End Segment of Troponin T Is A New Tropomyosin-Binding Site Modulating the Kinetics of Cardiac Muscle

NH2-Terminal Cleavage of Cardiac Troponin I Signals Adaptive Response to Cardiac Stressors

Deciphering the Binding of the Nuclear Localization Sequence of Myc Protein to the Nuclear Carrier Importin α3

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