Dilated Cardiomyopathy Mutations and Phosphorylation disrupt the Active Orientation of Cardiac Troponin C

Mahmud, Zabed; Dhami, Prabhpaul S.; Rans, Caleb; Liu, Philip B.; Hwang, Peter M.

doi:10.1016/j.jmb.2021.167010

Cited by 9 publications

(14 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our initial study of wild type troponin 21 used a complete model of the human sequence core domain of cTn (419 residues, 6812 atoms), a larger solvent box, and 20-times more sampling than the previous studies but we could not ascertain with statistical significance if phosphorylation changed any of the intra-subunit interactions of cTnI. This could be because a small number of independent MD trajectories of only a few hundred nanoseconds (ns) of length is inadequate but it seemed more likely that phosphorylation and mutations primarily act by altering the dynamics of the troponin molecule in ways that have not been previously analysed 19 .…”

mentioning

confidence: 75%

“…The principal motion of troponin is a hinge-like motion between the two quasi-rigid domains of troponin, NcTnC and the ITC domain 21,4 . The hinge angle is altered by Ca 2+ activation 32 and is also proposed to be modulated by phosphorylation 18,19,33 The simulations indicate that upon phosphorylation the distribution of hinge angles in WT troponin shows an increase in the mean angle with a significant rigidification and decrease of the accessible range. This is consistent with the studies of Hwang et al, 18 who proposed that phosphorylation modified the positioning of NcTnC relative to the ITC domain, based on NMR measurements.…”

Section: Global Changes Calculated By MD Correlate With Changes In Ex...mentioning

confidence: 95%

“…To understand the mechanism of regulation by troponin I phosphorylation and the effects of mutations, methods that can describe the dynamics of troponin such as NMR [17][18][19] have been employed but they have their limitations of studying only peptide fragments of troponin. Recently computational molecular modelling and all atom molecular dynamics simulations (MD) have become the method of choice for understanding the phosphorylation-dependent modulation of the cardiac troponin 20,21 .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Modulation of structure and dynamics of cardiac troponin by phosphorylation and mutations revealed by molecular dynamics simulations

Yang

Marston

Gould

2022

Preprint

View full text Add to dashboard Cite

Phosphorylation of cardiac muscle troponin I by protein kinase A enhances troponin regulatory dynamics and is an essential part of the’ flight or fight’ response to adrenaline. Elucidating how phosphorylation at serines 22 and 23 modulates structural dynamics has been difficult as key regulatory segments of troponin are unresolved. The effect of phosphorylation on the wild type, obtained from all-atom molecular dynamics simulations of the troponin core, demonstrates a significant rigidification of the structure that involves a rearrangement of the cTnI(1-33) - cTnC interaction, and changes in the distribution of the cTnC helix A/B angle and the interdomain angle, between the regulatory head and ITC arm. The familiar dilated cardiomyopathy cTnC G159D mutation whose Ca2+-sensitivity is not modulated by cTnI phosphorylation exhibits a structure inherently more rigid than WT, with phosphorylation reversing the direction of all metrics relative to WT.

show abstract

mentioning

confidence: 75%

Section: Global Changes Calculated By MD Correlate With Changes In Ex...mentioning

confidence: 95%

mentioning

confidence: 99%

See 1 more Smart Citation

Modulation of structure and dynamics of cardiac troponin by phosphorylation and mutations revealed by molecular dynamics simulations

Yang

Marston

Gould

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The protein produced by mutant alleles affects the formation and function of sarcomere [25] . Mutations in the gene encoding cTnT, TNNT2, were signi cantly correlated with DCM [26][27] . Genetic screening of some Chinese DCM patients found that the deletion of tnnt2 may be one of the causes [28][29] .…”

Section: Discussionmentioning

confidence: 99%

Protection role of Astragalus polysaccharide against Cardiac injury in tnnt2a mutant Zebrafish model of Dilated Cardiomyopathy

Zhou¹

2023

Preprint

View full text Add to dashboard Cite

Background Dilated cardiomyopathy(DCM) is a severe and irreversible heart disease characterized by dilated ventricles and decreased myocardial function. DCM has a poor prognosis and a very low survival rate, with a 5-year mortality rate of 15–50%, and is an important cause of sudden cardiac death and heart failure.Genetic factors play an important role in the pathogenesis of DCM. Mutations in the cardiac troponin T (tnnt2) gene represent an important subset of known pathogenic variants that bind to DCM. However, there are currently few specific drugs available to treat DCM caused by these gene mutations. Astragalus polysaccharide (APS), the main active ingredient of Astragalus mongholicus Bunge(Huangqi), is widely used in China to treat cardiovascular diseases, including DCM. This study explored drugs for the treatment of DCM caused by tnnt2a mutation and found the protective effect of Astragalus polysaccharide on tnnt2a-mutant dilated cardiomyopathy.Methods The tnnt2a-/- mutant zebrafish was used as a DCM model to compare with the APS-administered group. Counting the survival rate and measuring the sinus venosus-bulbus arteriosus (SV-BA) distance to observe changes in cardiac output.Histopathological changes were observed with hematoxylin and eosin (HE) staining and Tunel staining.Transcriptomes of zebrafish DCM group and APS-treated group were investigated by RNA-seq method. qRT-PCR detection of apoptosis-related genes expression.Results We found that APS markedly increased the heart rate and ATP content,significantly inhibited the level of cardiac tissue edema,which are essential for improving survival rate in tnnt2a-/- zebrafish.Moreover,APS interfere some key genes related to muscle fibers,such as titin b (ttnb)and myomesin 3 (myom3),APS intervention significantly participated in Rap1 signaling pathway,PI3K-Akt signaling pathway,Jak-STAT signaling pathway,Wnt signaling pathway.The qRT-PCR results revealed that APS decreased the expression of Bax,Caspase-3,Caspase-9 but incresaed the expression of Bcl-2 in DCM zebrafish.Conclusions Our findings suggest that APS could improve survival rate in Dilated Cardiomyopathy, and has a positive protective effect on the myocardium in the tnnt2a mutant zebrafish model of DCM.

show abstract

“…Serines 22 and 23 represented as spheres. TnC is coloured green techniques (Hwang et al, 2014;Matsuo et al, 2015;Mahmud et al, 2021) have been employed but they have their limitations since only incomplete peptides of troponin are studied. The first attempt to model the NcTnI peptide docked onto the N-terminal troponin was by Howarth et al (Howarth et al, 2007).…”

mentioning

confidence: 99%

Recent studies of the molecular mechanism of lusitropy due to phosphorylation of cardiac troponin I by protein kinase A

Marston

2022

J Muscle Res Cell Motil

View full text Add to dashboard Cite

Ca2+ acts on troponin and tropomyosin to switch the thin filament on and off, however in cardiac muscle a more graded form of regulation is essential to tailor cardiac output to the body’s needs. This is achieved by the action of adrenaline on β1 receptors of heart muscle cells leading to enhanced contractility, faster heart rate and faster relaxation (lusitropy) via activation of the cyclic AMP-dependent protein kinase, PKA. PKA phosphorylates serines 22 and 23 in the N-terminal peptide of cardiac troponin I. As a consequence the rate of Ca2+release from troponin is increased. This is the key determinant of lusitropy. The molecular mechanism of this process has remained unknown long after the mechanism of the troponin Ca2+ switch itself was defined. Investigation of this subtle process at the atomic level poses a challenge, since the change in Ca2+-sensitivity is only about twofold and key parts of the troponin modulation and regulation system are disordered and cannot be fully resolved by conventional structural approaches. We will review recent studies using molecular dynamics simulations together with functional, cryo-em and NMR techniques that have started to give us a precise picture of how phosphorylation of troponin I modulates the dynamics of troponin to produce the lusitropic effect.

show abstract

Dilated Cardiomyopathy Mutations and Phosphorylation disrupt the Active Orientation of Cardiac Troponin C

Cited by 9 publications

References 65 publications

Modulation of structure and dynamics of cardiac troponin by phosphorylation and mutations revealed by molecular dynamics simulations

Modulation of structure and dynamics of cardiac troponin by phosphorylation and mutations revealed by molecular dynamics simulations

Protection role of Astragalus polysaccharide against Cardiac injury in tnnt2a mutant Zebrafish model of Dilated Cardiomyopathy

Recent studies of the molecular mechanism of lusitropy due to phosphorylation of cardiac troponin I by protein kinase A

Contact Info

Product

Resources

About