Phosphorylation of Troponin I finely controls the positioning of Troponin for the optimal regulation of cardiac muscle contraction

Kachooei, Ehsan; Cordina, Nicole M.; Potluri, Phani R.; Guse, Joanna A.; McCamey, Dane R.; Brown, Louise J.

doi:10.1016/j.yjmcc.2020.10.007

Cited by 13 publications

(10 citation statements)

References 44 publications

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“…We highlight the upstream effect that TNNI3 may be having on heart muscle contraction, which may be having a negative downstream effect on a wide range of biological processes in the nervous, respiratory and digestive systems (see Supplementary Figure 1 for a bubble plot of genetically associated processes with TNNI3). In addition, we identify levosimendan, a positive inotropic agent having ATP-dependent potassium-channel-opening and calcium-sensitizing effects by binding to a calcium sensing myocardial complex consisting of cardiac troponin C and troponin I(20) ,(21,22) . This is a clinically approved drug used for heart failure, kidney failure and SARS (https://www.targetvalidation.org/summary?drug=CHEMBL2051955).…”

Section: Resultsmentioning

confidence: 99%

“…Given the importance of ACE2 in COVID-19,(42) this further implicates TNNI3 as an important target of severe disease pathophysiology (see Supplementary Table 5 for TNNI3 associated proteins). Levosimendan has been shown to exert action on the myocardial troponin complex,(20) (21,22)which involves complex interactions between troponin I and troponin C (43,44). Levosimendan is a calcium sensitiser, which canonically also exerts action on troponin C that is implicated in several diseases, including hypertrophic cardiomyopathy (45).…”

Section: Discussionmentioning

confidence: 99%

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Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

Palmos

Millischer

Menon

et al. 2021

Preprint

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The COVID-19 pandemic death toll now surpasses two million individuals and there is a need for early identification of individuals at increased risk of mortality. Host genetic variation partially drives the immune and biochemical responses to COVID-19 that lead to risk of mortality. We identify and prioritise blood proteins and biomarkers that may indicate increased risk for severe COVID-19, via a proteome Mendelian randomization approach by collecting genome-wide association study (GWAS) summary statistics for >4,000 blood proteins. After multiple testing correction, troponin I3, cardiac type (TNNI3) had the strongest effect (odds ratio (O.R.) of 6.86 per standard deviation increase in protein level), with proteinase 3 (PRTN3) (O.R.=2.48), major histocompatibility complex, class II, DQ alpha 2 (HLA-DQA2) (O.R.=2.29), the C4A-C4B heterodimer (O.R.=1.76) and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) (O.R.=1.73) also being associated with higher odds of severe COVID-19. Conversely, major histocompatibility complex class I polypeptide-related sequence A (MHC1A) (O.R.=0.6) and natural cytotoxicity triggering receptor 3 (NCR3) (O.R.=0.46) were associated with lower odds. These proteins are involved in heart muscle contraction, natural killer and antigen presenting cells, and the major histocompatibility complex. Based on these findings, it may be possible to better predict which patients may develop severe COVID-19 and to design better treatments targeting the implicated mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

Palmos

Millischer

Menon

et al. 2021

Preprint

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“…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: 96%

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

Yang

Marston

Gould

2022

Preprint

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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.

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“…The effects of cTnI-ND and cTnI-S23D, S24D to correcte myofilament response to Ca 2+ inform the identifications of targets for small molecules for use in HCM. Targeting the cTnI-cTnC interface with such compounds is also aided by earlier work [12,13,33] and recent findings [11] identifying the regions of interaction of the unphosphorylated NH 2 region of cTnI with the cTnI switch-peptide binding region as well as the Ca 2+ binding site II of cTnC.…”

Section: Ctni-nd Reduces the Biophysical Trigger In Sarcomeres Expressing A Mutant Tm Linked To Hcmmentioning

confidence: 99%

“…Compared to the phosphorylated state, unphosphorylated cTnI NH 2 stabilizes the cTnI-Sw-cTnC activated state by binding relatively tightly to cTnC regulatory site II and the region of Sw binding (Figure 1). When cTnI is phosphorylated, binding of its NH 2terminus with cTnC is modified inducing a weakening of the cTnI-Sw-cTnC interaction [11]. Structure-function and cross-linking studies demonstrated that when cTnI is phosphorylated, the acidic domain in the highly mobile cTnI-NH 2 -terminus is free to interact in an intramolecular interaction with the basic Ip [12,13].…”

Section: Introductionmentioning

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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Phosphorylation of Troponin I finely controls the positioning of Troponin for the optimal regulation of cardiac muscle contraction

Cited by 13 publications

References 44 publications

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

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

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

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