Cardiac Troponin I Mutants

Noland, Thomas A.; Guo, Xiaodu; Raynor, Robert L.; Jideama, Nathan M.; Averyhart-Fullard, Vera; Solaro, R. John; Kuo, J.F.

doi:10.1074/jbc.270.43.25445

Cited by 157 publications

(197 citation statements)

References 77 publications

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“…3 and 4). Although phosphorylation of cTnI by PKC can occur at Ser 43 / Ser 45 and Thr 144 , which decreases the myofilament Ca 2ϩ sensitivity (18,39,40), our results coincide with previous studies (31), which show that serines 23 and 24 are the only two sites basally phosphorylated in vivo within the WT murine cTnI protein. These findings suggest that one or more of the following may occur in the murine heart: 1) phosphorylation of Ser 23 / Ser 24 is dominant over the phosphorylation of Ser 43 /Ser 45 and Thr 144 and/or 2) PKC-mediated phosphorylation of cTnI does not increase as a compensatory mechanism for the decrease in PKA-mediated phosphorylation.…”

Section: Discussionsupporting

confidence: 81%

“…Deletion of cTnI residues 2-26 in a transgenic mouse model facilitated the diastolic and systolic functions of both young and aged hearts (15,16). Furthermore, it has been shown that phosphorylation within the cTnI N-terminal extension: 1) increases the rate of relaxation and cross-bridge cycling kinetics (17)(18)(19); and 2) decreases both the Ca 2ϩ affinity of cTnC (20) and the Ca 2ϩ sensitivity of force generation (19). Altogether, these reports indicate that a major role for the cTnI N-terminal extension is to assist in the lusitropic effects of cardiac muscle relaxation (14).…”

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

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Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy

Wang

Pinto

Solis

et al. 2012

Journal of Biological Chemistry

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Background: The R21C substitution in cardiac troponin I (cTnI) is associated with hypertrophic cardiomyopathy in man. Results: The R21C mutation disrupts the consensus sequence for cTnI phosphorylation. Conclusion: The KI mouse model showed remarkable degree of cardiac hypertrophy and fibrosis after 12 months of age. Significance: One of the physiological roles for the phosphorylation of the cTnI N-terminal extension is to prevent cardiac hypertrophy.

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Section: Discussionsupporting

confidence: 81%

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy

Wang

Pinto

Solis

et al. 2012

Journal of Biological Chemistry

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“…Cardiac TnI also can be phosphorylated by PKC at Ser-42 and Ser-44 in the N-domain and Thr-143 in the inhibitory region of cTnI [57]. Phosphorylation at Ser-42/Ser-44 is known to decrease maximal actomyosin Mg 2+ ATPase activity and Ca 2+ -sensitivity by stabilizing the inactive state of the thin filament [24][25][26]58].…”

Section: Molecular Mechanisms Of the Effects Of Ctni Phosphorylation mentioning

confidence: 99%

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Solaro

Rosevear

Kobayashi

2008

Biochemical and Biophysical Research Communications

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We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I. KeywordsCardiac; Sarcomeres; Adrenergic stimulation; Mechanics; Kinases; Phosphatases In the time since the troponin discovery and naming by the laboratory of Setsuro Ebashi [1], there has been a constant stream of evidence indicating the substantial role of modifications in cardiac troponin (cTn) as a critical control element in the body's response to physiological stressors such as the hemodynamic demands of exercise. It is now widely recognized that regulatory processes at the level of the sarcomeres and the hetero-trimeric Tn complex involve not only the reception of Ca 2+ by cTnC, but also transduction of this Ca-binding signal by cTnI and cTnT [2,3]. Multiple interactions of cTnI and cTnT with actin and tropomyosin (Tm) control the number and kinetics of interactions of cross-bridges with the thin filament. Our focus here on cTnI serves to highlight the significant impact of modifications in the function of Tn in working cardiac myocytes and in the integrated physiological responses to exercise, which we have reviewed previously [4,5]. Evidence summarized below indicates that phosphorylation of cTnI by adrenergic signaling cascades is an indispensable control mechanism in matching cardiac output to venous return and myocyte dynamics to heart rate. Specific modifications in troponin I affect the dynamics and intensity of the heart beatElucidation of the function of an N-terminal extension of ~30 amino acids with sites (Ser-23, Ser-24) of phosphorylation by protein kinase A (PKA), not present in the fast skeletal (fsTnI) or slow skeletal isoforms (ssTnI), provided the first evidence that cTnI may have a special role * Corresponding

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“…␤-Adrenergic stimulation leads to protein kinase A phosphorylation at Ser 23 and Ser 24 of cTnI, enhancing relaxation by decreasing the Ca 2ϩ affinity at site II (7,8). Cardiac TnI can also be phosphorylated by PKC at Ser 43 , Ser 45 , and Thr 144 (9). Phosphorylation at Ser 43 and Ser 45 is known to decrease maximal actomyosin MgATPase activity, Ca 2ϩ sensitivity, and cross-bridge binding to the thin filament (4, 9 -11).…”

mentioning

confidence: 99%

Introduction of Negative Charge Mimicking Protein Kinase C Phosphorylation of Cardiac Troponin I

Finley¹,

Rosevear

2004

Journal of Biological Chemistry

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Protein kinase C phosphorylation of cardiac troponin, the Ca 2؉ -sensing switch in muscle contraction, is capable of modulating the response of cardiac muscle to a Ca 2؉ ion concentration. The N-domain of cardiac troponin I contains two protein kinase C phosphorylation sites. Although the physiological consequences of phosphorylation at Ser 43 /Ser 45 are known, the molecular mechanisms responsible for these functional changes have yet to be established. In this work, NMR was used to identify conformational and dynamic changes in cardiac troponin C upon binding a phosphomimetic troponin I, having Ser 43 /Ser 45 mutated to Asp. Chemical shift perturbation mapping indicated that residues in helix G were most affected. Smaller chemical shift changes were observed in residues located in the Ca 2؉ /Mg 2؉ -binding loops. Amide hydrogen/deuterium exchange rates in the C-lobe of troponin C were compared in complexes containing either the wild-type or phosphomimetic N-domain of troponin I. In the presence of a phosphomimetic domain, exchange rates in helix G increased, whereas a decrease in exchange rates for residues mapping to Ca 2؉ /Mg 2؉ -binding loops III and IV was observed. Increased exchange rates are consistent with destabilization of the Thr 129 -Asp 132 helix capping box previously characterized in helix G. The perturbation of helix G and metal binding loops III and IV suggests that phosphorylation alters metal ion affinity and inter-subunit interactions. Our studies support a novel mechanism for protein kinase C signal transduction, emphasizing the importance of C-lobe Ca 2؉ /Mg 2؉ -dependent troponin interactions.Troponin and tropomyosin form the Ca 2ϩ -sensitive switch that regulates striated muscle contraction. Troponin is a ternary assembly of proteins composed of the Ca 2ϩ -binding subunit troponin C (TnC), 1 the inhibitory subunit troponin I (TnI), and the tropomyosin-binding protein troponin T that anchors troponin to the thin filament. Troponin C, a member of the EF-hand family of Ca 2ϩ -binding proteins, contains two globular domains connected by a linker. Each domain of cTnC contains two EF-hand or Ca 2ϩ -binding motifs. The N-lobe contains two lower affinity Ca 2ϩ -binding motifs, sites I and II, that control muscle contraction. Site I is naturally inactive in the cardiac isoform because of several amino acid substitutions and an amino acid insertion (1). Thus, Ca 2ϩ binding at site II in cTnC regulates muscle contraction. The C-lobe contains two high affinity Ca 2ϩ -binding sites, III and IV, which also bind Mg 2ϩ with lower affinity. Interactions between the C-lobe of cTnC and the N-domain of cTnI form the Ca 2ϩ /Mg 2ϩ -dependent cTnC/cTnI interaction site. In addition, the C-lobe of cTnC also interacts tightly with the C terminus of cardiac troponin T (2). These interactions form the core of the troponin complex, tethering all three subunits throughout the contraction cycle.A variety of effectors can modulate the frequency and intensity of myocardial contraction by charge modification upon the p...

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Cardiac Troponin I Mutants

Cited by 157 publications

References 77 publications

Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy

Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Introduction of Negative Charge Mimicking Protein Kinase C Phosphorylation of Cardiac Troponin I

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