Conformation of the critical pH sensitive region of troponin depends upon a single residue in troponin I

Robertson, Ian M.; Pineda-Sanabria, Sandra E.; Holmes, Peter C.; Sykes, Brian D.

doi:10.1016/j.abb.2013.12.003

Cited by 7 publications

(14 citation statements)

References 73 publications

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“…We recently published the structure of switch-sTnI bound to cNTnC at pH 6. 12 As predicted, the structure shows sTnI in the same conformation as sTnI when bound to sNTnC, with H130 in close proximity to E19. Because binding of the Cterminal region of cTnI to actin is necessary to achieve full inhibition, based on this structure and the orientation of sTnC in muscle fibers, 13 we proposed that introducing A162H in switch-cTnI increases Ca 2+ sensitivity by increasing the affinity of switch-cTnI A162H for cNTnC via the additional H162−E19 interaction.…”

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confidence: 69%

Structure and Dynamics of the Acidosis-Resistant A162H Mutant of the Switch Region of Troponin I Bound to the Regulatory Domain of Troponin C

2015

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Intracellular acidosis lowers the Ca²⁺ sensitivity of cardiac muscle, which results in decreased force generation, decreased cardiac output, and, eventually, heart failure. The A162H mutant of cardiac troponin I in the thin filament turns the heart acidosis-resistant. Physiological and structural studies have provided insights into the mechanism of protection by the A162H substitution; however, the effect of other native residues of cardiac troponin I is not fully understood. In this study, we determined the structure of the A162H mutant of the switch region of cardiac troponin I bound to the regulatory domain of troponin C at pH 6.1, and the dynamics as a function of pH, by NMR spectroscopy to evaluate the changes induced by protonation of A162H. The results indicate that A162H induces a transitory curved conformation on troponin I that promotes contraction, but it is countered by residue E164 to ensure proper relaxation. Our model explains the absence of diastolic impairment in the gain-of-function phenotype induced by the A162H substitution as well as the effects of a variety of mutants studied previously. The description of this mechanism underlines the fine quality of regulation on cardiac muscle contraction and anticipates pharmacological agents that induce modest changes in the contraction-relaxation equilibrium to produce marked effects in cardiac performance.

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supporting

confidence: 69%

Structure and Dynamics of the Acidosis-Resistant A162H Mutant of the Switch Region of Troponin I Bound to the Regulatory Domain of Troponin C

2015

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“…This is not surprising considering that a single histidine residue in TnI can play a critical pH-sensitive role in skeletal and cardiac muscle contraction. 42,43 ■ CONCLUSIONS Calcium sensitization of fast skeletal muscle may have benefits in numerous disease states involving muscle weakness and/or fatigue, such as neuromuscular diseases and heart failure. A challenge in the optimization of these molecules has been achieving the appropriate combination of on-target selectivity and potency, together with physiochemical and pharmacokinetic properties that are suitable for a human therapeutic agent.…”

Section: ■ Discussionmentioning

confidence: 99%

“…These few differences could play a key role in dictating the specificity of tirasemtiv for fast sTn over slow sTn and cTn. This is not surprising considering that a single histidine residue in TnI can play a critical pH-sensitive role in skeletal and cardiac muscle contraction. , …”

Section: Discussionmentioning

confidence: 99%

Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle

Mercier

Hartman

et al. 2021

J. Med. Chem.

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Troponin regulates the calcium-mediated activation of skeletal muscle. Muscle weakness in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy occurs from diminished neuromuscular output. The first direct fast skeletal troponin activator, tirasemtiv, amplifies the response of muscle to neuromuscular input. Tirasemtiv binds selectively and strongly to fast skeletal troponin, slowing the rate of calcium release and sensitizing muscle to calcium. We report the solution NMR structure of tirasemtiv bound to a fast skeletal troponin C–troponin I chimera. The structure reveals that tirasemtiv binds in a hydrophobic pocket between the regulatory domain of troponin C and the switch region of troponin I, which overlaps with that of Anapoe in the X-ray structure of skeletal troponin. Multiple interactions stabilize the troponin C–troponin I interface, increase the affinity of troponin C for the switch region of fast skeletal troponin I, and drive the equilibrium toward the active state.

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“…In the complex, His130 has a pKa of ~6.7 44 , becoming more positively charged as the intracellular pH drops below 7. Recent NMR studies of cNTnC•Ca 2+ bound to fsTnI 115 -131, as well as cNTnC•Ca 2+ bound to A162H–cTnI1 47 -163, have confirmed the importance of this electrostatic interaction 45 . The interaction is also present in the X-ray structure of the fast skeletal core troponin complex 46 , suggesting that it contributes to pH insensitivity in fast skeletal muscle as well.…”

Section: Structure and Function Of Cardiac Troponin C Within The Tropmentioning

confidence: 93%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

113

105

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In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

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Conformation of the critical pH sensitive region of troponin depends upon a single residue in troponin I

Cited by 7 publications

References 73 publications

Structure and Dynamics of the Acidosis-Resistant A162H Mutant of the Switch Region of Troponin I Bound to the Regulatory Domain of Troponin C

Structure and Dynamics of the Acidosis-Resistant A162H Mutant of the Switch Region of Troponin I Bound to the Regulatory Domain of Troponin C

Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

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