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

Abstract

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.

Structures reveal details of small molecule binding to cardiac troponin

“…Since dfbp-o and other compounds are known to bind to the interface between NTnC and TnI switch peptide[23], we developed a cardiac troponin C-troponin I chimera, cChimera, in which the switch region of cTnI is fused to the C terminus of cNTnC, building upon the previous design cNTnC-linker-switch peptide 144–173[21]. cChimera begins with residues 1 to 90 of human cNTnC (C35S, C84S), followed by residues 136–163 of cTnI (comprising the inhibitory 136–147 and switch 147–163 regions) and ending with a C-terminal His-tag.…”

TNNI1, TNNI2 and TNNI3: Evolution, regulation, and protein structure–function relationships

“…Contraction is produced by sliding between the thick and thin filaments, a process that is powered by actin-activated myosin ATPase and regulated by cytosolic Ca 2+ via the troponin complex associated with the sarcomeric thin filament (Jin et al, 2008). Troponin I functions along with the other two subunits of troponin, troponin T (TnT) (Wei and Jin, 2011) and troponin C (TnC) (Li and Hwang, 2015), to govern muscle contraction and relaxation. To summarize the current knowledge on the TnI isoform genes and products, this review focuses on the evolution, gene regulation, posttranslational modifications, and structure-function relationship of TnI isoform proteins.…”

Medicolegal Use of Troponin C Expression to Identify Different Causes of Cardiac Deaths at Different Postmortem Intervals

“…As calcium channels in the heart are under the effect of sympathetic (βreceptors) and parasympathetic (muscarinicreceptors) modulation (Reuter, 1983), the aforementioned sympathetic activity will lead to an increase in Ca 2+ influx, contributing to the increase in myocardial contractility (Noble, 1984). Troponin C is the calciumbinding protein in the troponin complex in cardiomyocytes, where a rise in the intracellular Ca 2+ , with subsequent increased cTnC binding, is the event that initiates contraction in cardiac muscle (Li and Hwang, 2015). Hence it can be concluded that traumatic events can cause an increase in the cTnC expression through sympathetic stimulation and a subsequent increase in the in Ca 2+ influx into cardiomyocytes.…”