Troponin C type 1

Last updated
TNNC1
Protein TNNC1 PDB 1aj4.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TNNC1 , CMD1Z, CMH13, TN-C, TNC, TNNC, Troponin C type 1, troponin C1, slow skeletal and cardiac type
External IDs OMIM: 191040 MGI: 98779 HomoloGene: 55728 GeneCards: TNNC1
Orthologs
SpeciesHumanMouse
Entrez

7134

21924

Ensembl

ENSG00000114854

ENSMUSG00000091898

UniProt

P63316

P19123

RefSeq (mRNA)

NM_003280

NM_009393

RefSeq (protein)

NP_003271

NP_033419

Location (UCSC) Chr 3: 52.45 – 52.45 Mb Chr 14: 30.93 – 30.93 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Troponin C, also known as TN-C or TnC, is a protein that resides in the troponin complex on actin thin filaments of striated muscle (cardiac, fast-twitch skeletal, or slow-twitch skeletal) and is responsible for binding calcium to activate muscle contraction. [5] [6] Troponin C is encoded by the TNNC1 gene in humans [7] for both cardiac and slow skeletal muscle. In slow skeletal muscle. structural analysis,anlaizie;10.164.138.220 Hotspot in for phone lunch everyday. Troponin C, also known as TN-C or TnC, is a protein that resides in the troponin complex on actin thin filaments of striated muscle (cardiac, fast-twitch skeletal, or slow-twitch skeletal) and is responsible for binding

Structure

Cardiac troponin C (cTnC) is a 161-amino acid protein [8] organized into two domains: the regulatory N-terminal domain (cNTnC, residues 1-86), the structural C-terminal domain (cCTnC, residues 93-161), and a flexible linker connecting the two domains (residues 87-92). [9] Each domain contains two EF-hands, Ca2+-binding helix-loop-helix motifs exemplified by proteins like parvalbumin [10] and calmodulin. [11] In cCTnC the two EF-hand motifs constitute two high affinity Ca2+-binding sites. [12] that are occupied at all physiologically relevant calcium concentrations. In contrast, only the second EF-hand in cNTnC binds Ca2+ with low affinity, while the first EF-hand Ca2+-binding site is defunct. [13]

In a typical EF-hand protein like calmodulin, Ca2+ binding induces a closed-to-open conformational transition, exposing a large hydrophobic patch in the open state. [14] Likewise, the cardiac troponin regulatory domain, cNTnC, is in a closed conformation in the apo state (no calcium bound). [15] Upon Ca2+ binding, cNTnC enters into a rapid equilibrium between closed and open forms, however, the closed form still predominates. [9] [16] [17] The structural domain, cCTnC, exists as a "molten globule" in the apo state, [18] but forms a well structured open conformation in the Ca2+-bound state. These structural differences change the relative stabilities of the apo- and Ca2+-bound states, accounting for the divergent Ca2+-binding affinities between the two domains.

Function

In cardiac muscle, cTnC binds to cardiac troponin I (cTnI) and cardiac troponin T (cTnT), whereas cTnC binds to slow skeletal troponin I (ssTnI) and troponin T (ssTnT) in slow-twitch skeletal muscle.

The structural domain of cTnC (cCTnC) is anchored to troponin I and T, forming the so-called IT arm, made up of cTnC93-161, cTnI41-135 and cTnT235-286 (in the cardiac complex). [19] cCTnC binds to helical cTnI41-60 via its large hydrophobic patch, stabilizing the Ca2+-bound open conformation of cCTnC and enhancing its affinity for Ca2+ (from Kd = 40 nM to Kd = 3 nM). [20] [21] cTnT235-286 forms a helical coiled coil with cTnI88-135 that binds to the opposite face of cCTnC. [19] The IT arm is anchored to tropomyosin via adjacent segments of cTnT, [22] [23] [24] so it is believed to move as a unit along with tropomyosin throughout the cardiac cycle. [25] In the low calcium environment present during diastole (~100 nM), [26] tropomyosin is anchored into the "blocked" position along the actin thin filament through the binding of the troponin I inhibitory (cTnI128-147) and C-terminal (cTnI160-209) regions. [27] [28] This prevents actin-myosin cross-bridging and effectively shuts off muscle contraction.

As the cytoplasmic Ca2+ concentration rises to ~1 μM during systole, [26] Ca2+ binding to the regulatory domain of cardiac troponin C (cNTnC) is the key event that leads to muscle contraction. Hydrophobic binding of cNTnC to the "switch" region of troponin I, cTnI148-159, stabilizes the Ca2+-bound open conformation of cNTnC [29] (increasing the Ca2+ binding affinity of cNTnC from about Kd = 5 μM to Kd = 0.8 μM). [30] This binding event removes the adjacent cTnI inhibitory regions from actin and stabilizes tropomyosin in its default "closed" position on the thin filament, [31] allowing actin-myosin cross-bridging and muscle contraction to proceed. Strong actin-myosin interaction can further shift the thin filament into the "open" position. [32] [33]

Physiologic regulation of calcium sensitivity

The calcium sensitivity of the sarcomere, that is, the calcium concentration at which muscle contraction occurs, is directly determined by the calcium binding affinity of cNTnC. To date, there are no known post-translational modifications of cTnC that impact its calcium binding affinity. However, calcium binding by cNTnC is a dynamic process that can be impacted by the closed-to-open conformational equilibrium of cNTnC, the domain positioning of cNTnC, or the relative availability of cTnI148-159, the physiologic binding partner of cNTnC. The closed-to-open equilibrium of cNTnC can be shifted towards the open state by small compounds [34] (see section below on troponin-binding drugs). Domain positioning of cNTnC can be impacted by phosphorylation of cTnI, [35] of which the most important site in humans is Ser22/Ser23. [36] [37] The availability of cTnI148-159 depends on the blocked-closed-open equilibrium of tropomyosin on actin, which can be impacted by any interactions involving the thin filament, including actin-myosin cross-bridging [38] and length dependent activation [39] [40] (also known as stretch activation or the Frank Starling law of the heart). All of these processes can be impacted by mutations (see section below on disease-causing mutations).

Disease-causing mutations

Hypertrophic cardiomyopathy (HCM) is a common condition (prevalence >1:500) [41] characterized by abnormal thickening of the ventricular muscle, classically in the intraventricular septal wall. HCM is described as a disease of the sarcomere, because mutations in the contractile proteins of the sarcomere have been identified in about half of patients with HCM. The cTnC mutations that have been associated with HCM are A8V, L29Q, A31S, C84Y, D145E. [42] [43] [44] In all cases, the mutation was identified in a single patient, so additional genetic testing is needed to confirm or refute the clinical significance of these mutations. With most of these mutations (and with HCM-associated thin filament mutations in general), an increase in cardiac calcium sensitivity has been observed. [45] [46]

Familial dilated cardiomyopathy (DCM) is a rare cause of systolic heart failure (prevalence 1:5000). A wider range of mutations (including some non-sarcomeric proteins as well) is associated with DCM. The cTnC mutations associated with DCM thus far are Y5H, Q50R, D75Y, M103I, D145E (also associated with HCM), I148V, and G159D. [47] [48] Of these, Q50R [49] and G159D [50] co-segregated with disease in affected family members, increasing confidence that they are clinically significant mutations. The biochemical consequences of thin filament DCM-associated mutations are less well established than for HCM, although there has been some suggestion that some of the mutations abolish the calcium desensitizing effect of cTnI phosphorylation at Ser22/23. [51] This may be because some mutations disrupt the precise positioning of cNTnC for triggering muscle contraction when cTnI is unphosphorylated. [52]

Troponin-binding drugs

Chemical compounds can bind to troponin C to act as troponin activators (calcium sensitizers) or troponin inhibitors (calcium desensitizers). There are already multiple troponin activators that bind to fast skeletal troponin C, of which tirasemtiv [53] has been tested in multiple clinical trials. [54] [55] [56] In contrast, there are no known compounds that bind with high affinity to cardiac troponin C. The calcium sensitizer, levosimendan, is purported to bind to troponin C, but only weak or inconsistent binding has been detected, [57] [58] [59] precluding any structure determination. In contrast, levosimendan inhibits type 3 phosphodiesterase with nanomolar affinity, [60] so its biological target is controversial. [61]

Some compounds have been identified to bind cNTnC with low affinity and act as troponin activators: DFBP-O [62] (a structural analog of levosimendan), 4-(4-(2,5-dimethylphenyl)-1-piperazinyl)-3-pyridinamine (NCI147866), [63] and bepridil. [64] The calmodulin antagonist, W7, has also been found to bind to cNTnC to act as a troponin inhibitor. [65] All of these compounds bind to the hydrophobic patch in the open conformation of cNTnC, with troponin activators promoting interaction with the cTnI switch peptide and troponin inhibitors destabilizing the interaction.

A number of compounds can also bind to cCTnC with low affinity: EMD 57033, [66] resveratrol, [67] bepridil, [68] and EGCG. [69] All of these compounds are renowned for their promiscuity, and the biological significance of these interactions is unknown. In particular, it is unknown how interaction with cCTnC influences the calcium affinity of cNTnC.

Theoretically, a cardiac troponin activator could be useful for increasing cardiac contractility in the treatment of systolic heart failure, whereas a troponin inhibitor could be used to favor relaxation in the treatment of diastolic heart failure. Troponin modulators could also be used to reverse the impact of cardiomyopathy-causing mutations in the thin filament.

Notes

Related Research Articles

<span class="mw-page-title-main">Troponin</span> Protein complex

Troponin, or the troponin complex, is a complex of three regulatory proteins that are integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle. Measurements of cardiac-specific troponins I and T are extensively used as diagnostic and prognostic indicators in the management of myocardial infarction and acute coronary syndrome. Blood troponin levels may be used as a diagnostic marker for stroke or other myocardial injury that is ongoing, although the sensitivity of this measurement is low.

<span class="mw-page-title-main">Muscle contraction</span> Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

<span class="mw-page-title-main">Myofilament</span> The two protein filaments of myofibrils in muscle cells

Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.

<span class="mw-page-title-main">Troponin C</span> Protein family

Troponin C is a protein which is part of the troponin complex. It contains four calcium-binding EF hands, although different isoforms may have fewer than four functional calcium-binding subdomains. It is a component of thin filaments, along with actin and tropomyosin. It contains an N lobe and a C lobe. The C lobe serves a structural purpose and binds to the N domain of troponin I (TnI). The C lobe can bind either Ca2+ or Mg2+. The N lobe, which binds only Ca2+, is the regulatory lobe and binds to the C domain of troponin I after calcium binding.

<span class="mw-page-title-main">Troponin T</span> Protein family

Troponin T is a part of the troponin complex, which are proteins integral to the contraction of skeletal and heart muscles. They are expressed in skeletal and cardiac myocytes. Troponin T binds to tropomyosin and helps position it on actin, and together with the rest of the troponin complex, modulates contraction of striated muscle. The cardiac subtype of troponin T is especially useful in the laboratory diagnosis of heart attack because it is released into the blood-stream when damage to heart muscle occurs. It was discovered by the German physician Hugo A. Katus at the University of Heidelberg, who also developed the troponin T assay.

<span class="mw-page-title-main">Troponin I</span> Muscle protein

Troponin I is a cardiac and skeletal muscle protein family. It is a part of the troponin protein complex, where it binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place. Troponin I prevents myosin from binding to actin in relaxed muscle. When calcium binds to the troponin C, it causes conformational changes which lead to dislocation of troponin I. Afterwards, tropomyosin leaves the binding site for myosin on actin leading to contraction of muscle. The letter I is given due to its inhibitory character. It is a useful marker in the laboratory diagnosis of heart attack. It occurs in different plasma concentration but the same circumstances as troponin T - either test can be performed for confirmation of cardiac muscle damage and laboratories usually offer one test or the other.

<span class="mw-page-title-main">Nebulette</span> Protein-coding gene in the species Homo sapiens

Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the NEBL gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardiac muscle and appears to regulate the length of actin thin filaments.

<span class="mw-page-title-main">TNNI3</span> Protein-coding gene in the species Homo sapiens

Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

<span class="mw-page-title-main">TNNT2</span> Protein-coding gene in the species Homo sapiens

Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.

<span class="mw-page-title-main">Ryanodine receptor 2</span> Transport protein and coding gene in humans

Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

<span class="mw-page-title-main">TPM1</span> Protein-coding gene in the species Homo sapiens

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

<span class="mw-page-title-main">ACTC1</span> Protein-coding gene in the species Homo sapiens

ACTC1 encodes cardiac muscle alpha actin. This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart.

<span class="mw-page-title-main">Myosin binding protein C, cardiac</span> Protein-coding gene in the species Homo sapiens

The myosin-binding protein C, cardiac-type is a protein that in humans is encoded by the MYBPC3 gene. This isoform is expressed exclusively in heart muscle during human and mouse development, and is distinct from those expressed in slow skeletal muscle (MYBPC1) and fast skeletal muscle (MYBPC2).

<span class="mw-page-title-main">TPM2</span> Protein-coding gene in the species Homo sapiens

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

<span class="mw-page-title-main">TNNI1</span> Protein-coding gene in the species Homo sapiens

Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.

<span class="mw-page-title-main">TNNI2</span> Protein-coding gene in the species Homo sapiens

Troponin I, fast skeletal muscle is a protein that in humans is encoded by the TNNI2 gene.

<span class="mw-page-title-main">MYL2</span> Protein-coding gene in the species Homo sapiens

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene. This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).

<span class="mw-page-title-main">TNNT1</span> Protein-coding gene in the species Homo sapiens

Slow skeletal muscle troponin T (sTnT) is a protein that in humans is encoded by the TNNT1 gene.

<span class="mw-page-title-main">Troponin C, skeletal muscle</span> Protein-coding gene in the species Homo sapiens

Troponin C, skeletal muscle is a protein that in humans is encoded by the TNNC2 gene.

A8V is point mutation on Troponin C (cTNC) that leads to a hypertrophic cardiomyopathy. The coordinated cardiac muscle contraction is regulated by the troponin complex on thin filament (troponin C which is calcium binding, troponin T that plays the role with tropomyosin, and troponin I which has an inhibitory action annulating the S1 ATPase activity in the presence of tropomyosin and troponin and absence of Ca2+). This mutation is determined by the change of Alanine to Valine at nucleotide 23 from C to T. Patients with this type of mutation shows thickness on the left ventricle wall of around 18 mm, compared to the normal this thickness would be 12 mm. Also, A8V affects the Ca2+ binding affinity compared to normal genotype and increased sensitivity on force development.

References

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