Troponin C type 1

Troponin C type 1 (slow)

PDB rendering based on 1aj4.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TNNC1 ; CMD1Z; CMH13; TN-C; TNC; TNNC
External IDs OMIM: 191040 MGI: 98779 HomoloGene: 55728 ChEMBL: 2066 GeneCards: TNNC1 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
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:
31.21 – 31.21 Mb
PubMed search

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.[1][2] Troponin C is encoded by the TNNC1 gene in humans[3] for both cardiac and slow skeletal muscle.

Structure

Cardiac troponin C (cTnC) is a 161-amino acid protein [4] 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).[5] Each domain contains two EF-hands, Ca2+-binding helix-loop-helix motifs exemplified by proteins like parvalbumin.[6] and calmodulin.[7] In cCTnC the two EF-hand motifs constitute two high affinity Ca2+-binding sites.[8] 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.[9]

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.[10] Likewise, the cardiac troponin regulatory domain, cNTnC, is in a closed conformation in the apo state (no calcium bound).[11] Upon Ca2+ binding, cNTnC enters into a rapid equilibrium between closed and open forms, however, the closed form still predominates.[5][12][13] The structural domain, cCTnC, exists as a "molten globule" in the apo state,[14] 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).[15] 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).[16][17] cTnT235-286 forms a helical coiled coil with cTnI88-135 that binds to the opposite face of cCTnC.[15] The IT arm is anchored to tropomyosin via adjacent segments of cTnT,[18][19][20] so it is believed to move as a unit along with tropomyosin throughout the cardiac cycle.[21] In the low calcium environment present during diastole (~100 nM),[22] 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.[23][24] This prevents actin-myosin cross-bridging and effectively shuts off muscle contraction.

As the cytoplasmic Ca2+ concentration rises to ~1 μM during systole,[22] 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[25] (increasing the Ca2+ binding affinity of cNTnC from about Kd = 5 μM to Kd = 0.8 μM).[26] This binding event removes the adjacent cTnI inhibitory regions from actin and stabilizes tropomyosin in its default "closed" position on the thin filament,[27] allowing actin-myosin cross-bridging and muscle contraction to proceed. Strong actin-myosin interaction can further shift the thin filament into the "open" position.[28]

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 [29](see section below on troponin-binding drugs). Domain positioning of cNTnC can be impacted by phosphorylation of cTnI,[30] of which the most important site in humans is Ser22/Ser23.[31][32] 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[33] and length dependent activation [34][35](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)[36] 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.[37][38][39] 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.[40][41]

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.[42][43] Of these, Q50R[44] and G159D[45] 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.[46] This may be because some mutations disrupt the precise positioning of cNTnC for triggering muscle contraction when cTnI is unphosphorylated.[47]

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[48] has been tested in multiple clinical trials.[49][50][51] 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,[52][53][54] precluding any structure determination. In contrast, levosimendan inhibits type 3 phosphodiesterase with nanomolar affinity,[55] so its biological target is controversial.[56]

Some compounds have been identified to bind cNTnC with low affinity and act as troponin activators: DFBP-O[57] (a structural analog of levosimendan), 4-(4-(2,5-dimethylphenyl)-1-piperazinyl)-3-pyridinamine (NCI147866),[58] and bepridil.[59] The calmodulin antagonist, W7, has also been found to bind to cNTnC to act as a troponin inhibitor.[60] 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,[61] resveratrol,[62] bepridil,[63] and EGCG.[64] 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.

References

  1. ↑ Schreier T, Kedes L, Gahlmann R (Dec 1990). "Cloning, structural analysis, and expression of the human slow twitch skeletal muscle/cardiac troponin C gene". The Journal of Biological Chemistry 265 (34): 21247–53. PMID 2250022.
  2. ↑ Townsend PJ, Yacoub MH, Barton PJ (Jul 1997). "Assignment of the human cardiac/slow skeletal muscle troponin C gene (TNNC1) between D3S3118 and GCT4B10 on the short arm of chromosome 3 by somatic cell hybrid analysis". Annals of Human Genetics 61 (Pt 4): 375–7. doi:10.1046/j.1469-1809.1997.6140375.x. PMID 9365790.
  3. ↑ "Entrez Gene: TNNC1 troponin C type 1 (slow)".
  4. ↑ "Troponin C, slow skeletal and cardiac muscles". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) — Protein Information.
  5. 1 2 Sia SK, Li MX, Spyracopoulos L, Gagné SM, Liu W, Putkey JA, Sykes BD (Jul 1997). "Structure of cardiac muscle troponin C unexpectedly reveals a closed regulatory domain". The Journal of Biological Chemistry 272 (29): 18216–21. doi:10.1074/jbc.272.29.18216. PMID 9218458.
  6. ↑ Kretsinger RH, Nockolds CE (May 1973). "Carp muscle calcium-binding protein. II. Structure determination and general description". The Journal of Biological Chemistry 248 (9): 3313–26. PMID 4700463.
  7. ↑ Strynadka NC, James MN (June 1989). "Crystal structures of the helix-loop-helix calcium-binding proteins". Annual Review of Biochemistry 58 (1): 951–999. doi:10.1146/annurev.bi.58.070189.004511. PMID 2673026.
  8. ↑ Li MX, Saude EJ, Wang X, Pearlstone JR, Smillie LB, Sykes BD (Jul 2002). "Kinetic studies of calcium and cardiac troponin I peptide binding to human cardiac troponin C using NMR spectroscopy". European Biophysics Journal 31 (4): 245–256. doi:10.1007/s00249-002-0227-1. PMID 12122471.
  9. ↑ van Eerd JP, Takahashi K (May 1975). "The amino acid sequence of bovine cardiac tamponin-C. Comparison with rabbit skeletal troponin-C". Biochemical and Biophysical Research Communications 64 (1): 122–7. doi:10.1016/0006-291x(75)90227-2. PMID 1170846.
  10. ↑ Gifford JL, Walsh MP, Vogel HJ (Jul 2007). "Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs". The Biochemical Journal 405 (2): 199. doi:10.1042/BJ20070255. PMID 17590154.
  11. ↑ Spyracopoulos L, Li MX, Sia SK, Gagné SM, Chandra M, Solaro RJ, Sykes BD (Oct 1997). "Calcium-induced structural transition in the regulatory domain of human cardiac troponin C". Biochemistry 36 (40): 12138–46. doi:10.1021/bi971223d. PMID 9315850.
  12. ↑ Eichmüller C, Skrynnikov NR (Aug 2005). "A new amide proton R1rho experiment permits accurate characterization of microsecond time-scale conformational exchange". Journal of Biomolecular NMR 32 (4): 281–293. doi:10.1007/s10858-005-0658-y. PMID 16211482.
  13. ↑ Cordina NM, Liew CK, Gell DA, Fajer PG, Mackay JP, Brown LJ (Mar 2013). "Effects of calcium binding and the hypertrophic cardiomyopathy A8V mutation on the dynamic equilibrium between closed and open conformations of the regulatory N-domain of isolated cardiac troponin C". Biochemistry 52 (11): 1950–1962. doi:10.1021/bi4000172. PMID 23425245.
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  15. 1 2 Takeda S, Yamashita A, Maeda K, Maéda Y (Jul 2003). "Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form". Nature 424 (6944): 35–41. doi:10.1038/nature01780. PMID 12840750.
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  40. ↑ Willott RH, Gomes AV, Chang AN, Parvatiyar MS, Pinto JR, Potter JD (May 2010). "Mutations in Troponin that cause HCM, DCM AND RCM: what can we learn about thin filament function?". Journal of Molecular and Cellular Cardiology 48 (5): 882–892. doi:10.1016/j.yjmcc.2009.10.031. PMID 19914256.
  41. ↑ Chang AN, Parvatiyar MS, Potter JD (Apr 2008). "Troponin and cardiomyopathy". Biochemical and Biophysical Research Communications 369 (1): 74–81. doi:10.1016/j.bbrc.2007.12.081. PMID 18157941.
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  47. ↑ Hwang PM, Cai F, Pineda-Sanabria SE, Corson DC, Sykes BD (Oct 2014). "The cardiac-specific N-terminal region of troponin I positions the regulatory domain of troponin C". Proceedings of the National Academy of Sciences of the United States of America 111 (40): 14412–14417. doi:10.1073/pnas.1410775111. PMID 25246568.
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  64. ↑ Robertson IM, Li MX, Sykes BD (Aug 2009). "Solution structure of human cardiac troponin C in complex with the green tea polyphenol, (-)-epigallocatechin 3-gallate". The Journal of Biological Chemistry 284 (34): 23012–23. doi:10.1074/jbc.M109.021352. PMID 19542563.

External links

  1. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
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