PDBsum entry 1mxl

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Calcium-binding protein PDB id
Protein chains
89 a.a. *
17 a.a. *
* Residue conservation analysis
PDB id:
Name: Calcium-binding protein
Title: Structure of cardiac troponin c-troponin i complex
Structure: Protein (troponin c). Chain: c. Fragment: regulatory n-domain residues 1-89. Synonym: cntnc. Engineered: yes. Other_details: calcium saturated n-domain of cardiac troponin c in complex with cardiac troponin i 147-163. Protein (troponin i). Chain: i.
Source: Homo sapiens. Human. Organism_taxid: 9606. Strain: bl21(de3) plyss. Organ: heart. Tissue: muscle. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_tissue: muscle.
NMR struc: 40 models
Authors: M.X.Li,L.Spyracopoulos,B.D.Sykes
Key ref:
M.X.Li et al. (1999). Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C. Biochemistry, 38, 8289-8298. PubMed id: 10387074 DOI: 10.1021/bi9901679
22-Apr-99     Release date:   06-Jul-99    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P63316  (TNNC1_HUMAN) -  Troponin C, slow skeletal and cardiac muscles
161 a.a.
89 a.a.
Protein chain
Pfam   ArchSchema ?
P19429  (TNNI3_HUMAN) -  Troponin I, cardiac muscle
210 a.a.
17 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     calcium ion binding     1 term  


DOI no: 10.1021/bi9901679 Biochemistry 38:8289-8298 (1999)
PubMed id: 10387074  
Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C.
M.X.Li, L.Spyracopoulos, B.D.Sykes.
The interaction of troponin-C (TnC) with troponin-I (TnI) plays a central role in skeletal and cardiac muscle contraction. We have recently shown that the binding of Ca2+ to cardiac TnC (cTnC) does not induce an "opening" of the regulatory domain in order to interact with cTnI [Sia, S. K., et al. (1997) J. Biol. Chem. 272, 18216-18221; Spyracopoulos et al. (1997) Biochemistry 36, 12138-12146], which is in contrast to the regulatory N-domain of skeletal TnC (sTnC). This implies that the mode of interaction between cTnC and cTnI may be different than that between sTnC and sTnI. In sTnI, a region downstream from the inhibitory region (residues 115-131) has been shown to bind the exposed hydrophobic pocket of Ca2+-saturated sNTnC [McKay, R. T., et al. (1997) J. Biol. Chem. 272, 28494-28500]. The present study demonstrates that the corresponding region in cTnI (residues 147-163) binds to the regulatory domain of cTnC only in the Ca2+-saturated state to form a 1:1 complex, with an affinity approximately six times weaker than that between the skeletal counterparts. Thus, while Ca2+ does not cause opening, it is required for muscle regulation. The solution structure of the cNTnC.Ca2+.cTnI147-163 complex has been determined by multinuclear multidimensional NMR spectroscopy. The structure reveals an open conformation for cNTnC, similar to that of Ca2+-saturated sNTnC. The bound peptide adopts a alpha-helical conformation spanning residues 150-157. The C-terminus of the peptide is unstructured. The open conformation for Ca2+-saturated cNTnC in the presence of cTnI (residues 147-163) accommodates hydrophobic interactions between side chains of the peptide and side chains at the interface of A and B helices of cNTnC. Thus the mechanistic differences between the regulation of cardiac and skeletal muscle contraction can be understood in terms of different thermodynamics and kinetics equilibria between essentially the same structure states.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19920153 D.Kowlessur, and L.S.Tobacman (2010).
Troponin regulatory function and dynamics revealed by H/D exchange-mass spectrometry.
  J Biol Chem, 285, 2686-2694.  
20116385 M.Oleszczuk, I.M.Robertson, M.X.Li, and B.D.Sykes (2010).
Solution structure of the regulatory domain of human cardiac troponin C in complex with the switch region of cardiac troponin I and W7: the basis of W7 as an inhibitor of cardiac muscle contraction.
  J Mol Cell Cardiol, 48, 925-933.
PDB code: 2krd
20617149 M.S.Parvatiyar, J.R.Pinto, D.Dweck, and J.D.Potter (2010).
Cardiac troponin mutations and restrictive cardiomyopathy.
  J Biomed Biotechnol, 2010, 350706.  
20128626 S.B.Tikunova, B.Liu, N.Swindle, S.C.Little, A.V.Gomes, D.R.Swartz, and J.P.Davis (2010).
Effect of calcium-sensitizing mutations on calcium binding and exchange with troponin C in increasingly complex biochemical systems.
  Biochemistry, 49, 1975-1984.  
19506933 A.Neulen, R.Stehle, and G.Pfitzer (2009).
The cardiac troponin C mutation Leu29Gln found in a patient with hypertrophic cardiomyopathy does not alter contractile parameters in skinned murine myocardium.
  Basic Res Cardiol, 104, 751-760.  
19321456 C.M.Warren, T.Kobayashi, and R.J.Solaro (2009).
Sites of Intra- and Intermolecular Cross-linking of the N-terminal Extension of Troponin I in Human Cardiac Whole Troponin Complex.
  J Biol Chem, 284, 14258-14266.  
19542563 I.M.Robertson, M.X.Li, and B.D.Sykes (2009).
Solution structure of human cardiac troponin C in complex with the green tea polyphenol, (-)-epigallocatechin 3-gallate.
  J Biol Chem, 284, 23012-23023.
PDB code: 2kdh
19369252 J.Xing, J.J.Jayasundar, Y.Ouyang, and W.J.Dong (2009).
Forster resonance energy transfer structural kinetic studies of cardiac thin filament deactivation.
  J Biol Chem, 284, 16432-16441.  
19141534 N.J.Palpant, L.G.D'Alecy, and J.M.Metzger (2009).
Single histidine button in cardiac troponin I sustains heart performance in response to severe hypercapnic respiratory acidosis in vivo.
  FASEB J, 23, 1529-1540.  
19419198 R.M.Hoffman, and B.D.Sykes (2009).
Structure of the inhibitor W7 bound to the regulatory domain of cardiac troponin C.
  Biochemistry, 48, 5541-5552.
PDB code: 2kfx
19137330 S.M.Mustafi, R.B.Mutalik, R.Jain, K.Chandra, A.Bhattacharya, and K.V.Chary (2009).
Structural characterization of a novel Ca2+-binding protein from Entamoeba histolytica: structural basis for the observed functional differences with its isoform.
  J Biol Inorg Chem, 14, 471-483.  
19483081 T.Kobayashi, S.E.Patrick, and M.Kobayashi (2009).
Ala scanning of the inhibitory region of cardiac troponin I.
  J Biol Chem, 284, 20052-20060.  
19580756 Z.Yang, M.Yamazaki, Q.W.Shen, and D.R.Swartz (2009).
Differences between cardiac and skeletal troponin interaction with the thin filament probed by troponin exchange in skeletal myofibrils.
  Biophys J, 97, 183-194.  
18212018 C.C.Lim, H.Yang, M.Yang, C.K.Wang, J.Shi, E.A.Berg, D.R.Pimentel, J.K.Gwathmey, R.J.Hajjar, M.Helmes, C.E.Costello, S.Huo, and R.Liao (2008).
A novel mutant cardiac troponin C disrupts molecular motions critical for calcium binding affinity and cardiomyocyte contractility.
  Biophys J, 94, 3577-3589.  
18570382 I.M.Robertson, O.K.Baryshnikova, M.X.Li, and B.D.Sykes (2008).
Defining the binding site of levosimendan and its analogues in a regulatory cardiac troponin C-troponin I complex.
  Biochemistry, 47, 7485-7495.  
18162171 M.X.Li, I.M.Robertson, and B.D.Sykes (2008).
Interaction of cardiac troponin with cardiotonic drugs: a structural perspective.
  Biochem Biophys Res Commun, 369, 88-99.  
18398685 O.K.Baryshnikova, T.C.Williams, and B.D.Sykes (2008).
Internal pH indicators for biomolecular NMR.
  J Biomol NMR, 41, 5-7.  
18162178 R.J.Solaro, P.Rosevear, and T.Kobayashi (2008).
The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation.
  Biochem Biophys Res Commun, 369, 82-87.  
18063575 W.J.Dong, J.Xing, Y.Ouyang, J.An, and H.C.Cheung (2008).
Structural kinetics of cardiac troponin C mutants linked to familial hypertrophic and dilated cardiomyopathy in troponin complexes.
  J Biol Chem, 283, 3424-3432.  
17180551 C.Eichmüller, and N.R.Skrynnikov (2007).
Observation of microsecond time-scale protein dynamics in the presence of Ln3+ ions: application to the N-terminal domain of cardiac troponin C.
  J Biomol NMR, 37, 79-95.  
17396243 S.M.Day, M.V.Westfall, and J.M.Metzger (2007).
Tuning cardiac performance in ischemic heart disease and failure by modulating myofilament function.
  J Mol Med, 85, 911-921.  
17676764 W.J.Dong, J.J.Jayasundar, J.An, J.Xing, and H.C.Cheung (2007).
Effects of PKA phosphorylation of cardiac troponin I and strong crossbridge on conformational transitions of the N-domain of cardiac troponin C in regulated thin filaments.
  Biochemistry, 46, 9752-9761.  
16531415 T.Kobayashi, and R.J.Solaro (2006).
Increased Ca2+ affinity of cardiac thin filaments reconstituted with cardiomyopathy-related mutant cardiac troponin I.
  J Biol Chem, 281, 13471-13477.  
16962989 W.J.Dong, J.An, J.Xing, and H.C.Cheung (2006).
Structural transition of the inhibitory region of troponin I within the regulated cardiac thin filament.
  Arch Biochem Biophys, 456, 135-142.  
17101992 Y.B.Sun, B.Brandmeier, and M.Irving (2006).
Structural changes in troponin in response to Ca2+ and myosin binding to thin filaments during activation of skeletal muscle.
  Proc Natl Acad Sci U S A, 103, 17771-17776.  
16211482 C.Eichmüller, and N.R.Skrynnikov (2005).
A new amide proton R1rho experiment permits accurate characterization of microsecond time-scale conformational exchange.
  J Biomol NMR, 32, 281-293.  
15709952 T.Kobayashi, and R.J.Solaro (2005).
Calcium, thin filaments, and the integrative biology of cardiac contractility.
  Annu Rev Physiol, 67, 39-67.  
15826946 T.M.Blumenschein, D.B.Stone, R.J.Fletterick, R.A.Mendelson, and B.D.Sykes (2005).
Calcium-dependent changes in the flexibility of the regulatory domain of troponin C in the troponin complex.
  J Biol Chem, 280, 21924-21932.  
14765112 B.Agianian, U.Krzic, F.Qiu, W.A.Linke, K.Leonard, and B.Bullard (2004).
A troponin switch that regulates muscle contraction by stretch instead of calcium.
  EMBO J, 23, 772-779.  
14978304 G.L.Gay, D.A.Lindhout, and B.D.Sykes (2004).
Using lanthanide ions to align troponin complexes in solution: order of lanthanide occupancy in cardiac troponin C.
  Protein Sci, 13, 640-651.  
15711886 M.X.Li, X.Wang, and B.D.Sykes (2004).
Structural based insights into the role of troponin in cardiac muscle pathophysiology.
  J Muscle Res Cell Motil, 25, 559-579.  
15205455 S.B.Tikunova, and J.P.Davis (2004).
Designing calcium-sensitizing mutations in the regulatory domain of cardiac troponin C.
  J Biol Chem, 279, 35341-35352.  
12886291 B.D.Sykes (2003).
Pulling the calcium trigger.
  Nat Struct Biol, 10, 588-589.  
12557238 B.Tripet, G.De Crescenzo, S.Grothe, M.O'Connor-McCourt, and R.S.Hodges (2003).
Kinetic analysis of the interactions between troponin C (TnC) and troponin I (TnI) binding peptides: evidence for separate binding sites for the 'structural' N-terminus and the 'regulatory' C-terminus of TnI on TnC.
  J Mol Recognit, 16, 37-53.  
12547787 C.Sheldahl, J.Xing, W.J.Dong, S.C.Harvey, and H.C.Cheung (2003).
The calcium-saturated cTnI/cTnC complex: structure of the inhibitory region of cTnI.
  Biophys J, 84, 1057-1064.  
12732641 D.A.Lindhout, and B.D.Sykes (2003).
Structure and dynamics of the C-domain of human cardiac troponin C in complex with the inhibitory region of human cardiac troponin I.
  J Biol Chem, 278, 27024-27034.
PDB code: 1ozs
12920131 D.M.Casey, T.Yagi, R.Kamiya, and G.B.Witman (2003).
DC3, the smallest subunit of the Chlamydomonas flagellar outer dynein arm-docking complex, is a redox-sensitive calcium-binding protein.
  J Biol Chem, 278, 42652-42659.  
14661957 M.X.Li, X.Wang, D.A.Lindhout, N.Buscemi, J.E.Van Eyk, and B.D.Sykes (2003).
Phosphorylation and mutation of human cardiac troponin I deferentially destabilize the interaction of the functional regions of troponin I with troponin C.
  Biochemistry, 42, 14460-14468.  
12937281 N.Piroddi, C.Tesi, M.A.Pellegrino, L.S.Tobacman, E.Homsher, and C.Poggesi (2003).
Contractile effects of the exchange of cardiac troponin for fast skeletal troponin in rabbit psoas single myofibrils.
  J Physiol, 552, 917-931.  
12475978 R.Maytum, B.Westerdorf, K.Jaquet, and M.A.Geeves (2003).
Differential regulation of the actomyosin interaction by skeletal and cardiac troponin isoforms.
  J Biol Chem, 278, 6696-6701.  
12840750 S.Takeda, A.Yamashita, K.Maeda, and Y.Maéda (2003).
Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form.
  Nature, 424, 35-41.
PDB codes: 1j1d 1j1e
12909617 W.J.Dong, J.M.Robinson, J.Xing, and H.C.Cheung (2003).
Kinetics of conformational transitions in cardiac troponin induced by Ca2+ dissociation determined by Förster resonance energy transfer.
  J Biol Chem, 278, 42394-42402.  
12511564 W.J.Dong, J.M.Robinson, S.Stagg, J.Xing, and H.C.Cheung (2003).
Ca2+-induced conformational transition in the inhibitory and regulatory regions of cardiac troponin I.
  J Biol Chem, 278, 8686-8692.  
12147696 A.Dvoretsky, E.M.Abusamhadneh, J.W.Howarth, and P.R.Rosevear (2002).
Solution structure of calcium-saturated cardiac troponin C bound to cardiac troponin I.
  J Biol Chem, 277, 38565-38570.
PDB code: 1la0
12044157 D.A.Lindhout, M.X.Li, D.Schieve, and B.D.Sykes (2002).
Effects of T142 phosphorylation and mutation R145G on the interaction of the inhibitory region of human cardiac troponin I with the C-domain of human cardiac troponin C.
  Biochemistry, 41, 7267-7274.  
12207022 D.G.Ward, M.P.Cornes, and I.P.Trayer (2002).
Structural consequences of cardiac troponin I phosphorylation.
  J Biol Chem, 277, 41795-41801.  
12011043 L.S.Tobacman, M.Nihli, C.Butters, M.Heller, V.Hatch, R.Craig, W.Lehman, and E.Homsher (2002).
The troponin tail domain promotes a conformational state of the thin filament that suppresses myosin activity.
  J Biol Chem, 277, 27636-27642.  
12060657 X.Wang, M.X.Li, and B.D.Sykes (2002).
Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil.
  J Biol Chem, 277, 31124-31133.
PDB code: 1lxf
11371454 D.A.Martyn, and A.M.Gordon (2001).
Influence of length on force and activation-dependent changes in troponin c structure in skinned cardiac and fast skeletal muscle.
  Biophys J, 80, 2798-2808.  
11159408 D.A.Martyn, M.Regnier, D.Xu, and A.M.Gordon (2001).
Ca2+ - and cross-bridge-dependent changes in N- and C-terminal structure of troponin C in rat cardiac muscle.
  Biophys J, 80, 360-370.  
11325712 D.Vigil, S.C.Gallagher, J.Trewhella, and A.E.García (2001).
Functional dynamics of the hydrophobic cleft in the N-domain of calmodulin.
  Biophys J, 80, 2082-2092.  
11352734 M.B.Abbott, W.J.Dong, A.Dvoretsky, B.DaGue, R.M.Caprioli, H.C.Cheung, and P.R.Rosevear (2001).
Modulation of cardiac troponin C-cardiac troponin I regulatory interactions by the amino-terminus of cardiac troponin I.
  Biochemistry, 40, 5992-6001.  
11423417 Z.Li, J.Gergely, and T.Tao (2001).
Proximity relationships between residue 117 of rabbit skeletal troponin-I and residues in troponin-C and actin.
  Biophys J, 81, 321-333.  
  10933496 C.S.Tung, M.E.Wall, S.C.Gallagher, and J.Trewhella (2000).
A model of troponin-I in complex with troponin-C using hybrid experimental data: the inhibitory region is a beta-hairpin.
  Protein Sci, 9, 1312-1326.
PDB code: 1ew7
11054120 K.Pääkkönen, T.Sorsa, T.Drakenberg, P.Pollesello, C.Tilgmann, P.Permi, S.Heikkinen, I.Kilpeläinen, and A.Annila (2000).
Conformations of the regulatory domain of cardiac troponin C examined by residual dipolar couplings.
  Eur J Biochem, 267, 6665-6672.  
10913289 M.X.Li, L.Spyracopoulos, N.Beier, J.A.Putkey, and B.D.Sykes (2000).
Interaction of cardiac troponin C with Ca(2+) sensitizer EMD 57033 and cardiac troponin I inhibitory peptide.
  Biochemistry, 39, 8782-8790.  
10715110 P.Mercier, M.X.Li, and B.D.Sykes (2000).
Role of the structural domain of troponin C in muscle regulation: NMR studies of Ca2+ binding and subsequent interactions with regions 1-40 and 96-115 of troponin I.
  Biochemistry, 39, 2902-2911.  
11027154 R.T.McKay, L.F.Saltibus, M.X.Li, and B.D.Sykes (2000).
Energetics of the induced structural change in a Ca2+ regulatory protein: Ca2+ and troponin I peptide binding to the E41A mutant of the N-domain of skeletal troponin C.
  Biochemistry, 39, 12731-12738.  
10757969 S.Y.Lee, and R.E.Klevit (2000).
The whole is not the simple sum of its parts in calmodulin from S. cerevisiae.
  Biochemistry, 39, 4225-4230.  
11056032 W.J.Dong, J.Xing, M.Chandra, J.Solaro, and H.C.Cheung (2000).
Structural mapping of single cysteine mutants of cardiac troponin I.
  Proteins, 41, 438-447.  
10792039 Y.Li, M.L.Love, J.A.Putkey, and C.Cohen (2000).
Bepridil opens the regulatory N-terminal lobe of cardiac troponin C.
  Proc Natl Acad Sci U S A, 97, 5140-5145.
PDB code: 1dtl
10531339 W.J.Dong, J.Xing, M.Villain, M.Hellinger, J.M.Robinson, M.Chandra, R.J.Solaro, P.K.Umeda, and H.C.Cheung (1999).
Conformation of the regulatory domain of cardiac muscle troponin C in its complex with cardiac troponin I.
  J Biol Chem, 274, 31382-31390.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.