Molecular mechanism of troponin-C function

Grabarek, Zenon; Tao, Terence; Gergely, J.

doi:10.1007/bf01738034

Cited by 146 publications

(114 citation statements)

References 114 publications

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“…Contraction is triggered when Ca2+ released from the sarcoplasmic reticulum binds to the lowaffinity sites. Calcium binding promotes large conformational changes in the TnC structure (7). Recently, NMR data (8,9) have suggested that Ca2+ binding to the low-affinity sites of TnC induces movement of helices B and C away from helices A, D, and N, confirming the general features of the model proposed by Herzberg et al (10).…”

supporting

confidence: 62%

“…The conformation induced by subzero temperatures binds the hydrophobic probe bis-aminonaphthalene sulfonate, and the tryptophan has the same fluorescence lifetime (7 ns) as in the Ca2+-bound form. The decrease in volume (AV = -25.4 ml/mol) corresponds to an increase in surface area.…”

mentioning

confidence: 99%

“…The N-and C-terminal domains are structurally homologous, each having two divalent-cation binding sites that consist of a helix-loophelix motif in which 6 of 12 amino acid residues of the loop contribute to coordination of the cation. The C-domain has two high-affinity sites for Ca2> that also bind Mg2+, whereas the N-domain has two low-affinity, Ca2+-specific sites (7).…”

mentioning

confidence: 99%

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Mimicry of the calcium-induced conformational state of troponin C by low temperature under pressure.

Foguel

Suarez²,

Barbosa³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Calcium binding to the N-domain of troponin C initiates a series of conformational changes that lead to muscle contraction. Calcium binding provides the free energy for a hydrophobic region in the core of N-domain to assume a more open configuration. Fluorescence measurements on a tryptophan mutant (F29W) show that a similar conformational change occurs in the absence of Ca2l when the temperature is lowered under pressure. The conformation induced by subzero temperatures binds the hydrophobic probe bis-aminonaphthalene sulfonate, and the tryptophan has the same fluorescence lifetime (7 ns) as in the Ca2+-bound form. The decrease in volume (AV = -25.4 ml/mol) corresponds to an increase in surface area. Thermodynamic measurements suggest an enthalpy-driven conformational change that leads to an intermediate with an exposed N-domain core and a high affinity for Ca>.

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supporting

confidence: 62%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mimicry of the calcium-induced conformational state of troponin C by low temperature under pressure.

Foguel

Suarez²,

Barbosa³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The fact that the three troponin subunits can refold and reassociate in vitro (Greaser & Gergely, 1971) has allowed the use of troponin subunits produced in Escherichia coli to study the molecular mechanism of this regulatory complex. Expression of TnC in bacteria (Chen et al, 1988;Reinach & Karlsson, 1988;Xu & HitchcockDeGregori, 1988) and the analysis of site-directed mutants (Fujimori et al, 1990;Grabarek et al, 1990;Putkey et al, 1991;Sheng et a]., 1991;Negele et al, 1992;Pearlstone et al, 1992;Silva et al, 1993) in conjunction with the determination of the crystal structure of TnC (Herzberg & James, 1985;Sundarlingam et al, 1985) has provided a better understanding of the calcium-induced conformational change in TnC (Silva & Reinach, 1991;Grabarek et al, 1992). This conformational change is responsible for the modulation of the inhibitory action of Tnl.…”

mentioning

confidence: 99%

Cloning and expression of chicken skeletal muscle troponin I in Escherichia coli: The role of rare codons on the expression level

et al. 1993

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“…Each domain contains a hydrophobic cleft and two helix-loop-helix EF-hand metal binding motifs; two high-affinity Ca 2ϩ ͞Mg 2ϩ sites in the C-terminal domain (sites III and IV) and two low-affinity Ca 2ϩ specific sites in the N-terminal domain (sites I and II). In skeletal TnC, sites III and IV are permanently occupied by Mg 2ϩ and facilitate the structural binding of TnC to the contractile apparatus (5). Binding of Ca 2ϩ to sites I and II is the physiological trigger for muscle contraction.…”

mentioning

confidence: 99%

Structure of the inhibitory region of troponin by site directed spin labeling electron paramagnetic resonance

Brown

Sale

Hills

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Site-directed spin labeling EPR (SDSL-EPRtroponin I ͉ spin labels ͉ Fourier transform electron paramagnetic resonance ͉ DEER ͉ dipolar R egulation of striated muscle contraction is associated with Ca 2ϩ -dependent structural transitions in the muscle thin filament, which is composed of the troponin complex, tropomyosin, and actin. Troponin is composed of three components: TnC, which binds Ca 2ϩ ; TnI, which inhibits actomyosin activity; and TnT, which anchors TnC and TnI to tropomyosin. Muscle contraction is initiated by the binding of Ca 2ϩ to the N-lobe regulatory sites of TnC. The N lobe then undergoes a structural transition from a closed to an open form, which then facilitates the release of the inhibitory region of TnI from actin, binding to TnC and stimulation of the actomyosin ATPase. The mechanism of this signaling pathway is still tentative (for review, see ref. 1).Crystal and NMR structures are available for TnC and several complexes of TnC with TnI fragments. The crystal structure of TnC reveals a dumbbell-shaped protein consisting of two globular domains, joined by a 22-residue central ␣-helix (2-4). Each domain contains a hydrophobic cleft and two helix-loop-helix EF-hand metal binding motifs; two high-affinity Ca 2ϩ ͞Mg 2ϩ sites in the C-terminal domain (sites III and IV) and two low-affinity Ca 2ϩ specific sites in the N-terminal domain (sites I and II). In skeletal TnC, sites III and IV are permanently occupied by Mg 2ϩ and facilitate the structural binding of TnC to the contractile apparatus (5). Binding of Ca 2ϩ to sites I and II is the physiological trigger for muscle contraction. In cardiac TnC, binding site I is inactive and Ca 2ϩ binding to site II does not induce as large a structural change as observed in skeletal TnC (6). TnI is capable of inhibiting actomyosin ATPase in the absence of other subunits, but Ca 2ϩ -dependent regulation requires TnC, TnT, and tropomyosin. The inhibitory region (skTnI 96-117) alone can fully inhibit actomyosin ATPase activity (7) possibly by binding either to actin or to TnC in the ''on'' or ''off'' states (8-10). The corresponding residues for the cardiac inhibitory region are 129-150 because of a unique Ϸ32 residue N-terminal extension of cTnI.Structural information for the intact troponin complex is limited to low-resolution neutron diffraction and electron microscopy studies (11-13), though several high-resolution structures of TnC with bound TnI peptides are available. Two computational models have been recently proposed for the binary complex of TnC and TnI (14,15). Both models have TnI and TnC in an antiparallel arrangement with multiple interaction sites between the two subunits. NMR, crystallography, and neutron scattering was used by Tung et al. (15) to develop a computational model of the binary complex in which TnI winds around TnC in either a left-handed manner (model ''L'') or a right-handed manner (model ''R''). In both structures, the inhibitory region of TnI is modeled as a flexible ␤-hairpin in close proximity to the central helix of TnC. ...

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Molecular mechanism of troponin-C function

Cited by 146 publications

References 114 publications

Mimicry of the calcium-induced conformational state of troponin C by low temperature under pressure.

Mimicry of the calcium-induced conformational state of troponin C by low temperature under pressure.

Cloning and expression of chicken skeletal muscle troponin I in Escherichia coli: The role of rare codons on the expression level

Structure of the inhibitory region of troponin by site directed spin labeling electron paramagnetic resonance

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