Structure of Cardiac Muscle Troponin C Unexpectedly Reveals a Closed Regulatory Domain

Sia, Samuel K.; Li, Monica X.; Spyracopoulos, Leo; Gagné, Stéphane M.; Wen, Lihui; Putkey, John A.; Sykes, Brian D.

doi:10.1074/jbc.272.29.18216

Cited by 212 publications

(270 citation statements)

References 35 publications

(29 reference statements)

Supporting

Mentioning

249

Contrasting

Unclassified

Order By: Relevance

“…Ca 2þ bound, closed EF-hand has only been reported for two other EF-hand calcium sensors [calpain 40 and cardiac troponin C (cTnC) 41 ] and in the pseudo-EF-hand of S100 proteins (calcyclin 42 and S100B 43 ).…”

Section: Discussionmentioning

confidence: 99%

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca²⁺‐bound closed state: Implications for target recognition

Park

Ames

2011

Protein Science

View full text Add to dashboard Cite

Calcium-binding protein 1 (CaBP1), a neuron-specific member of the calmodulin (CaM) superfamily, regulates the Ca 21 -dependent activity of inositol 1,4,5-triphosphate receptors (InsP3Rs) and various voltage-gated Ca 21 channels. Here, we present the NMR structure of fulllength CaBP1 with Ca 21 bound at the first, third, and fourth EF-hands. A total of 1250 nuclear Overhauser effect distance measurements and 70 residual dipolar coupling restraints define the overall main chain structure with a root-mean-squared deviation of 0.54 Å (N-domain) and 0.48 Å (C-domain). The first 18 residues from the N-terminus in CaBP1 (located upstream of the first EFhand) are structurally disordered and solvent exposed. The Ca 21 -saturated CaBP1 structure contains two independent domains separated by a flexible central linker similar to that in calmodulin and troponin C. The N-domain structure of CaBP1 contains two EF-hands (EF1 and EF2), both in a closed conformation [interhelical angles 5 129°(EF1) and 142°(EF2)]. The C-domain contains EF3 and EF4 in the familiar Ca 21 -bound open conformation [interhelical angles 5 105°( EF3) and 91°(EF4)]. Surprisingly, the N-domain adopts the same closed conformation in the presence or absence of Ca 21 bound at EF1. The Ca 21 -bound closed conformation of EF1 is reminiscent of Ca 21 -bound EF-hands in a closed conformation found in cardiac troponin C and calpain. We propose that the Ca 21 -bound closed conformation of EF1 in CaBP1 might undergo an induced-fit opening only in the presence of a specific target protein, and thus may help explain the highly specialized target binding by CaBP1.

show abstract

Section: Discussionmentioning

confidence: 99%

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca²⁺‐bound closed state: Implications for target recognition

Park

Ames

2011

Protein Science

View full text Add to dashboard Cite

show abstract

“…cNTnC mutants have been used in previous studies to examine the structure and Ca 2ϩ activation of the NH 2 -terminal domain (20,34,35). Spyracopoulos et al (35) have demonstrated that the Ca 2ϩ -saturated NMR solution structure of McNTnC is similar to that of the Ca 2ϩ -saturated NH 2 domain of the full-length mutant (C35S/C84S) chicken cTnC (33). In the present study, ScNTnC and McNTnC had a higher Ca 2ϩ affin- ity than the respective full-length isoforms.…”

Section: Discussionmentioning

confidence: 99%

Sequence mutations in teleost cardiac troponin C that are permissive of high Ca²⁺ affinity of site II

Gillis

Tibbits

2003

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Cardiac myofibrils isolated from trout heart have been demonstrated to have a higher sensitivity for Ca2+ than mammalian cardiac myofibrils. Using cardiac troponin C (cTnC) cloned from trout and mammalian hearts, we have previously demonstrated that this comparatively high Ca2+ sensitivity is due, in part, to trout cTnC (ScTnC) having twice the Ca2+ affinity of mammalian cTnC (McTnC) over a broad range of temperatures. The amino acid sequence of ScTnC is 92% identical to McTnC. To determine the residues responsible for the high Ca2+ affinity, the function of a number of ScTnC and McTnC mutants was characterized by monitoring an intrinsic fluorescent reporter that monitors Ca2+ binding to site II (F27W). The removal of the COOH terminus (amino acids 90–161) from ScTnC and McTnC maintained the difference in Ca2+ affinity between the truncated cTnC isoforms (ScNTnC and McNTnC). The replacement of Gln29 and Asp30 in ScNTnC with the corresponding residues from McNTnC, Leu and Gly, respectively, reduced Ca2+ affinity to that of McNTnC. These results demonstrate that Gln29 and Asp30 in ScTnC are required for the high Ca2+ affinity of site II.

show abstract

“…SANS studies of the ternary cTn further revealed the effect of phosphorylation of the two protein kinase A dependent phosphorylation sites in the cardiac-specific N-terminal extension in cTnI ($ 27-33 residues); this phosphorylation in known to result in a reduction in myofilament Ca 21 sensitivity and an increase in relaxation and cross-bridging cycle kinetics. [25][26][27] All of the high-resolution structures of sTnC and cTnC show the characteristic dumbbell shape with two globular domains separated by an extended, solvent-exposed helix of 7-8 turns [28][29][30][31][32] 41 and Heidorn and Trewhella 42 presented the first SAXS studies of rabbit sTnC that showed that the two globular domains of sTnC are on average closer together in solution than they are in the crystal structure. This interpretation was evident in the P(r) profile, which showed a peak with a shoulder in the distribution rather than the two resolved peaks indicative of two separate domains and suggested that, like calmodulin, the helix connecting the two globular EF-hand domains was flexible in solution.…”

Section: Skeletal and Cardiac Isoforms Of Troponinmentioning

confidence: 99%

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

Jeffries

Trewhella

2011

Biopolymers

View full text Add to dashboard Cite

Small‐angle X‐ray and neutron scattering with contrast variation have made important contributions in advancing our understanding of muscle regulatory protein structures in the context of the dynamic molecular processes governing muscle action. The contributions of the scattering investigations have depended upon the results of key crystallographic, NMR, and electron microscopy experiments that have provided detailed structural information that has aided in the interpretation of the scattering data. This review will cover the advances made using small‐angle scattering techniques, in combination with the results from these complementary techniques, in probing the structures of troponin and myosin binding protein C. A focus of the troponin work has been to understand the isoform differences between the skeletal and cardiac isoforms of this major calcium receptor in muscle. In the case of myosin binding protein C, significant data are accumulating, indicating that this protein may act to modulate the primary calcium signals from troponin, and interest in its biological role has grown because of linkages between gene mutations in the cardiac isoform and serious heart disease. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 505–516, 2011.

show abstract

Structure of Cardiac Muscle Troponin C Unexpectedly Reveals a Closed Regulatory Domain

Cited by 212 publications

References 35 publications

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca²⁺‐bound closed state: Implications for target recognition

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca²⁺‐bound closed state: Implications for target recognition

Sequence mutations in teleost cardiac troponin C that are permissive of high Ca²⁺ affinity of site II

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

Contact Info

Product

Resources

About

Structure of Cardiac Muscle Troponin C Unexpectedly Reveals a Closed Regulatory Domain

Cited by 212 publications

References 35 publications

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca2+‐bound closed state: Implications for target recognition

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca2+‐bound closed state: Implications for target recognition

Sequence mutations in teleost cardiac troponin C that are permissive of high Ca2+ affinity of site II

Invited review: Probing the structures of muscle regulatory proteins using small‐angle solution scattering

Contact Info

Product

Resources

About

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca²⁺‐bound closed state: Implications for target recognition

Nuclear magnetic resonance structure of calcium‐binding protein 1 in a Ca²⁺‐bound closed state: Implications for target recognition

Sequence mutations in teleost cardiac troponin C that are permissive of high Ca²⁺ affinity of site II