Structure of the calcium regulatory muscle protein troponin-C at 2.8 Å resolution

Herzberg, Osnat; James, Michael N.G.

doi:10.1038/313653a0

Cited by 639 publications

(341 citation statements)

References 39 publications

Supporting

Mentioning

324

Contrasting

Unclassified

Order By: Relevance

“…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

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

show abstract

“…The first three-dimensional structure of skeletal TnC (sTnC) was solved by X-ray crystallography in 1985 [4,5]. In this structure, the two N-domain (sNTnC) Ca 2+ -binding sites were unoccupied, while the C-domain (sCTnC) was in two Ca 2+ -bound state.…”

Section: Introductionmentioning

confidence: 99%

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Robertson

Sykes

2008

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Over the forty years since its discovery, many studies have focused on understanding the role of troponin as a myofilament based molecular switch in regulating the Ca 2+ -dependent activation of striated muscle contraction. Recently, studies have explored the role of cardiac troponin as a target for cardiotonic agents. These drugs are clinically useful for treating heart failure, a condition in which the heart is no longer able to pump enough blood to other organs. These agents act via a mechanism that modulates the Ca 2+ -sensitivity of troponin; such a mode of action is therapeutically desirable because intracellular Ca 2+ concentration is not perturbed, preserving the regulation of other Ca 2+ -based signaling pathways. This review describes molecular details of the interaction of cardiac troponin with a variety of cardiotonic drugs. We present recent structural work that has identified the docking sites of several cardiotonic drugs in the troponin C -troponin I interface and discuss their relevance in the design of troponin based drugs for the treatment of heart disease.

show abstract

“…This is in sharp contrast to other calcium binding proteins such as calmodulin (25,26), troponin C (27,28), and calbindin (29) or other Gla-containing proteins (1)(2)(3). A high-resolution structure of Ca 2+ -osteocalcin will provide information on a new class of proteins.…”

mentioning

confidence: 96%

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

Dowd

Rosen

et al. 2003

Biochemistry

View full text Add to dashboard Cite

Structural information on osteocalcin or other noncollagenous bone proteins is very limited. We have solved the three-dimensional structure of calcium bound osteocalcin using 1 H 2D NMR techniques and proposed a mechanism for mineral binding. The protons in the 49 amino acid sequence were assigned using standard two-dimensional homonuclear NMR experiments. Distance constraints, dihedral angle constraints, hydrogen bonds, and 1 H and 13 C chemical shifts were all used to calculate a family of 13 structures. The tertiary structure of the protein consisted of an unstructured N terminus and a C-terminal loop (residues 16-49) formed by long-range hydrophobic interactions. Elements of secondary structure within residues 16-49 include type III turns (residues 20-25) and two α-helical regions (residues 27-35 and 41-44). The three Gla residues project from the same face of the helical turns and are surface exposed. The genetic algorithm-molecular dynamics simulation approach was used to place three calcium atoms on the NMR-derived structure. One calcium atom was coordinated by three side chain oxygen atoms, two from Asp30, and one from Gla24. The second calcium atom was coordinated to four oxygen atoms, two from the side chain in Gla 24, and two from the side chain of Gla 21. The third calcium atom was coordinated to two oxygen atoms of the side chain of Gla17. The best correlation of the distances between the uncoordinated Gla oxygen atoms is with the intercalcium distance of 9.43 Å in hydroxyapatite. The structure may provide further insight into the function of osteocalcin.The family of vitamin K-dependent γ-carboxylated calcium binding proteins is important in a variety of tissues and cellular functions. The formation of γ-carboxyglutamic acid (Gla) 1 in the liver derived blood clotting factors, for example, results in calcium-dependent conformational changes in the proteins and functionally important interactions with acidic phospholipid surfaces (1-3). The predominant Gla protein found in bone matrix is † Support for this project was provided by NIH Grant ES-02030 to T.D., support from the Division of Environmental Sciences,Children's Hospital at Montefiore (CHAM), at the Albert Einstein College of Medicine to T.D., and NIH Grant AR-38460 to C.G. *Corresponding author. Address: Montefiore Medical Center, Moses Bldg. Rm. 401, 111 East 210th Street, Bronx, NY, 10467. Phone: 718-920-2276. Fax: 718-920-4377. dowd@aecom.yu.edu. 1 Abbreviations: Gla, γ-carboxyglutamic acid; Fmoc, 9-flourenyl-methyloxycarbonyl; CD, circular dichroism; NMR, nuclear magnetic resonance; HSQC, heteronuclear single-quantum correlation; NOE, nuclear Overhauser effect; NOESY, NOE spectroscopy; rmsd, root-mean-square deviation; TOCSY, total correlation spectroscopy. HHS Public Access Author manuscriptBiochemistry. Author manuscript; available in PMC 2015 July 28. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript osteocalcin (4, 5), a small Ca 2+ binding protein containing three Gla residues which are thought to facil...

show abstract

Structure of the calcium regulatory muscle protein troponin-C at 2.8 Å resolution

Cited by 639 publications

References 39 publications

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

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

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

Contact Info

Product

Resources

About

Structure of the calcium regulatory muscle protein troponin-C at 2.8 Å resolution

Cited by 639 publications

References 39 publications

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

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

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using 1H NMR Spectroscopy

Contact Info

Product

Resources

About

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy