An Interplay between Protein Disorder and Structure Confers the Ca2+ Regulation of Striated Muscle

Hoffman, Ryan M. B.; Blumenschein, Tharin M. A.; Sykes, Brian D.

doi:10.1016/j.jmb.2006.06.031

Cited by 59 publications

(82 citation statements)

References 37 publications

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“…The Ca 2+ -CaM-induced exchange broadening of residues mapping to the M-motif of ssC1C2 is likely the consequence of highly dynamic interactions at the binding interface. This exchange broadening phenomenon and conformational fluctuations have been reported in other muscle proteins [42,43]. The NMR observation of conformational plasticity in the M-motif and the C2 linker in ssC1C2 is also consistent with our DSF data showing partial destabilization in the ssC1C2/CaM complex as evidenced by the lowered T m .…”

Section: Discussionsupporting

confidence: 92%

Calcium-Dependent Interaction Occurs between Slow Skeletal Myosin Binding Protein C and Calmodulin

et al. 2017

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Abstract:Myosin binding protein C (MyBP-C) is a multi-domain protein that participates in the regulation of muscle contraction through dynamic interactions with actin and myosin. Three primary isoforms of MyBP-C exist: cardiac (cMyBP-C), fast skeletal (fsMyBP-C), and slow skeletal (ssMyBP-C). The N-terminal region of cMyBP-C contains the M-motif, a three-helix bundle that binds Ca 2+ -loaded calmodulin (CaM), but less is known about N-terminal ssMyBP-C and fsMyBP-C. Here, we characterized the conformation of a recombinant N-terminal fragment of ssMyBP-C (ssC1C2) using differential scanning fluorimetry, nuclear magnetic resonance, and molecular modeling. Our studies revealed that ssC1C2 has altered thermal stability in the presence and absence of CaM. We observed that site-specific interaction between CaM and the M-motif of ssC1C2 occurs in a Ca 2+ -dependent manner. Molecular modeling supported that the M-motif of ssC1C2 likely adopts a three-helix bundle fold comparable to cMyBP-C. Our study provides evidence that ssMyBP-C has overlapping structural determinants, in common with the cardiac isoform, which are important in controlling protein-protein interactions. We shed light on the differential molecular regulation of contractility that exists between skeletal and cardiac muscle.

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Section: Discussionsupporting

confidence: 92%

Calcium-Dependent Interaction Occurs between Slow Skeletal Myosin Binding Protein C and Calmodulin

et al. 2017

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“…This is based on FRET measurements of the Ca 2+ -dependent distance change between the inhibitory and the switch regions of cTnI in a cardiac troponin complex reconstituted in the presence of tropomyosin, actin, and myosin subfragment-1 (S1). An alternative mechanism based on NMR relaxation data for sTnI in the Tn complex [45] proposes that any structure in the C-terminal regions of sTnI (sTnI ) is nascent, and stabilized only upon binding to actin [46].…”

Section: Introductionmentioning

confidence: 99%

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Robertson

Sykes

2008

Biochemical and Biophysical Research Communications

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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.

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“…Naturally, dynamic interactions among the thin filament proteins form a main feature of the Ca 2ϩ -dependent activation of cardiac muscle with multiple transitions in dynamic state occurring at the thin filament protein interfaces (13,14). Some interactions have been shown to be notably rigid and invariant in terms of conformational dynamics, whereas others involve structural regions marked by flexibility and prone to facilitating conformational changes (15,16).…”

mentioning

confidence: 99%

Structural Dynamics of C-domain of Cardiac Troponin I Protein in Reconstituted Thin Filament

Zhou

Rieck

et al. 2012

Journal of Biological Chemistry

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Background:The kinetics and dynamics of the C-domain of cTnI were studied. Results: Fluorescence anisotropy data show support for the fly casting model and a fourth state of thin filament activation. Conclusion: The fly casting model holds true in the thin filament, but the presence of S1 modulates the process. Significance: Our study provides information on the role of the cTnI C-domain in thin filament regulation.

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An Interplay between Protein Disorder and Structure Confers the Ca2+ Regulation of Striated Muscle

Cited by 59 publications

References 37 publications

Calcium-Dependent Interaction Occurs between Slow Skeletal Myosin Binding Protein C and Calmodulin

Calcium-Dependent Interaction Occurs between Slow Skeletal Myosin Binding Protein C and Calmodulin

Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Structural Dynamics of C-domain of Cardiac Troponin I Protein in Reconstituted Thin Filament

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