An Atomic Model of the Thin Filament in the Relaxed and Ca2+-Activated States

Pirani, Alnoor; Vinogradova, Maia; Curmi, Paul M. G.; King, W. A.; Fletterick, Robert J.; Craig, Roger; Tobacman, Larry S.; Xu, Chen; Hatch, Victoria; Lehman, William

doi:10.1016/j.jmb.2005.12.050

Cited by 131 publications

(140 citation statements)

References 42 publications

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“…These in situ orientations of the troponin core complex with Ca 2ϩ bound to the regulatory sites are similar but not identical to that proposed recently on the basis of fitting the same core complex structure (9) into electron microscopic reconstructions of isolated thin filaments in the Ca 2ϩ -bound state (31). In that case, the IT coiled-coil was estimated to be at 21°to the filament axis, and the D/E helix roughly perpendicular to it.…”

Section: Discussionsupporting

confidence: 84%

Structural changes in troponin in response to Ca ²⁺ and myosin binding to thin filaments during activation of skeletal muscle

Sun

Brandmeier

Irving

2006

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

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Contraction of skeletal and cardiac muscle is regulated by Ca 2؉ -dependent structural changes in troponin that control the interaction between myosin and actin. We measured the orientations of troponin domains in skeletal muscle fibers using polarized fluorescence from bifunctional rhodamine probes on the C and E helices of troponin C. The C helix, in the regulatory head domain, tilts by Ϸ30°when muscle is activated in physiological conditions, with a Ca 2؉ -sensitivity similar to that of active force. Complete inhibition of active force did not affect C-helix orientation, and binding of rigor myosin heads did not affect its orientation at saturating [Ca 2؉ ]. The E helix, in the IT arm of troponin, tilted by Ϸ10°on activation, and this was reduced to only 3°when active force was inhibited. Binding of rigor myosin heads produced a larger tilt of the E helix. Thus, in situ, the regulatory head acts as a pure Ca 2؉ -sensor, whereas the IT arm is primarily sensitive to myosin head binding. The polarized fluorescence data from active muscle are consistent with an in vitro structure of the troponin core complex in which the D and E helices of troponin C are collinear. The present data were used to orient this structure in the fiber and suggest that the IT arm is at Ϸ30°to the filament axis in active muscle. In relaxed muscle, the IT arm tilts to Ϸ40°but the D/E helix linker melts, allowing the regulatory head to tilt through a larger angle.

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Section: Discussionsupporting

confidence: 84%

Structural changes in troponin in response to Ca ²⁺ and myosin binding to thin filaments during activation of skeletal muscle

Sun

Brandmeier

Irving

2006

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

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“…Although the specific structural features of this extension cannot be deduced from the low-resolution neutron models, the novel finding of this structural change in sTnI has laid a foundation for further high-resolution studies. 15,[63][64][65] All optimized SANS-derived models point to a similar shape for sTnC, that of a fully extended dumbbell shape in both Ca 21 -free and Ca 21 -bound states, consistent with previous interpretations 48,49 as opposed to the somewhat more compact conformation observed in the cTn crystal structure 60 and SANS models for cTn. 50,51 In the SANS-derived model for sTn, the N-terminal domain of Ca 21 -bound sTnC rotates more than 1008 away from the position seen in the crystal structure.…”

Section: Probing the Structures Of Muscle Regulatory Proteins 509supporting

confidence: 84%

“…The inherent flexibility within key muscle protein complexes has often frustrated X-ray crystallographic analyses (e.g., in obtaining crystals for the apo and Ca 21 -bound states of the Tn and Tn/Tm complexes), while NMR investigations are limited to relatively small, isolated components. Electron microscopy images have been exceptionally informative for probing the structures of huge macromolecular assemblies, [14][15][16] but they generally have insufficient resolution to resolve subunit boundaries and intersubunit distances. Small-angle solution scattering, when combined with the results of these more traditional structural biology tools, has provided important complementary information that has aided in advancing our understanding of muscle regulatory proteins.…”

mentioning

confidence: 99%

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

Jeffries

Trewhella

2011

Biopolymers

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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.

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“…The approximate position of the inhibitory region of TnI is indicated in the top panel by the white arrow. The structure and relative positions employed to construct these projections are based on data obtained for rabbit skeletal muscle (actin) and bovine cardiac muscle (troponin and tropomyosin) by the Lehman group using electron microscopy data and helical and single particle reconstruction [55,56] …”

Section: Future Perspectivesmentioning

confidence: 99%

“…In addition, recent evidence suggests that the structural states of the seven actin monomers in the regulatory unit are not identical, supporting the notion of a preferential binding site for myosin halfway between the Tm-Tm overlap region close to the location of Tn on the actin filament [55,77,78]. Finally, whether simultaneous independent cross-bridge formation can take place on opposite sides of the Factin filament is not known.…”

Section: Introduction and Scopementioning

confidence: 99%

Cardiac thin filament regulation

Kobayashi

Liu

Tombe

2008

Pflugers Arch - Eur J Physiol

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Myocardial contraction is initiated upon the release of calcium into the cytosol from the sarcoplasmic reticulum following membrane depolarization. The fundamental physiological role of the heart is to pump an amount blood that is determined by the prevailing requirements of the body. The physiological control systems employed to accomplish this task include regulation of heart rate, the amount of calcium release, and the response of the cardiac myofilaments to activator calcium ions. Thin filament activation and relaxation dynamics has emerged as a pivotal regulatory system tuning myofilament function to the beat-to-beat regulation of cardiac output. Maladaptation of thin filament dynamics, in addition to dysfunctional calcium cycling, is now recognized as an important cellular mechanism causing reduced cardiac pump function in a variety of cardiac diseases. Here, we review current knowledge regarding protein-protein interactions involved in the dynamics of thin filament activation and relaxation and the regulation of these processes by protein kinase-mediated phosphorylation.

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An Atomic Model of the Thin Filament in the Relaxed and Ca2+-Activated States

Cited by 131 publications

References 42 publications

Structural changes in troponin in response to Ca ²⁺ and myosin binding to thin filaments during activation of skeletal muscle

Structural changes in troponin in response to Ca ²⁺ and myosin binding to thin filaments during activation of skeletal muscle

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

Cardiac thin filament regulation

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An Atomic Model of the Thin Filament in the Relaxed and Ca2+-Activated States

Cited by 131 publications

References 42 publications

Structural changes in troponin in response to Ca 2+ and myosin binding to thin filaments during activation of skeletal muscle

Structural changes in troponin in response to Ca 2+ and myosin binding to thin filaments during activation of skeletal muscle

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

Cardiac thin filament regulation

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Product

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Structural changes in troponin in response to Ca ²⁺ and myosin binding to thin filaments during activation of skeletal muscle

Structural changes in troponin in response to Ca ²⁺ and myosin binding to thin filaments during activation of skeletal muscle