Structure of the mid-region of tropomyosin: Bending and binding sites for actin

Brown, Jerry H.; Zhou, Zhaocai; Reshetnikova, L.; Robinson, Howard; Yammani, Rama D.; Tobacman, Larry S.; Cohen, Carolyn

doi:10.1073/pnas.0509269102

Cited by 140 publications

(155 citation statements)

References 59 publications

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“…5 B and C. The multiple weak but specific electrostatic interactions between Tm, actin, and myosin allow dynamic regulation of the thin filament that must change its functional state rapidly and in a cooperative manner. The mutations in the first and second halves of periods also approximately correspond to the α-and β-bands of Tm that (33,34) in a 8 Å rigor actin-Tm-myosin S1 complex determined by cryo-EM (10). A minor modification was made in the axial and rotational alignment of Tm in the EM model by positioning crystal structures of Tm fragments to optimize electrostatic interactions of the mutated Tm residues in second-half of P3-P6 with charged residues on actin and myosin, while maintaining the azimuthal alignment.…”

Section: Discussionmentioning

confidence: 86%

“…1) are close to actin residues D25, K326, K328, and P333 (23,33,40). The weak but specific electrostatic interactions with actin place Tm in the closed position in the absence of myosin, partially occupying the myosin binding site on actin.…”

Section: Discussionmentioning

confidence: 99%

“…The results provide a basis for establishing models for binding of Tm to the actin filament in the different regulatory states and the residues involved in switching it from one state to another. We have constructed a molecular model of Tm bound to F-actin in the open state by docking high-resolution Tm structures (33,34) to a proposed binding site in a 8 Å rigor actin-Tm-myosin S1 complex determined by cryo-EM (10). Because of the necessity of applying the helical symmetry of actomyosin to achieve maximum resolution, the molecular ends of Tm as well as the axial and rotational position of Tm with respect to actomyosin are not defined in the EM structure.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of actin-myosin interaction by conserved periodic sites of tropomyosin

Barua

Winkelmann

White

et al. 2012

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

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Cooperative activation of actin-myosin interaction by tropomyosin (Tm) is central to regulation of contraction in muscle cells and cellular and intracellular movements in nonmuscle cells. The steric blocking model of muscle regulation proposed 40 y ago has been substantiated at both the kinetic and structural levels. Even with atomic resolution structures of the major players, how Tm binds and is designed for regulatory function has remained a mystery. Here we show that a set of periodically distributed evolutionarily conserved surface residues of Tm is required for cooperative regulation of actomyosin. Based on our results, we propose a model of Tm on a structure of actin-Tm-myosin in the "open" (on) state showing potential electrostatic interactions of the residues with both actin and myosin. The sites alternate with a second set of conserved surface residues that are important for actin binding in the inhibitory state in the absence of myosin. The transition from the closed to open states requires the sites identified here, even when troponin + Ca 2+ is present. The evolutionarily conserved residues are important for actomyosin regulation, a universal function of Tm that has a common structural basis and mechanism.actin filament structure | cell motility | cytoskeleton | muscle contraction | motility assay A ctin and myosin are found in almost all eukaryotic cells and are required for diverse cellular functions, including muscle contraction, cell motility, cell adhesion, cytokinesis, and organelle transport (1). The actin-myosin interaction produces two types of movements: force generation between actin filaments leading to contractions, such as in muscle contraction, cell motility, and cytokinesis; and transport of subcellular organelles and macromolecular complexes by myosin motors along actin filaments. The actomyosin contractile apparatus is best characterized in striated muscle contraction, which is regulated in a Ca 2+ -dependent manner by the proteins, tropomyosin (Tm) and troponin (Tn).Tm is a universal regulator of the actin cytoskeleton. It is a twochained, α-helical coiled-coil actin binding protein that associates end-to-end to form a continuous strand along both sides of actin filaments and regulates the functions and stability of actin filaments (2, 3). Tm regulates the interaction of actin filaments with actin binding proteins, including myosin, Tn, ADF-cofilin, Arp2/3, formin, and tropomodulin. Tm can activate or inhibit actomyosin, depending on the myosin and Tm isoforms (4-7). The Tm-dependent regulation is widespread, having been reported in fission yeast and mammalian muscle and nonmuscle systems. The regulation of actomyosin by Tm may be viewed as universal, although there is little understanding of the mechanism or structural basis, the focus of the present work.In striated muscle, regulation of myosin binding to the thin filament (actin-Tm-Tn) is described by a three-state model, where the three kinetic states are thought to correspond to three positions of Tm on the actin filament (8-1...

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of actin-myosin interaction by conserved periodic sites of tropomyosin

Barua

Winkelmann

White

et al. 2012

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

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“…Biochemical data also has suggested that TnT modulates the equilibrium between closed and open states (28). The proposed azimuthal shift of tropomyosin between blocks IV and V is supported by tropomyosin crystal structures (29), which showed that the coiled coil is disturbed around residues 151-162, located in the C-terminal half of block IV. The flexibility generated by an alanine cluster (Ala-151, 155, and 158) and nearby Tyr-162 in the coiled-coil core would also help accommodate the difference in the azimuthal position between blocks IV and V. When the alanine cluster (156-162) is replaced, the actin-activated myosin ATPase is suppressed (30).…”

Section: Implications For Regulation Of Striated Muscle Contractionmentioning

confidence: 87%

“…Some tropomyosin heptad repeats deviate from the canonical pattern in having either bulky or small hydrophobic residues in positions a and d (10). It has been proposed (11) that the small side chains might be able to move within the large holes facilitating the flexibility required for tropomyosin's wide range of functions on actin filaments and this has been verified experimentally (12). Tropomyosin (284 residues in most isoforms) also has a 7-fold (Ϸ40 residue) sequence repeat (13), and each motif is thought to interact similarly with one actin monomer (8,11).…”

mentioning

confidence: 96%

Structural basis for tropomyosin overlap in thin (actin) filaments and the generation of a molecular swivel by troponin-T

Murakami

Stewart

Nozawa

et al. 2008

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

103

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-C caused a marked decrease in the affinity of troponin for actin-tropomyosin filaments. The highly conserved region of TnT, in which most cardiomyopathy mutations reside, is crucial for interacting with tropomyosin. The structure of the ternary complex also explains why the skeletal-and cardiac-muscle specific C-terminal region is required to bind TnT and why tropomyosin homodimers bind only a single TnT. On actin filaments, the head-to-tail junction can function as a molecular swivel to accommodate irregularities in the coiled-coil path between successive tropomyosins enabling each to interact equivalently with the actin helix.calcium ͉ cardiomyopathy ͉ troponin

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Molecular Genetics of Myopathies Caused by β‐Tropomyosin Mutations

Pelin

Marttila

Wallgren‐Pettersson

2014

Encyclopedia of Life Sciences

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Mutations in the gene encoding β‐tropomyosin, TPM2 , cause clinically and histologically overlapping congenital myopathies such as nemaline myopathy, cap myopathy and core‐rod myopathy, and often also a fibre size disproportion between type 1 and type 2 muscle fibres. In addition, TPM2 mutations can cause distal arthrogryposis and Escobar syndrome, or unspecific myopathies with various combinations of clinical and histological features. The vast majority of the TPM2 mutations are dominant, either de novo or familial. Missense mutations and in‐frame deletions or insertions of single amino acids are the most common types of mutation. Three dominant donor splice site mutations have also been described, predicted to cause exon skipping and subsequent loss of 42 amino acids. Only one recessive mutation has been identified in TPM2 , that is, a nonsense mutation causing nemaline myopathy with Escobar syndrome. Of the 30 different TPM2 mutations identified to date, six are gain‐of‐function mutations causing increased muscle contractility. Key Concepts: Dominant mutations in the TPM2 gene cause a variety of congenital myopathies and distal arthrogryposis. Recessive mutations in TPM2 are rare. Tropomyosin mutations alter actin‐tropomyosin interactions, tropomyosin dimer formation and muscle contraction. Gain‐of‐function mutations cause increased muscle contractility. Hypercontractile molecular phenotypes result in distal arthrogryposis and congenital myopathies with contractures.

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Structure of the mid-region of tropomyosin: Bending and binding sites for actin

Cited by 140 publications

References 59 publications

Regulation of actin-myosin interaction by conserved periodic sites of tropomyosin

Regulation of actin-myosin interaction by conserved periodic sites of tropomyosin

Structural basis for tropomyosin overlap in thin (actin) filaments and the generation of a molecular swivel by troponin-T

Molecular Genetics of Myopathies Caused by β‐Tropomyosin Mutations

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