The Shape and Flexibility of Tropomyosin Coiled Coils: Implications for Actin Filament Assembly and Regulation

Li, Xiaochuan Edward; Holmes, Kenneth C.; Lehman, William; Jung, Hyun Suk; Fischer, Stefan

doi:10.1016/j.jmb.2009.10.060

Cited by 108 publications

(241 citation statements)

References 67 publications

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“…23 Others have viewed the molecule as having a ''pre-shaped semi-rigid architecture'' designed on average to match the shape of F-actin, based on the modeling of certain crystal structures onto F-actin 22 and on a combined study using electron microscopy and molecular dynamics simulations. 30 This latter viewpoint is consistent with the relatively conserved direction of bending of tropomyosin among different crystal environments (Fig. 2)-but only when the structure adopts the bent rather than straight conformations ( Fig.…”

supporting

confidence: 82%

How sequence directs bending in tropomyosin and other two‐stranded alpha‐helical coiled coils

Brown

2010

Protein Science

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A quantitative analysis of the direction of bending of two-stranded alpha-helical coiled coils in crystal structures has been carried out to help determine how the amino acid sequence of the coiled coil influences its shape and function. Change in the axial staggering of the coiled coil, occurring at the boundaries of either clusters of core alanines in tropomyosin or of clusters of core bulky residues in the myosin rod, causes bending within the plane of the local dimer. The results also reveal that large gaps in the core of the coiled coil, which are seen for small core residues near large core residues or for unbranched core residues near canonical branched core residues, are correlated with bending out of the local dimeric plane. Comparison of tropomyosin structures determined in independent crystal environments provides further evidence for the concept that sequence directs the bending of the coiled coil, but that crystal environment is at least as important as sequence for determining the magnitude of bending. Tropomyosin thus appears to consist of more directionally restrained hinge-like joints rather than directionally variable universal joints, which helps account for and predicts the geometric and dynamic nature of its binding to F-actin.

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supporting

confidence: 82%

How sequence directs bending in tropomyosin and other two‐stranded alpha‐helical coiled coils

Brown

2010

Protein Science

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“…There is mounting evidence from systems as diverse as yeast and mammals that individual tropomyosin dimers form largely homopolymers along the length of actin filaments and regulate the functional capacity of the filament in an isoform-specific manner (10)(11)(12)(13)(14)(15). This specificity of tropomyosin isoform composition provides an opportunity to target distinct actin filament populations both within a given cell type and between cell types (9,16).…”

Section: Introductionmentioning

confidence: 99%

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells

et al. 2013

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The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers. Cancer Res; 73(16); 5169-82. Ó2013 AACR.

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“…In contrast, tropomyosin conformational flexibility has been achieved by the inclusion of alanine residues in the a and d positions at seven locations (24,25). This molecular arrangement, which results in looser packing of the α-helices but maintains the overall coiled-coil structure, allows the molecule to wrap continuously around the actin filament, and to adopt different local positions, depending upon its regulatory state (26,27). Distortions from a canonical coiled-coil are common and are often implicated in mediating proteinprotein interactions as observed in intermediate filaments (28).…”

Section: Discussionmentioning

confidence: 99%

Skip residues modulate the structural properties of the myosin rod and guide thick filament assembly

Taylor

Buvoli

Korkmaz

et al. 2015

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

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The rod of sarcomeric myosins directs thick filament assembly and is characterized by the insertion of four skip residues that introduce discontinuities in the coiled-coil heptad repeats. We report here that the regions surrounding the first three skip residues share high structural similarity despite their low sequence homology. Near each of these skip residues, the coiled-coil transitions to a nonclose-packed structure inducing local relaxation of the superhelical pitch. Moreover, molecular dynamics suggest that these distorted regions can assume different conformationally stable states. In contrast, the last skip residue region constitutes a true molecular hinge, providing C-terminal rod flexibility. Assembly of myosin with mutated skip residues in cardiomyocytes shows that the functional importance of each skip residue is associated with rod position and reveals the unique role of the molecular hinge in promoting myosin antiparallel packing. By defining the biophysical properties of the rod, the structures and molecular dynamic calculations presented here provide insight into thick filament formation, and highlight the structural differences occurring between the coiled-coils of myosin and the stereotypical tropomyosin. In addition to extending our knowledge into the conformational and biological properties of coiled-coil discontinuities, the molecular characterization of the four myosin skip residues also provides a guide to modeling the effects of rod mutations causing cardiac and skeletal myopathies.myosin | cardiac/skeletal myopathies | molecular dynamics | coiled-coils | protein structure M uscle contraction is primarily driven by the interactions between actin and myosin and the associated ATP hydrolysis, but the long-range transmission of force is based on the intrinsic ability of both proteins to self-assemble into organized filaments. The myosin thick filament is a well-characterized bipolar structure. The central area, or bare zone, is

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The Shape and Flexibility of Tropomyosin Coiled Coils: Implications for Actin Filament Assembly and Regulation

Cited by 108 publications

References 67 publications

How sequence directs bending in tropomyosin and other two‐stranded alpha‐helical coiled coils

How sequence directs bending in tropomyosin and other two‐stranded alpha‐helical coiled coils

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells

Skip residues modulate the structural properties of the myosin rod and guide thick filament assembly

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