2z5h Citations

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

Proc Natl Acad Sci U S A 105 7200-5 (2008)
Cited: 64 times
EuropePMC logo PMID: 18483193

Abstract

Head-to-tail polymerization of tropomyosin is crucial for its actin binding, function in actin filament assembly, and the regulation of actin-myosin contraction. Here, we describe the 2.1 A resolution structure of crystals containing overlapping tropomyosin N and C termini (TM-N and TM-C) and the 2.9 A resolution structure of crystals containing TM-N and TM-C together with a fragment of troponin-T (TnT). At each junction, the N-terminal helices of TM-N were splayed, with only one of them packing against TM-C. In the C-terminal region of TM-C, a crucial water in the coiled-coil core broke the local 2-fold symmetry and helps generate a kink on one helix. In the presence of a TnT fragment, the asymmetry in TM-C facilitates formation of a 4-helix bundle containing two TM-C chains and one chain each of TM-N and TnT. Mutating the residues that generate the asymmetry in TM-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.

Reviews - 2z5h mentioned but not cited (2)

  1. Thin filament mutations: developing an integrative approach to a complex disorder. Tardiff JC. Circ Res 108 765-782 (2011)
  2. The Mechanisms of Thin Filament Assembly and Length Regulation in Muscles. Szikora S, Görög P, Mihály J. Int J Mol Sci 23 5306 (2022)

Articles - 2z5h mentioned but not cited (11)



Reviews citing this publication (14)

  1. The streptococcal M protein: a highly versatile molecule. Smeesters PR, McMillan DJ, Sriprakash KS. Trends Microbiol 18 275-282 (2010)
  2. Gestalt-binding of tropomyosin to actin filaments. Holmes KC, Lehman W. J Muscle Res Cell Motil 29 213-219 (2008)
  3. The physiological role of cardiac cytoskeleton and its alterations in heart failure. Sequeira V, Nijenkamp LL, Regan JA, van der Velden J. Biochim Biophys Acta 1838 700-722 (2014)
  4. Alpha-tropomyosin mutations in inherited cardiomyopathies. Redwood C, Robinson P. J Muscle Res Cell Motil 34 285-294 (2013)
  5. Troponin structure and function: a view of recent progress. Marston S, Zamora JE. J Muscle Res Cell Motil 41 71-89 (2020)
  6. Historical perspective on heart function: the Frank-Starling Law. Sequeira V, van der Velden J. Biophys Rev 7 421-447 (2015)
  7. Mechanism of the calcium-regulation of muscle contraction--in pursuit of its structural basis. Wakabayashi T. Proc Jpn Acad Ser B Phys Biol Sci 91 321-350 (2015)
  8. Moving beyond simple answers to complex disorders in sarcomeric cardiomyopathies: the role of integrated systems. Deranek AE, Klass MM, Tardiff JC. Pflugers Arch 471 661-671 (2019)
  9. Tropomyosin dynamics. El-Mezgueldi M. J Muscle Res Cell Motil 35 203-210 (2014)
  10. Tropomyosin de-phosphorylation in the heart: what are the consequences? Schulz EM, Wieczorek DF. J Muscle Res Cell Motil 34 239-246 (2013)
  11. Biophysical Derangements in Genetic Cardiomyopathies. Lynn ML, Lehman SJ, Tardiff JC. Heart Fail Clin 14 147-159 (2018)
  12. Modeling Human Cardiac Thin Filament Structures. Rynkiewicz MJ, Pavadai E, Lehman W. Front Physiol 13 932333 (2022)
  13. Functional outcomes of structural peculiarities of striated muscle tropomyosin. Kopylova GV, Matyushenko AM, Koubassova NA, Shchepkin DV, Bershitsky SY, Levitsky DI, Tsaturyan AK. J Muscle Res Cell Motil 41 55-70 (2020)
  14. Myosin and Other Energy-Transducing ATPases: Structural Dynamics Studied by Electron Paramagnetic Resonance. Arata T. Int J Mol Sci 21 E672 (2020)

Articles citing this publication (37)