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A new twist on tropomyosin binding to actin filaments: perspectives on thin filament function, assembly and biomechanics

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Abstract

Tropomyosin, best known for its role in the steric regulation of muscle contraction, polymerizes head-to-tail to form cables localized along the length of both muscle and non-muscle actin-based thin filaments. In skeletal and cardiac muscles, tropomyosin, under the control of troponin and myosin, moves in a cooperative manner between blocked, closed and open positions on filaments, thereby masking and exposing actin-binding sites necessary for myosin crossbridge head interactions. While the coiled-coil signature of tropomyosin appears to be simple, closer inspection reveals surprising structural complexity required to perform its role in steric regulation. For example, component α-helices of coiled coils are typically zippered together along a continuous core hydrophobic stripe. Tropomyosin, however, contains a number of anomalous, functionally controversial, core amino acid residues. We argue that the atypical residues at this interface, including clusters of alanines and a charged aspartate, are required for preshaping tropomyosin to readily fit to the surface of the actin filament, but do so without compromising tropomyosin rigidity once the filament is assembled. Indeed, persistence length measurements of tropomyosin are characteristic of a semi-rigid cable, in this case conducive to cooperative movement on thin filaments. In addition, we also maintain that tropomyosin displays largely unrecognized and residue-specific torsional variance, which is involved in optimizing contacts between actin and tropomyosin on the assembled thin filament. Corresponding twist-induced stiffness may also enhance cooperative translocation of tropomyosin across actin filaments. We conclude that anomalous core residues of tropomyosin facilitate thin filament regulatory behavior in a multifaceted way.

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Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data presented calculated from coordinates in Li et al. (2010, 2011) and Lehman et al. (2018) and from new MD studies on actin-D137L tropomyosin (performed as previously) (Li et al. 2011; Lehman et al. 2018). (Color figure online)

Fig. 5

Figure generated from coordinates in Li et al. (2010) and Moore et al. (2011)  using VMD (Humphrey et al. 1996) and CHIMERA (Pettersen et al. 2004) software. (Color figure online)

Fig. 6

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Acknowledgements

These studies were supported by NIH Grants R01HL036153 (to W.L.) and R01HL123774 (to J.R.M. and W.L.). The Massachusetts Green High Performance Computing Center provided considerable computational resources to analyze the data presented. We thank Dr. Anita Ghosh for her analysis of crystal structure B factors. The current paper can be regarded as a sequel to Holmes and Lehman (2008), also published in the Journal of Muscle Research and Cell Motility, and is a tribute to Kenneth C. Holmes, who first conceptualized the notion of tropomyosin’s ‘Gestalt-Binding’ to actin filaments, as well as to Brown and Cohen who laid out tropomyosin’s building blocks and to Lehrer and Geeves who clarified thin filament cooperativity for us.

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  1. Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA

    William Lehman & Michael J. Rynkiewicz

  2. Department of Biological Sciences, University of Massachusetts-Lowell, Lowell, MA, USA

    Jeffrey R. Moore

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  1. William Lehman
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Lehman, W., Rynkiewicz, M.J. & Moore, J.R. A new twist on tropomyosin binding to actin filaments: perspectives on thin filament function, assembly and biomechanics. J Muscle Res Cell Motil 41, 23–38 (2020). https://doi.org/10.1007/s10974-019-09501-5

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  • DOI: https://doi.org/10.1007/s10974-019-09501-5

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