Tropomyosin must interact weakly with actin to effectively regulate thin filament function
Elongated tropomyosin, associated with actin-subunits along the surface of thin filaments, makes electrostatic interactions with clusters of conserved residues, K326, K328, and R147, on actin. The association is weak, permitting low-energy cost regulatory movement of tropomyosin across the filament...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
December 2017
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| In: |
Biophysical journal
Year: 2017, Volume: 113, Issue: 11, Pages: 2444-2451 |
| ISSN: | 1542-0086 |
| DOI: | 10.1016/j.bpj.2017.10.004 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.bpj.2017.10.004 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0006349517310895 
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| Author Notes: | Michael J. Rynkiewicz, Thavanareth Prum, Stephen Hollenberg, Farooq A. Kiani, Patricia M. Fagnant, Steven B. Marston, Kathleen M. Trybus, Stefan Fischer, Jeffrey R. Moore and William Lehman |
| Summary: | Elongated tropomyosin, associated with actin-subunits along the surface of thin filaments, makes electrostatic interactions with clusters of conserved residues, K326, K328, and R147, on actin. The association is weak, permitting low-energy cost regulatory movement of tropomyosin across the filament during muscle activation. Interestingly, acidic D292 on actin, also evolutionarily conserved, lies adjacent to the three-residue cluster of basic amino acids and thus may moderate the combined local positive charge, diminishing tropomyosin-actin interaction and facilitating regulatory-switching. Indeed, charge neutralization of D292 is connected to muscle hypotonia in individuals with D292V actin mutations and linked to congenital fiber-type disproportion. Here, the D292V mutation may predispose tropomyosin-actin positioning to a myosin-blocking state, aberrantly favoring muscle relaxation, thus mimicking the low-Ca2+ effect of troponin even in activated muscles. To test this hypothesis, interaction energetics and in vitro function of wild-type and D292V filaments were measured. Energy landscapes based on F-actin-tropomyosin models show the mutation localizes tropomyosin in a blocked-state position on actin defined by a deeper energy minimum, consistent with augmented steric-interference of actin-myosin binding. In addition, whereas myosin-dependent motility of troponin/tropomyosin-free D292V F-actin is normal, motility is dramatically inhibited after addition of tropomyosin to the mutant actin. Thus, D292V-induced blocked-state stabilization appears to disrupt the delicately poised energy balance governing thin filament regulation. Our results validate the premise that stereospecific but necessarily weak binding of tropomyosin to F-actin is required for effective thin filament function. |
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| Item Description: | Gesehen am 29.05.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1542-0086 |
| DOI: | 10.1016/j.bpj.2017.10.004 |