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Arch Biochem Biophys. 2015 Apr 1;571:10-5. doi: 10.1016/j.abb.2015.02.026. Epub 2015 Feb 26.

Phosphorylation of Ser283 enhances the stiffness of the tropomyosin head-to-tail overlap domain.

Author information

1
Department of Physiology & Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. Electronic address: wlehman@bu.edu.
2
Department of Bioengineering, University of Washington, South Research Building, 950 Republican Street, Seattle, WA 98109, USA.
3
Department of Physiology & Biophysics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
4
School of Biosciences, Stacey Building, University of Kent, Canterbury, Kent CT2 7NJ, UK.
5
Computational Biochemistry Group, Interdisciplinary Center for Scientific Computing (IWR), University of Heidelberg, Im Neuenheimer Feld 368, Heidelberg D69120, Germany.

Abstract

The ends of coiled-coil tropomyosin molecules are joined together by nine to ten residue-long head-to-tail "overlapping domains". These short four-chained interconnections ensure formation of continuous tropomyosin cables that wrap around actin filaments. Molecular Dynamics simulations indicate that the curvature and bending flexibility at the overlap is 10-20% greater than over the rest of the molecule, which might affect head-to-tail filament assembly on F-actin. Since the penultimate residue of striated muscle tropomyosin, Ser283, is a natural target of phosphorylating enzymes, we have assessed here if phosphorylation adjusts the mechanical properties of the tropomyosin overlap domain. MD simulations show that phosphorylation straightens the overlap to match the curvature of the remainder of tropomyosin while stiffening it to equal or exceed the rigidity of canonical coiled-coil regions. Corresponding EM data on phosphomimetic tropomyosin S283D corroborate these findings. The phosphorylation-induced change in mechanical properties of tropomyosin likely results from electrostatic interactions between C-terminal phosphoSer283 and N-terminal Lys12 in the four-chain overlap bundle, while promoting stronger interactions among surrounding residues and thus facilitating tropomyosin cable assembly. The stiffening effect of D283-tropomyosin noted correlates with previously observed enhanced actin-tropomyosin activation of myosin S1-ATPase, suggesting a role for the tropomyosin phosphorylation in potentiating muscle contraction.

KEYWORDS:

Actin; Cardiomyopathy; Molecular Dynamics; Muscle regulation; Phosphorylation; Tropomyosin

PMID:
25726728
PMCID:
PMC4385494
DOI:
10.1016/j.abb.2015.02.026
[Indexed for MEDLINE]
Free PMC Article

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