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Tropomyosin-binding properties modulate competition between tropomodulin isoforms.

ABSTRACT: The formation and fine-tuning of cytoskeleton in cells are governed by proteins that influence actin filament dynamics. Tropomodulin (Tmod) regulates the length of actin filaments by capping the pointed ends in a tropomyosin (TM)-dependent manner. Tmod1, Tmod2 and Tmod3 are associated with the cytoskeleton of non-muscle cells and their expression has distinct consequences on cell morphology. To understand the molecular basis of differences in the function and localization of Tmod isoforms in a cell, we compared the actin filament-binding abilities of Tmod1, Tmod2 and Tmod3 in the presence of Tpm3.1, a non-muscle TM isoform. Tmod3 displayed preferential binding to actin filaments when competing with other isoforms. Mutating the second or both TM-binding sites of Tmod3 destroyed its preferential binding. Our findings clarify how Tmod1, Tmod2 and Tmod3 compete for binding actin filaments. Different binding mechanisms and strengths of Tmod isoforms for Tpm3.1 contribute to their divergent functional capabilities.

SUBMITTER: Colpan M

PROVIDER: S-EPMC5079755 | biostudies-other | 2016 Jun

REPOSITORIES: biostudies-other

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Tropomyosin-binding properties modulate competition between tropomodulin isoforms.

Colpan Mert M Moroz Natalia A NA Gray Kevin T KT Cooper Dillon A DA Diaz Christian A CA Kostyukova Alla S AS

Archives of biochemistry and biophysics 20160426

The formation and fine-tuning of cytoskeleton in cells are governed by proteins that influence actin filament dynamics. Tropomodulin (Tmod) regulates the length of actin filaments by capping the pointed ends in a tropomyosin (TM)-dependent manner. Tmod1, Tmod2 and Tmod3 are associated with the cytoskeleton of non-muscle cells and their expression has distinct consequences on cell morphology. To understand the molecular basis of differences in the function and localization of Tmod isoforms in a c ...[more]

PMID: 27091317

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Project description:The proteins involved in smooth muscle's molecular contractile mechanism - the anti-parallel motion of actin and myosin filaments driven by myosin heads interacting with actin - are found as different isoforms. While their expression levels are altered in disease states, their relevance to the mechanical interaction of myosin with actin is not sufficiently understood. Here, we analyzed in vitro actin filament propulsion by smooth muscle myosin for [Formula: see text]-actin ([Formula: see text]A), [Formula: see text]-actin-tropomyosin-[Formula: see text] ([Formula: see text]A-Tm[Formula: see text]), [Formula: see text]-actin-tropomyosin-[Formula: see text] ([Formula: see text]A-Tm[Formula: see text]), [Formula: see text]-actin ([Formula: see text]A), [Formula: see text]-actin-tropomyosin-[Formula: see text] ([Formula: see text]A-Tm[Formula: see text]), and [Formula: see text]-actin-tropomoysin-[Formula: see text] ([Formula: see text]A-Tm[Formula: see text]). Actin sliding analysis with our specifically developed video analysis software followed by statistical assessment (Bootstrapped Principal Component Analysis) indicated that the in vitro motility of [Formula: see text]A, [Formula: see text]A, and [Formula: see text]A-Tm[Formula: see text] is not distinguishable. Compared to these three 'baseline conditions', statistically significant differences ([Formula: see text]) were: [Formula: see text]A-Tm[Formula: see text] - actin sliding velocity increased 1.12-fold, [Formula: see text]A-Tm[Formula: see text] - motile fraction decreased to 0.96-fold, stop time elevated 1.6-fold, [Formula: see text]A-Tm[Formula: see text] - run time elevated 1.7-fold. We constructed a mathematical model, simulated actin sliding data, and adjusted the kinetic parameters so as to mimic the experimentally observed differences: [Formula: see text]A-Tm[Formula: see text] - myosin binding to actin, the main, and the secondary myosin power stroke are accelerated, [Formula: see text]A-Tm[Formula: see text] - mechanical coupling between myosins is stronger, [Formula: see text]A-Tm[Formula: see text] - the secondary power stroke is decelerated and mechanical coupling between myosins is weaker. In summary, our results explain the different regulatory effects that specific combinations of actin and smooth muscle tropomyosin have on smooth muscle actin-myosin interaction kinetics.

Dataset Information

Tropomyosin-binding properties modulate competition between tropomodulin isoforms.

Publications

Tropomyosin-binding properties modulate competition between tropomodulin isoforms.

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