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Abstract
The tropomyosin family of proteins form end-to-end polymers along the actin filament. Tumour cells rely on specific tropomyosin-containing actin filament populations for growth and survival. To dissect out the role of tropomyosin in actin filament regulation we use the small molecule TR100 directed against the C terminus of the tropomyosin isoform Tpm3.1. TR100 nullifies the effect of Tpm3.1 on actin depolymerisation but surprisingly Tpm3.1 retains the capacity to bind F-actin in a cooperative manner. In vivo analysis also confirms that, in the presence of TR100, fluorescently tagged Tpm3.1 recovers normally into stress fibers. Assembling end-to-end along the actin filament is thereby not sufficient for tropomyosin to fulfil its function. Rather, regulation of F-actin stability by tropomyosin requires fidelity of information communicated at the barbed end of the actin filament. This distinction has significant implications for perturbing tropomyosin-dependent actin filament function in the context of anti-cancer drug development.
Highlights
The tropomyosin family of proteins form end-to-end polymers along the actin filament
It has been suggested that inhibition of actin polymerisation by Tpm may be a direct result of changing the barbed end elongation rate[14,15] or the ability of Tpm to promote end-to-end annealing of actin filaments, effectively reducing the number of barbed ends primed for actin monomer addition[15,16]
We propose that TR100 acts to compromise the integrity of Tpm cables rather than prevent overlap complex formation
Summary
The tropomyosin family of proteins form end-to-end polymers along the actin filament. Pre-incubation of Tpm3.1 with TR100 prior to mixing with G-actin and initiating polymerisation did not affect its ability to reduce actin polymerisation (Fig. 1a).
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