A small molecule inhibitor of tropomyosin dissociates actin binding from tropomyosin-directed regulation of actin dynamics.

Autor: Bonello TT; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Janco M; School of Medical Sciences and ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, Sydney, NSW, 2052, Australia., Hook J; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Byun A; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Appaduray M; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Dedova I; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Hitchcock-DeGregori S; Pathology &Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA., Hardeman EC; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Stehn JR; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Böcking T; School of Medical Sciences and ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, Sydney, NSW, 2052, Australia., Gunning PW; School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2016 Jan 25; Vol. 6, pp. 19816. Date of Electronic Publication: 2016 Jan 25.
DOI: 10.1038/srep19816
Abstrakt: 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.
Databáze: MEDLINE
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