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A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity

Toxoplasma gondii is an obligate intracellular parasite that enters cells by a process of active penetration. Host cell penetration and parasite motility are driven by a myosin motor complex consisting of four known proteins: TgMyoA, an unconventional Class XIV myosin; TgMLC1, a myosin light chain;...

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Detalles Bibliográficos
Autores principales: Heaslip, Aoife T., Leung, Jacqueline M., Carey, Kimberly L., Catti, Federica, Warshaw, David M., Westwood, Nicholas J., Ballif, Bryan A., Ward, Gary E.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2800044/
https://www.ncbi.nlm.nih.gov/pubmed/20084115
http://dx.doi.org/10.1371/journal.ppat.1000720
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author Heaslip, Aoife T.
Leung, Jacqueline M.
Carey, Kimberly L.
Catti, Federica
Warshaw, David M.
Westwood, Nicholas J.
Ballif, Bryan A.
Ward, Gary E.
author_facet Heaslip, Aoife T.
Leung, Jacqueline M.
Carey, Kimberly L.
Catti, Federica
Warshaw, David M.
Westwood, Nicholas J.
Ballif, Bryan A.
Ward, Gary E.
author_sort Heaslip, Aoife T.
collection PubMed
description Toxoplasma gondii is an obligate intracellular parasite that enters cells by a process of active penetration. Host cell penetration and parasite motility are driven by a myosin motor complex consisting of four known proteins: TgMyoA, an unconventional Class XIV myosin; TgMLC1, a myosin light chain; and two membrane-associated proteins, TgGAP45 and TgGAP50. Little is known about how the activity of the myosin motor complex is regulated. Here, we show that treatment of parasites with a recently identified small-molecule inhibitor of invasion and motility results in a rapid and irreversible change in the electrophoretic mobility of TgMLC1. While the precise nature of the TgMLC1 modification has not yet been established, it was mapped to the peptide Val46-Arg59. To determine if the TgMLC1 modification is responsible for the motility defect observed in parasites after compound treatment, the activity of myosin motor complexes from control and compound-treated parasites was compared in an in vitro motility assay. TgMyoA motor complexes containing the modified TgMLC1 showed significantly decreased motor activity compared to control complexes. This change in motor activity likely accounts for the motility defects seen in the parasites after compound treatment and provides the first evidence, in any species, that the mechanical activity of Class XIV myosins can be modulated by posttranslational modifications to their associated light chains.
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spelling pubmed-28000442010-01-16 A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity Heaslip, Aoife T. Leung, Jacqueline M. Carey, Kimberly L. Catti, Federica Warshaw, David M. Westwood, Nicholas J. Ballif, Bryan A. Ward, Gary E. PLoS Pathog Research Article Toxoplasma gondii is an obligate intracellular parasite that enters cells by a process of active penetration. Host cell penetration and parasite motility are driven by a myosin motor complex consisting of four known proteins: TgMyoA, an unconventional Class XIV myosin; TgMLC1, a myosin light chain; and two membrane-associated proteins, TgGAP45 and TgGAP50. Little is known about how the activity of the myosin motor complex is regulated. Here, we show that treatment of parasites with a recently identified small-molecule inhibitor of invasion and motility results in a rapid and irreversible change in the electrophoretic mobility of TgMLC1. While the precise nature of the TgMLC1 modification has not yet been established, it was mapped to the peptide Val46-Arg59. To determine if the TgMLC1 modification is responsible for the motility defect observed in parasites after compound treatment, the activity of myosin motor complexes from control and compound-treated parasites was compared in an in vitro motility assay. TgMyoA motor complexes containing the modified TgMLC1 showed significantly decreased motor activity compared to control complexes. This change in motor activity likely accounts for the motility defects seen in the parasites after compound treatment and provides the first evidence, in any species, that the mechanical activity of Class XIV myosins can be modulated by posttranslational modifications to their associated light chains. Public Library of Science 2010-01-15 /pmc/articles/PMC2800044/ /pubmed/20084115 http://dx.doi.org/10.1371/journal.ppat.1000720 Text en Heaslip et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Heaslip, Aoife T.
Leung, Jacqueline M.
Carey, Kimberly L.
Catti, Federica
Warshaw, David M.
Westwood, Nicholas J.
Ballif, Bryan A.
Ward, Gary E.
A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity
title A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity
title_full A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity
title_fullStr A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity
title_full_unstemmed A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity
title_short A Small-Molecule Inhibitor of T. gondii Motility Induces the Posttranslational Modification of Myosin Light Chain-1 and Inhibits Myosin Motor Activity
title_sort small-molecule inhibitor of t. gondii motility induces the posttranslational modification of myosin light chain-1 and inhibits myosin motor activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2800044/
https://www.ncbi.nlm.nih.gov/pubmed/20084115
http://dx.doi.org/10.1371/journal.ppat.1000720
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