A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair

Abstract The Mre11-Rad50 protein complex is an initial responder to sites of DNA double strand breaks. Many studies have shown that ATP binding to Rad50 causes global changes to the Mre11-Rad50 structure, which are important for DNA repair functions. Here we used methyl-based NMR spectroscopy on a s...

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Autores principales:	Zachary K. Boswell, Samiur Rahman, Marella D. Canny, Michael P. Latham
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9483ddab1c2f42be85f632a0db182db5
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spelling	oai:doaj.org-article:9483ddab1c2f42be85f632a0db182db52021-12-02T15:09:04ZA dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair10.1038/s41598-018-19908-82045-2322https://doaj.org/article/9483ddab1c2f42be85f632a0db182db52018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-19908-8https://doaj.org/toc/2045-2322Abstract The Mre11-Rad50 protein complex is an initial responder to sites of DNA double strand breaks. Many studies have shown that ATP binding to Rad50 causes global changes to the Mre11-Rad50 structure, which are important for DNA repair functions. Here we used methyl-based NMR spectroscopy on a series of mutants to describe a dynamic allosteric pathway within Rad50. Mutations result in changes in the side chain methyl group chemical environment that are correlated with altered nanosecond timescale dynamics. We also observe striking relationships between the magnitude of chemical shift perturbations and Rad50 and Mre11 activities. Together, these data suggest an equilibrium between a ground state and an “active” dimerization competent state of Rad50 that has locally altered structure and dynamics and is poised for ATP-induced dimerization and eventual ATP hydrolysis. Thus, this sparsely populated intermediate is critical for Mre11-Rad50-directed DNA double strand break repair.Zachary K. BoswellSamiur RahmanMarella D. CannyMichael P. LathamNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zachary K. Boswell Samiur Rahman Marella D. Canny Michael P. Latham A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair
description	Abstract The Mre11-Rad50 protein complex is an initial responder to sites of DNA double strand breaks. Many studies have shown that ATP binding to Rad50 causes global changes to the Mre11-Rad50 structure, which are important for DNA repair functions. Here we used methyl-based NMR spectroscopy on a series of mutants to describe a dynamic allosteric pathway within Rad50. Mutations result in changes in the side chain methyl group chemical environment that are correlated with altered nanosecond timescale dynamics. We also observe striking relationships between the magnitude of chemical shift perturbations and Rad50 and Mre11 activities. Together, these data suggest an equilibrium between a ground state and an “active” dimerization competent state of Rad50 that has locally altered structure and dynamics and is poised for ATP-induced dimerization and eventual ATP hydrolysis. Thus, this sparsely populated intermediate is critical for Mre11-Rad50-directed DNA double strand break repair.
format	article
author	Zachary K. Boswell Samiur Rahman Marella D. Canny Michael P. Latham
author_facet	Zachary K. Boswell Samiur Rahman Marella D. Canny Michael P. Latham
author_sort	Zachary K. Boswell
title	A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair
title_short	A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair
title_full	A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair
title_fullStr	A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair
title_full_unstemmed	A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair
title_sort	dynamic allosteric pathway underlies rad50 abc atpase function in dna repair
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/9483ddab1c2f42be85f632a0db182db5
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A dynamic allosteric pathway underlies Rad50 ABC ATPase function in DNA repair

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