Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.

<h4>Background</h4>DevR (also called as DosR) is a two-domain response regulator of the NarL subfamily that controls dormancy adaptation of Mycobacterium tuberculosis (M. tb). In response to inducing signals such as hypoxia and ascorbic acid, the N-terminal receiver domain of DevR (DevR(...

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Autores principales:	Uma Shankar Gautam, Santosh Chauhan, Jaya Sivaswami Tyagi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2ad861171d794912b344231182b8b44c
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spelling	oai:doaj.org-article:2ad861171d794912b344231182b8b44c2021-11-18T06:59:42ZDeterminants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.1932-620310.1371/journal.pone.0016500https://doaj.org/article/2ad861171d794912b344231182b8b44c2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21304599/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>DevR (also called as DosR) is a two-domain response regulator of the NarL subfamily that controls dormancy adaptation of Mycobacterium tuberculosis (M. tb). In response to inducing signals such as hypoxia and ascorbic acid, the N-terminal receiver domain of DevR (DevR(N)) is phosphorylated at Asp54. This results in DevR binding to DNA via its C-terminal domain (DevR(C)) and subsequent induction of the DevR regulon. The mechanism of phosphorylation-mediated activation is not known. The present study was designed to understand the role of the N- and C-terminal domains of DevR in DevR regulon genes activation.<h4>Methodology/principal findings</h4>Towards deciphering the activation mechanism of DevR, we compared the DNA binding properties of DevR(C) and DevR and correlated the findings with their ability to activate gene expression. We show that isolated DevR(C) can interact with DNA, but only with the high affinity site of a representative target promoter. Therefore, one role of DevR(N) is to mask the intrinsic DNA binding function of DevR(C). However, unlike phosphorylated DevR, isolated DevR(C) does not interact with the adjacent low affinity binding site suggesting that a second role of DevR(N) is in cooperative binding to the secondary site. Transcriptional analysis shows that consistent with unmasking of its DNA binding property, DevR(C) supports the aerobic induction, albeit feebly, of DevR regulon genes but is unable to sustain gene activation during hypoxia.<h4>Conclusions/significance</h4>DevR is a unique response regulator that employs a dual activation mechanism including relief of inhibition and cooperative interaction with binding sites. Importantly, both these functions reside outside the C-terminal domain. DevR(N) is also essential for stabilizing DevR and sustaining autoregulation under hypoxia. Hence, both domains of DevR are required for robust transcription activation.Uma Shankar GautamSantosh ChauhanJaya Sivaswami TyagiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 1, p e16500 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Uma Shankar Gautam Santosh Chauhan Jaya Sivaswami Tyagi Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.
description	<h4>Background</h4>DevR (also called as DosR) is a two-domain response regulator of the NarL subfamily that controls dormancy adaptation of Mycobacterium tuberculosis (M. tb). In response to inducing signals such as hypoxia and ascorbic acid, the N-terminal receiver domain of DevR (DevR(N)) is phosphorylated at Asp54. This results in DevR binding to DNA via its C-terminal domain (DevR(C)) and subsequent induction of the DevR regulon. The mechanism of phosphorylation-mediated activation is not known. The present study was designed to understand the role of the N- and C-terminal domains of DevR in DevR regulon genes activation.<h4>Methodology/principal findings</h4>Towards deciphering the activation mechanism of DevR, we compared the DNA binding properties of DevR(C) and DevR and correlated the findings with their ability to activate gene expression. We show that isolated DevR(C) can interact with DNA, but only with the high affinity site of a representative target promoter. Therefore, one role of DevR(N) is to mask the intrinsic DNA binding function of DevR(C). However, unlike phosphorylated DevR, isolated DevR(C) does not interact with the adjacent low affinity binding site suggesting that a second role of DevR(N) is in cooperative binding to the secondary site. Transcriptional analysis shows that consistent with unmasking of its DNA binding property, DevR(C) supports the aerobic induction, albeit feebly, of DevR regulon genes but is unable to sustain gene activation during hypoxia.<h4>Conclusions/significance</h4>DevR is a unique response regulator that employs a dual activation mechanism including relief of inhibition and cooperative interaction with binding sites. Importantly, both these functions reside outside the C-terminal domain. DevR(N) is also essential for stabilizing DevR and sustaining autoregulation under hypoxia. Hence, both domains of DevR are required for robust transcription activation.
format	article
author	Uma Shankar Gautam Santosh Chauhan Jaya Sivaswami Tyagi
author_facet	Uma Shankar Gautam Santosh Chauhan Jaya Sivaswami Tyagi
author_sort	Uma Shankar Gautam
title	Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.
title_short	Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.
title_full	Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.
title_fullStr	Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.
title_full_unstemmed	Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.
title_sort	determinants outside the devr c-terminal domain are essential for cooperativity and robust activation of dormancy genes in mycobacterium tuberculosis.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/2ad861171d794912b344231182b8b44c
work_keys_str_mv	AT umashankargautam determinantsoutsidethedevrcterminaldomainareessentialforcooperativityandrobustactivationofdormancygenesinmycobacteriumtuberculosis AT santoshchauhan determinantsoutsidethedevrcterminaldomainareessentialforcooperativityandrobustactivationofdormancygenesinmycobacteriumtuberculosis AT jayasivaswamityagi determinantsoutsidethedevrcterminaldomainareessentialforcooperativityandrobustactivationofdormancygenesinmycobacteriumtuberculosis
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Determinants outside the DevR C-terminal domain are essential for cooperativity and robust activation of dormancy genes in Mycobacterium tuberculosis.

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