EmbR is a transcriptional regulator that is phosphorylated by the cognate mycobacterial STPK (serine/threonine protein kinase) PknH. Recent studies demonstrated that PknH-dependent phosphorylation of EmbR enhances its DNA-binding activity and activates the transcription of the embCAB genes encoding arabinosyltransferases, which participate in arabinan biosynthesis. In the present study, we identified a genomic region of 4425 bp, which is present in Mycobacterium tuberculosis CDC1551, but absent from M. tuberculosis H37Rv, comprising the MT3428 gene, which is homologous with embR. Homology modelling of the MT3428 gene product illustrated its close relationship (56% identity) to EmbR, and it was hence termed EmbR2. In marked contrast with EmbR, EmbR2 was not phosphorylated by PknH, although it is a substrate of other M. tuberculosis kinases, including PknE and PknF. Tryptophan fluorescence emission of EmbR2 was monitored in the presence of three different PknH-derived phosphopeptides and demonstrated that EmbR2 binds to at least two of the threonine sites known to undergo autophosphorylation in PknH. We observed that the capacity of EmbR2 to interact physically with PknH without being phosphorylated was a result of EmbR2-mediated inhibition of kinase activity: incubation of PknH with increasing concentrations of EmbR2 led to a dose–response inhibition of the autokinase activity, similarly to O6-cyclohexylmethylguanine, a known inhibitor of eukaryotic cyclin-dependent kinases. Moreover, EmbR2 inhibited PknH-dependent phosphorylation of EmbR in a dose-dependent manner. Together, these results suggest that EmbR2 is a regulator of PknH activation, thus directly participating in the control of the PknH/EmbR pair and potentially in mycobacterial physiology/virulence of M. tuberculosis CDC1551.
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March 2008
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February 12 2008
EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR Available to Purchase
Virginie Molle;
Virginie Molle
*Institut de Biologie et Chimie des Protéines, CNRS, Université de Lyon I, Lyon, France
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Robert C. Reynolds;
Robert C. Reynolds
†Drug Discovery Division, Southern Research Institute, PO Box 55305, Birmingham, AL 35225-5305, U.S.A.
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Luke J. Alderwick;
Luke J. Alderwick
‡School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Gurdyal S. Besra;
Gurdyal S. Besra
‡School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Alain J. Cozzone;
Alain J. Cozzone
*Institut de Biologie et Chimie des Protéines, CNRS, Université de Lyon I, Lyon, France
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Klaus Fütterer;
Klaus Fütterer
‡School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Laurent Kremer
Laurent Kremer
1
§Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS, UMR 5235, Université de Montpellier II et I, case 107, Place Eugène Bataillon, 34095 Montpellier Cedex 05, France
∥Inserm, DIMNP (Dynamique des Interactions Membranaires Normales et Pathologiques), Place Eugène Bataillon, 34095 Montpellier Cedex 05, France
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 09 2007
Revision Received:
November 07 2007
Accepted:
November 14 2007
Accepted Manuscript online:
November 14 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 410 (2): 309–317.
Article history
Received:
October 09 2007
Revision Received:
November 07 2007
Accepted:
November 14 2007
Accepted Manuscript online:
November 14 2007
Citation
Virginie Molle, Robert C. Reynolds, Luke J. Alderwick, Gurdyal S. Besra, Alain J. Cozzone, Klaus Fütterer, Laurent Kremer; EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR. Biochem J 1 March 2008; 410 (2): 309–317. doi: https://doi.org/10.1042/BJ20071384
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