EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR - Université Claude Bernard Lyon 1 Accéder directement au contenu
Article Dans Une Revue Biochemical Journal Année : 2008

EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR

Résumé

EmbR is a transcriptional regulator which is phosphorylated by the cognate mycobacterial serine/threonine protein kinase PknH. Recent studies demonstrated that PknH-dependent phosphorylation of EmbR enhances its DNA-binding activity and activates transcription of the embCAB genes encoding arabinosyltransferases which participate in arabinan biosynthesis. Herein, we identified a genomic region of 4425-bp, that is present in Mycobacterium tuberculosis CDC1551, but absent from M. tuberculosis H37Rv, comprising the MT3428 gene, which is homologous to embR. Homology modelling of the MT3428 gene product illustrated its close relationship (56% identity) to EmbR, and was hence termed EmbR2. In marked contrast to 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 physically interact 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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Bactériologie
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hal-00478893 , version 1 (30-04-2010)

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Virginie Molle, Robert C Reynolds, Luke J Alderwick, Gurdyal S Besra, Alain J Cozzone, et al.. EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR. Biochemical Journal, 2008, 410 (2), pp.309-317. ⟨10.1042/BJ20071384⟩. ⟨hal-00478893⟩
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