The phosphohistidine phosphatase SixA dephosphorylates the phosphocarrier NPr

Abstract

Histidine phosphorylation is a posttranslational modification that alters protein function and also serves as an intermediate of phosphoryl transfer. Although phosphohistidine is relatively unstable, enzymatic dephosphorylation of this residue is apparently needed in some contexts, since both prokaryotic and eukaryotic phosphohistidine phosphatases have been reported. Here we identify the mechanism by which a bacterial phosphohistidine phosphatase dephosphorylates the nitrogen-related phosphotransferase system, a broadly conserved bacterial pathway that controls diverse metabolic processes. We show that the phosphatase SixA dephosphorylates the phosphocarrier protein NPr and that the reaction proceeds through phosphoryl transfer from a histidine on NPr to a histidine on SixA. In addition, we show that Escherichia coli lacking SixA are outcompeted by wild-type E. coli in the context of commensal colonization of the mouse intestine. Notably, this colonization defect requires NPr and is distinct from a previously identified in vitro growth defect associated with dysregulation of the nitrogen-related phosphotransferase system. The widespread conservation of SixA, and its coincidence with the phosphotransferase system studied here, suggests that this dephosphorylation mechanism may be conserved in other bacteria. Histidine phosphorylation is a posttranslational modification that alters protein function and also serves as an intermediate of phosphoryl transfer. Although phosphohistidine is relatively unstable, enzymatic dephosphorylation of this residue is apparently needed in some contexts, since both prokaryotic and eukaryotic phosphohistidine phosphatases have been reported. Here we identify the mechanism by which a bacterial phosphohistidine phosphatase dephosphorylates the nitrogen-related phosphotransferase system, a broadly conserved bacterial pathway that controls diverse metabolic processes. We show that the phosphatase SixA dephosphorylates the phosphocarrier protein NPr and that the reaction proceeds through phosphoryl transfer from a histidine on NPr to a histidine on SixA. In addition, we show that Escherichia coli lacking SixA are outcompeted by wild-type E. coli in the context of commensal colonization of the mouse intestine. Notably, this colonization defect requires NPr and is distinct from a previously identified in vitro growth defect associated with dysregulation of the nitrogen-related phosphotransferase system. The widespread conservation of SixA, and its coincidence with the phosphotransferase system studied here, suggests that this dephosphorylation mechanism may be conserved in other bacteria. Histidine phosphorylation occurs in numerous metabolic and signal transduction pathways. In many cases, phosphohistidine appears in enzyme intermediates of phosphoryl transfer reactions between proteins or small molecules (1Rigden D.J. 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A. 2000; PubMed Scopus Google Scholar) with and with as in is a with a to the NPr its in E. coli the of to a the and also by a by with the and with The resulting DNA and on The of by DNA of both the and the of and on both and by with and for on as previously M. Z. R. K. S. S. E. J. M. Escherichia coli for studying colonization of the mouse and its to PubMed Scopus (33) Google with an and the a from with the a from with to the a from with in by and the by transduction as in of for the and in mouse in the that the possible between the and Cell from of to cell by in of on and cell to cell or in Protein for and with an of by on to protein with of or the the of the Protein transfer to with transfer with and in to to in detection with Substrate and with a the and to the from The resulting DNA with and and which with the the by with the with and the resulting DNA by with DNA and from of the NPr the residues the NPr and SixA proteins with the DNA protein the protein the residues the the with the residues the The with a the from and the from DNA The with a as the for the of with the of with and the with The with a The from and the from DNA The with a the from the of from with and the of from with The in to be by DNA in and the Protein with to and for an to by on or by in histidine by with and protein from the reaction by with and the by or with The for NPr proteins also Protein with the Protein a with and from in reaction for and are of and in 2017; Scopus Google Scholar). reaction and for Protein and in phosphorylation reactions are in the to NPr phosphorylation as for cell with and for protein with the dephosphorylation reactions in of NPr phosphorylation reactions with SixA, or and for an by in by the phosphorylation reaction through a to the with a and the through a to reactions SixA, or and by with by on as that with protein the in with of the which in lacking to detection as in with by the and of the of mice for mouse as previously M. 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