UniProt functional annotation for P0AE82



	UniProt functional annotation for P0AE82

UniProt code: P0AE82.

Organism: Escherichia coli (strain K12).

Taxonomy: Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales; Enterobacteriaceae; Escherichia.

Function: Histidine kinase member of the two-component regulatory system CpxA/CpxR which responds to envelope stress response by activating expression of downstream genes including cpxP, degP, dsbA and ppiA (PubMed:7883164, PubMed:9401031, PubMed:9473036). Activates CpxR by phosphorylation; has autokinase, phosphotransferase and (in the presence of Mg(2+) and/or ATP or ADP) phosphatase activity (PubMed:9401031, PubMed:17259177, PubMed:24492262). The kinase activity is inhibited by periplasmic accessory protein CpxP; proteolysis of CpxP relieves inhibition (PubMed:16166523, PubMed:17259177, PubMed:25207645). Involved in several diverse cellular processes, including the functioning of acetohydroxyacid synthetase I, the biosynthesis of isoleucine and valine, the TraJ protein activation activity for tra gene expression in F plasmid (PubMed:8432716), and the synthesis, translocation, or stability of cell envelope proteins (PubMed:7883164). Activates transcription of periplasmic protease degP, probably by phosphorylating the cognate response protein CpxR; overexpression of an outer membrane lipoprotein NlpE also leads to transcription of degP via CpxRA (PubMed:7883164). Required for efficient binding of stationary phase cells to hydrophobic surfaces, part of the process of biofilm formation (PubMed:11830644). {ECO:0000269|PubMed:16166523, ECO:0000269|PubMed:17259177, ECO:0000269|PubMed:24492262, ECO:0000269|PubMed:25207645, ECO:0000269|PubMed:7883164, ECO:0000269|PubMed:8432716, ECO:0000269|PubMed:9401031, ECO:0000269|PubMed:9473036, ECO:0000305|PubMed:11830644}.

Catalytic activity: Reaction=ATP + protein L-histidine = ADP + protein N-phospho-L- histidine.; EC=2.7.13.3; Evidence={ECO:0000269|PubMed:9401031};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:9401031}; Note=Phosphotransfer to CpxR is stimulated by Mg(2+) and/or Mn(2+). {ECO:0000269|PubMed:9401031};

Activity regulation: The two-component system is activated by envelope stress such as overexpression of some (misfolded) periplasmic proteins (PubMed:7883164, PubMed:9351822). Activated by spheroplasting (which removes the periplasm) in an autoregulatory cpxA-cpxR-dependent fashion (PubMed:10972835). Cpx two-component system is induced at pH 8.0; in a degP deletion mutant induction is halved (PubMed:9473036, PubMed:16166523). The kinase activity is inhibited by periplasmic accessory protein CpxP; proteolysis of CpxP relieves inhibition (PubMed:16166523, PubMed:17259177, PubMed:25207645). Autokinase activity reconstituted in liposomes is 50% inhibited by periplasmic accessory protein CpxP, but CpxP has no effect on phosphatase activity; autokinase stimulated by KCl, NH(4)Cl, RbCl, pH 7.5 and 8.0, inhibited by sensor kinase inhibitors tetrachlorosalicylanilid and ethodin (PubMed:17259177). {ECO:0000269|PubMed:10972835, ECO:0000269|PubMed:16166523, ECO:0000269|PubMed:17259177, ECO:0000269|PubMed:25207645, ECO:0000269|PubMed:7883164, ECO:0000269|PubMed:9351822, ECO:0000269|PubMed:9473036}.

Subunit: The isolated cytoplasmic domain (residues 188-457) crystallizes as a homodimer, and forms dimers of dimers in solution which may be catalytically important (PubMed:24492262). Interacts with periplasmic accessory protein CpxP (PubMed:16166523, PubMed:21317318, PubMed:21239493, PubMed:25207645); interaction with CpxP is not seen in vivo when cells are grown in 0.3 M NaCl, or if the misfolded P pili protein PapE is overexpressed (PubMed:25207645). Interacts with cognate response regulator CpxR (PubMed:25207645). {ECO:0000269|PubMed:24492262, ECO:0000269|PubMed:25207645, ECO:0000305|PubMed:16166523}.

Subcellular location: Cell inner membrane {ECO:0000269|PubMed:15919996, ECO:0000269|PubMed:25207645, ECO:0000269|PubMed:3058985}; Multi-pass membrane protein {ECO:0000305|PubMed:15919996, ECO:0000305|PubMed:3058985}.

Domain: The periplasmic segment (residues 30-163) defines the sensory domain (PubMed:9401031). Conformational changes in the cytoplasmic HAMP domain modulate the mobility of the central alpha-helices (which bend at Ser-238 and Pro-253) that allows formation of 1 kinase-active state. {ECO:0000269|PubMed:24492262, ECO:0000269|PubMed:9401031}.

Ptm: Autophosphorylated (PubMed:9401031, PubMed:24492262). Maximal phosphorylation of the dimeric isolated cytoplasmic domain (residues 188-457) is about 70%, suggesting the protein may be hemiphosphorylated in vivo; probably occurs via a trans-autophosphorylation mechanism, i.e. one subunit phosphorylates the other (PubMed:24492262). {ECO:0000269|PubMed:24492262, ECO:0000269|PubMed:9401031}.

Disruption phenotype: Loss of the Cpx envelope stress response (PubMed:10972835). Decreased resistance to the antibiotic amnikacin (PubMed:2185221). Single cpxA and double cpxR-cpxA mutant decrease transcription of degP (PubMed:7883164). Decreased transcription of cpxP (PubMed:9473036). Hypersensitive to alkaline pH (greater than pH 8.8) (PubMed:9473036). Decreased numbers of stationary phase cells bind to hydrophobic surfaces (PubMed:11830644). Greatly increased resistance to hydroxyurea, probably due to decreased recognition of mis-folded proteins which eventually leads to decreased OH radical formation (PubMed:20005847). {ECO:0000269|PubMed:10972835, ECO:0000269|PubMed:11830644, ECO:0000269|PubMed:20005847, ECO:0000269|PubMed:2185221, ECO:0000269|PubMed:7883164, ECO:0000269|PubMed:9473036}.

Sequence caution: Sequence=AAA72540.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Escherichia coli (strain K12).
Taxonomy:		Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales; Enterobacteriaceae; Escherichia.



Function:		Histidine kinase member of the two-component regulatory system CpxA/CpxR which responds to envelope stress response by activating expression of downstream genes including cpxP, degP, dsbA and ppiA (PubMed:7883164, PubMed:9401031, PubMed:9473036). Activates CpxR by phosphorylation; has autokinase, phosphotransferase and (in the presence of Mg(2+) and/or ATP or ADP) phosphatase activity (PubMed:9401031, PubMed:17259177, PubMed:24492262). The kinase activity is inhibited by periplasmic accessory protein CpxP; proteolysis of CpxP relieves inhibition (PubMed:16166523, PubMed:17259177, PubMed:25207645). Involved in several diverse cellular processes, including the functioning of acetohydroxyacid synthetase I, the biosynthesis of isoleucine and valine, the TraJ protein activation activity for tra gene expression in F plasmid (PubMed:8432716), and the synthesis, translocation, or stability of cell envelope proteins (PubMed:7883164). Activates transcription of periplasmic protease degP, probably by phosphorylating the cognate response protein CpxR; overexpression of an outer membrane lipoprotein NlpE also leads to transcription of degP via CpxRA (PubMed:7883164). Required for efficient binding of stationary phase cells to hydrophobic surfaces, part of the process of biofilm formation (PubMed:11830644). {ECO:0000269\|PubMed:16166523, ECO:0000269\|PubMed:17259177, ECO:0000269\|PubMed:24492262, ECO:0000269\|PubMed:25207645, ECO:0000269\|PubMed:7883164, ECO:0000269\|PubMed:8432716, ECO:0000269\|PubMed:9401031, ECO:0000269\|PubMed:9473036, ECO:0000305\|PubMed:11830644}.


Catalytic activity:		Reaction=ATP + protein L-histidine = ADP + protein N-phospho-L- histidine.; EC=2.7.13.3; Evidence={ECO:0000269\|PubMed:9401031};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:9401031}; Note=Phosphotransfer to CpxR is stimulated by Mg(2+) and/or Mn(2+). {ECO:0000269\|PubMed:9401031};
Activity regulation:		The two-component system is activated by envelope stress such as overexpression of some (misfolded) periplasmic proteins (PubMed:7883164, PubMed:9351822). Activated by spheroplasting (which removes the periplasm) in an autoregulatory cpxA-cpxR-dependent fashion (PubMed:10972835). Cpx two-component system is induced at pH 8.0; in a degP deletion mutant induction is halved (PubMed:9473036, PubMed:16166523). The kinase activity is inhibited by periplasmic accessory protein CpxP; proteolysis of CpxP relieves inhibition (PubMed:16166523, PubMed:17259177, PubMed:25207645). Autokinase activity reconstituted in liposomes is 50% inhibited by periplasmic accessory protein CpxP, but CpxP has no effect on phosphatase activity; autokinase stimulated by KCl, NH(4)Cl, RbCl, pH 7.5 and 8.0, inhibited by sensor kinase inhibitors tetrachlorosalicylanilid and ethodin (PubMed:17259177). {ECO:0000269\|PubMed:10972835, ECO:0000269\|PubMed:16166523, ECO:0000269\|PubMed:17259177, ECO:0000269\|PubMed:25207645, ECO:0000269\|PubMed:7883164, ECO:0000269\|PubMed:9351822, ECO:0000269\|PubMed:9473036}.
Subunit:		The isolated cytoplasmic domain (residues 188-457) crystallizes as a homodimer, and forms dimers of dimers in solution which may be catalytically important (PubMed:24492262). Interacts with periplasmic accessory protein CpxP (PubMed:16166523, PubMed:21317318, PubMed:21239493, PubMed:25207645); interaction with CpxP is not seen in vivo when cells are grown in 0.3 M NaCl, or if the misfolded P pili protein PapE is overexpressed (PubMed:25207645). Interacts with cognate response regulator CpxR (PubMed:25207645). {ECO:0000269\|PubMed:24492262, ECO:0000269\|PubMed:25207645, ECO:0000305\|PubMed:16166523}.
Subcellular location:		Cell inner membrane {ECO:0000269\|PubMed:15919996, ECO:0000269\|PubMed:25207645, ECO:0000269\|PubMed:3058985}; Multi-pass membrane protein {ECO:0000305\|PubMed:15919996, ECO:0000305\|PubMed:3058985}.
Domain:		The periplasmic segment (residues 30-163) defines the sensory domain (PubMed:9401031). Conformational changes in the cytoplasmic HAMP domain modulate the mobility of the central alpha-helices (which bend at Ser-238 and Pro-253) that allows formation of 1 kinase-active state. {ECO:0000269\|PubMed:24492262, ECO:0000269\|PubMed:9401031}.
Ptm:		Autophosphorylated (PubMed:9401031, PubMed:24492262). Maximal phosphorylation of the dimeric isolated cytoplasmic domain (residues 188-457) is about 70%, suggesting the protein may be hemiphosphorylated in vivo; probably occurs via a trans-autophosphorylation mechanism, i.e. one subunit phosphorylates the other (PubMed:24492262). {ECO:0000269\|PubMed:24492262, ECO:0000269\|PubMed:9401031}.
Disruption phenotype:		Loss of the Cpx envelope stress response (PubMed:10972835). Decreased resistance to the antibiotic amnikacin (PubMed:2185221). Single cpxA and double cpxR-cpxA mutant decrease transcription of degP (PubMed:7883164). Decreased transcription of cpxP (PubMed:9473036). Hypersensitive to alkaline pH (greater than pH 8.8) (PubMed:9473036). Decreased numbers of stationary phase cells bind to hydrophobic surfaces (PubMed:11830644). Greatly increased resistance to hydroxyurea, probably due to decreased recognition of mis-folded proteins which eventually leads to decreased OH radical formation (PubMed:20005847). {ECO:0000269\|PubMed:10972835, ECO:0000269\|PubMed:11830644, ECO:0000269\|PubMed:20005847, ECO:0000269\|PubMed:2185221, ECO:0000269\|PubMed:7883164, ECO:0000269\|PubMed:9473036}.
Sequence caution:		Sequence=AAA72540.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};