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Protein

Sensor histidine kinase CpxA

Gene

cpxA

Organism
Escherichia coli (strain K12)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 Mg2+ 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).1 Publication8 Publications

Catalytic activityi

ATP + protein L-histidine = ADP + protein N-phospho-L-histidine.1 Publication

Cofactori

Mg2+1 PublicationNote: Phosphotransfer to CpxR is stimulated by Mg2+ and/or Mn2+.1 Publication

Activity regulationi

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, NH4Cl, RbCl, pH 7.5 and 8.0, inhibited by sensor kinase inhibitors tetrachlorosalicylanilid and ethodin (PubMed:17259177).7 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei248Nucleophile1 Publication1
Binding sitei248ATP1 Publication1
Binding sitei386ATP1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi248 – 251ATP1 Publication4
Nucleotide bindingi359 – 364ATP1 Publication6
Nucleotide bindingi405 – 406ATP1 Publication2
Nucleotide bindingi416 – 421ATP1 Publication6

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • identical protein binding Source: IntAct
  • phosphorelay sensor kinase activity Source: EcoCyc

GO - Biological processi

Keywordsi

Molecular functionKinase, Transferase
Biological processCell adhesion, Two-component regulatory system
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciEcoCyc:CPXA-MONOMER

Names & Taxonomyi

Protein namesi
Recommended name:
Sensor histidine kinase CpxA (EC:2.7.13.31 Publication)
Gene namesi
Name:cpxA
Synonyms:ecfB, eup, ssd
Ordered Locus Names:b3911, JW3882
OrganismiEscherichia coli (strain K12)
Taxonomic identifieri83333 [NCBI]
Taxonomic lineageiBacteriaProteobacteriaGammaproteobacteriaEnterobacteralesEnterobacteriaceaeEscherichia
Proteomesi
  • UP000000318 Componenti: Chromosome
  • UP000000625 Componenti: Chromosome

Organism-specific databases

EcoGeneiEG10163 cpxA

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 7Cytoplasmic1 Publication7
Transmembranei8 – 29HelicalCuratedAdd BLAST22
Topological domaini30 – 163Periplasmic2 PublicationsAdd BLAST134
Transmembranei164 – 184HelicalCuratedAdd BLAST21
Topological domaini185 – 457Cytoplasmic2 PublicationsAdd BLAST273

GO - Cellular componenti

Keywords - Cellular componenti

Cell inner membrane, Cell membrane, Membrane

Pathology & Biotechi

Disruption phenotypei

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).6 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi33R → C in cpxA104; a cpxA gain of function mutant, constitutively active. 1 Publication1
Mutagenesisi93 – 124Missing in cpxA24; a cpxA gain of function mutant, constitutively active, up-regulation of the Cpx regulon members. 1 PublicationAdd BLAST32
Mutagenesisi185S → R: Nearly complete loss of response to excess periplasmic protein. 1 Publication1
Mutagenesisi186L → Q: 30% decrease in response to excess periplasmic protein. 1 Publication1
Mutagenesisi197A → V: Slight decrease in response to excess periplasmic protein. 1 Publication1
Mutagenesisi204N → Y: 80% decrease in response to excess periplasmic protein. 1 Publication1
Mutagenesisi222G → D: 90% decrease in response to excess periplasmic protein. 1 Publication1
Mutagenesisi222G → R: 75% decrease in response to excess periplasmic protein. 1 Publication1
Mutagenesisi228M → V: No response to excess periplasmic protein, decreased autophosphorylation, no phosphotransfer to CpxR, no tetramer formation of the C-terminal domain in solution. 1 Publication1
Mutagenesisi252T → P in cpxA101; a cpxA gain of function mutant, decreased autophosphorylation, decreased phosphotransfer to CpxR, loss of phosphatase activity, responds to periplasmic protein overproduction. 1 Publication1
Mutagenesisi356N → Y: Nearly complete loss of response to excess periplasmic protein. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000747391 – 457Sensor histidine kinase CpxAAdd BLAST457

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei248Phosphohistidine; by autocatalysisPROSITE-ProRule annotation2 Publications1

Post-translational modificationi

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 phopshorylates the other (PubMed:24492262).2 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiP0AE82
PRIDEiP0AE82

PTM databases

iPTMnetiP0AE82

Interactioni

Subunit structurei

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).1 Publication2 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi4262644, 15 interactors
DIPiDIP-48358N
IntActiP0AE82, 2 interactors
STRINGi316385.ECDH10B_4101

Structurei

Secondary structure

1457
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP0AE82
SMRiP0AE82
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini185 – 237HAMPPROSITE-ProRule annotationAdd BLAST53
Domaini245 – 455Histidine kinasePROSITE-ProRule annotationAdd BLAST211

Domaini

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.2 Publications

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG4105E0F Bacteria
ENOG410XTWD LUCA
HOGENOMiHOG000269851
InParanoidiP0AE82
KOiK07640
PhylomeDBiP0AE82

Family and domain databases

CDDicd06225 HAMP, 1 hit
cd00075 HATPase_c, 1 hit
cd00082 HisKA, 1 hit
Gene3Di3.30.450.210, 1 hit
3.30.565.10, 1 hit
InterProiView protein in InterPro
IPR032404 CpxA_peri
IPR038515 CpxA_peri_sf
IPR003660 HAMP_dom
IPR003594 HATPase_C
IPR036890 HATPase_C_sf
IPR005467 His_kinase_dom
IPR003661 HisK_dim/P
IPR036097 HisK_dim/P_sf
IPR004358 Sig_transdc_His_kin-like_C
PfamiView protein in Pfam
PF16527 CpxA_peri, 1 hit
PF00672 HAMP, 1 hit
PF02518 HATPase_c, 1 hit
PF00512 HisKA, 1 hit
PRINTSiPR00344 BCTRLSENSOR
SMARTiView protein in SMART
SM00304 HAMP, 1 hit
SM00387 HATPase_c, 1 hit
SM00388 HisKA, 1 hit
SUPFAMiSSF47384 SSF47384, 1 hit
SSF55874 SSF55874, 1 hit
PROSITEiView protein in PROSITE
PS50885 HAMP, 1 hit
PS50109 HIS_KIN, 1 hit

Sequencei

Sequence statusi: Complete.

P0AE82-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MIGSLTARIF AIFWLTLALV LMLVLMLPKL DSRQMTELLD SEQRQGLMIE
60 70 80 90 100
QHVEAELAND PPNDLMWWRR LFRAIDKWAP PGQRLLLVTT EGRVIGAERS
110 120 130 140 150
EMQIIRNFIG QADNADHPQK KKYGRVELVG PFSVRDGEDN YQLYLIRPAS
160 170 180 190 200
SSQSDFINLL FDRPLLLLIV TMLVSTPLLL WLAWSLAKPA RKLKNAADEV
210 220 230 240 250
AQGNLRQHPE LEAGPQEFLA AGASFNQMVT ALERMMTSQQ RLLSDISHEL
260 270 280 290 300
RTPLTRLQLG TALLRRRSGE SKELERIETE AQRLDSMIND LLVMSRNQQK
310 320 330 340 350
NALVSETIKA NQLWSEVLDN AAFEAEQMGK SLTVNFPPGP WPLYGNPNAL
360 370 380 390 400
ESALENIVRN ALRYSHTKIE VGFAVDKDGI TITVDDDGPG VSPEDREQIF
410 420 430 440 450
RPFYRTDEAR DRESGGTGLG LAIVETAIQQ HRGWVKAEDS PLGGLRLVIW

LPLYKRS
Length:457
Mass (Da):51,624
Last modified:December 6, 2005 - v1
Checksum:i720EE4A62885BA33
GO

Sequence cautioni

The sequence AAA72540 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti68W → WW in AAA23600 (PubMed:3007473).Curated1
Sequence conflicti68W → WW in CAA31687 (PubMed:3058985).Curated1
Sequence conflicti330K → R in AAA23600 (PubMed:3007473).Curated1
Sequence conflicti330K → R in AAA72540 (PubMed:3007473).Curated1
Sequence conflicti330K → R in CAA31687 (PubMed:3058985).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13493 Genomic DNA Translation: AAA72540.1 Different initiation.
M36795 Genomic DNA Translation: AAA23600.1
X13307 Genomic DNA Translation: CAA31687.1
L19201 Genomic DNA Translation: AAB03044.1
U00096 Genomic DNA Translation: AAC76893.1
AP009048 Genomic DNA Translation: BAE77398.1
PIRiS40855
RefSeqiNP_418347.1, NC_000913.3
WP_000580417.1, NZ_LN832404.1

Genome annotation databases

EnsemblBacteriaiAAC76893; AAC76893; b3911
BAE77398; BAE77398; BAE77398
GeneIDi948405
KEGGiecj:JW3882
eco:b3911
PATRICifig|1411691.4.peg.2793

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13493 Genomic DNA Translation: AAA72540.1 Different initiation.
M36795 Genomic DNA Translation: AAA23600.1
X13307 Genomic DNA Translation: CAA31687.1
L19201 Genomic DNA Translation: AAB03044.1
U00096 Genomic DNA Translation: AAC76893.1
AP009048 Genomic DNA Translation: BAE77398.1
PIRiS40855
RefSeqiNP_418347.1, NC_000913.3
WP_000580417.1, NZ_LN832404.1

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4BIUX-ray3.65A/B/C/D/E/F188-457[»]
4BIVX-ray3.40A/B188-457[»]
4BIWX-ray2.85A/B188-457[»]
4BIXX-ray2.00A/B188-457[»]
4BIYX-ray3.30A/B/C/D188-457[»]
4BIZX-ray2.65A/B/C/D/E/F188-457[»]
4CB0X-ray3.30A/B188-457[»]
5LFKX-ray3.09A/B188-457[»]
ProteinModelPortaliP0AE82
SMRiP0AE82
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi4262644, 15 interactors
DIPiDIP-48358N
IntActiP0AE82, 2 interactors
STRINGi316385.ECDH10B_4101

PTM databases

iPTMnetiP0AE82

Proteomic databases

PaxDbiP0AE82
PRIDEiP0AE82

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaiAAC76893; AAC76893; b3911
BAE77398; BAE77398; BAE77398
GeneIDi948405
KEGGiecj:JW3882
eco:b3911
PATRICifig|1411691.4.peg.2793

Organism-specific databases

EchoBASEiEB0161
EcoGeneiEG10163 cpxA

Phylogenomic databases

eggNOGiENOG4105E0F Bacteria
ENOG410XTWD LUCA
HOGENOMiHOG000269851
InParanoidiP0AE82
KOiK07640
PhylomeDBiP0AE82

Enzyme and pathway databases

BioCyciEcoCyc:CPXA-MONOMER

Miscellaneous databases

PROiPR:P0AE82

Family and domain databases

CDDicd06225 HAMP, 1 hit
cd00075 HATPase_c, 1 hit
cd00082 HisKA, 1 hit
Gene3Di3.30.450.210, 1 hit
3.30.565.10, 1 hit
InterProiView protein in InterPro
IPR032404 CpxA_peri
IPR038515 CpxA_peri_sf
IPR003660 HAMP_dom
IPR003594 HATPase_C
IPR036890 HATPase_C_sf
IPR005467 His_kinase_dom
IPR003661 HisK_dim/P
IPR036097 HisK_dim/P_sf
IPR004358 Sig_transdc_His_kin-like_C
PfamiView protein in Pfam
PF16527 CpxA_peri, 1 hit
PF00672 HAMP, 1 hit
PF02518 HATPase_c, 1 hit
PF00512 HisKA, 1 hit
PRINTSiPR00344 BCTRLSENSOR
SMARTiView protein in SMART
SM00304 HAMP, 1 hit
SM00387 HATPase_c, 1 hit
SM00388 HisKA, 1 hit
SUPFAMiSSF47384 SSF47384, 1 hit
SSF55874 SSF55874, 1 hit
PROSITEiView protein in PROSITE
PS50885 HAMP, 1 hit
PS50109 HIS_KIN, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCPXA_ECOLI
AccessioniPrimary (citable) accession number: P0AE82
Secondary accession number(s): P08336, Q2M8K8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: December 6, 2005
Last modified: November 7, 2018
This is version 118 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. Escherichia coli
    Escherichia coli (strain K12): entries and cross-references to EcoGene
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