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Protein

Serine/threonine-protein kinase HipA

Gene

hipA

Organism
Escherichia coli (strain K12)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Toxic component of a toxin-antitoxin (TA) module. Phosphorylates Glu-tRNA-ligase (GltX, on 'Ser-239') in vivo. Phosphorylation of GltX prevents it from being charged, leading to an increase in uncharged tRNA(Glu). This induces amino acid starvation and the stringent response via RelA/SpoT and increased ppGpp levels, which inhibits replication, transcription, translation and cell wall synthesis, reducing growth and leading to multidrug resistance and persistence. The hipA7 mutation (a double G22S D291A mutation) leads to increased generation of persister cells, cells that survive antibiotic treatment probably by entering into a dormant state. Wild-type cells produce persisters at a frequency of 10(-6) to 10(-5) whereas mutant hipA7 cells produce persisters at a frequency of 10(-2). Generation of persister cells requires ppGpp as cells lacking relA or relA/spoT generate fewer or no persister cells respectively compared to hipA7. Low level expression of HipA induces dormancy and depending on the protein level, can be toxic enough to reduce cell growth or even kill cells. Low levels of wild-type HipA lead to high beta-lactam antibiotic tolerance of the survivor cells, also dependent on relA and relA/spoT. The toxic effect of HipA is neutralized by its cognate antitoxin HipB. With HipB acts as a corepressor for transcription of the hipBA promoter; binding to DNA induces a 70 degree bend.8 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Enzyme regulationi

Once phosphorylated no longer has kinase activity.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei181ATP1 Publication1
Active sitei309Proton acceptor1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi152 – 157ATP1 Publication6
Nucleotide bindingi234 – 236ATP1 Publication3
Nucleotide bindingi311 – 314ATP1 Publication4
Nucleotide bindingi331 – 332ATP1 Publication2
DNA bindingi379 – 3821 Publication4

GO - Molecular functioni

  • ATP binding Source: EcoCyc
  • DNA binding Source: UniProtKB-KW
  • magnesium ion binding Source: EcoCyc
  • protein serine/threonine kinase activity Source: EcoCyc

GO - Biological processi

  • dormancy process Source: EcoCyc
  • negative regulation of catalytic activity Source: EcoCyc
  • peptidyl-serine autophosphorylation Source: EcoCyc
  • response to antibiotic Source: UniProtKB-KW
  • single-species biofilm formation Source: EcoCyc
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Repressor, Serine/threonine-protein kinase, Toxin, Transferase

Keywords - Biological processi

Antibiotic resistance

Keywords - Ligandi

ATP-binding, DNA-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciEcoCyc:EG10443-MONOMER.
ECOL316407:JW1500-MONOMER.
MetaCyc:EG10443-MONOMER.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase HipA (EC:2.7.11.11 Publication)
Short name:
Ser/Thr-protein kinase HipA
Alternative name(s):
Toxin HipA
Gene namesi
Name:hipA
Ordered Locus Names:b1507, JW1500
OrganismiEscherichia coli (strain K12)
Taxonomic identifieri83333 [NCBI]
Taxonomic lineageiBacteriaProteobacteriaGammaproteobacteriaEnterobacteralesEnterobacteriaceaeEscherichia
Proteomesi
  • UP000000318 Componenti: Chromosome
  • UP000000625 Componenti: Chromosome

Organism-specific databases

EcoGeneiEG10443. hipA.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: EcoCyc
Complete GO annotation...

Pathology & Biotechi

Disruption phenotypei

Cells lacking hipA or the hipBA operon cannot produce persister cells at a high frequency.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi22G → S: Loss of toxicity, does not confer high persistence. Loss of toxicity, high persistence and cold sensitivity; in hipA7; when associated with A-291. 1 Publication1
Mutagenesisi88D → N: Loss of toxicity, still confers high persistence. 1 Publication1
Mutagenesisi150S → A: No phosphorylation; cells grow normally. 1 Publication1
Mutagenesisi291D → A: Retains toxicity and high persistence but not cold-sensitive. Loss of toxicity, high persistence and cold sensitivity; in hipA7; when associated with S-22. 1 Publication1
Mutagenesisi309D → Q: Loss of autophosphorylation; cells grow normally; protein can accumulate to high levels in E.coli. 1 Publication1
Mutagenesisi332D → Q: Loss of autophosphorylation; cells grow normally. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000839881 – 440Serine/threonine-protein kinase HipAAdd BLAST440

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei150Phosphoserine; by autocatalysis2 Publications1

Post-translational modificationi

Autophosphorylates intermolecularly on Ser-150; phosphorylated form not seen to bind ATP and no longer has kinase activity.2 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiP23874.
PRIDEiP23874.

PTM databases

iPTMnetiP23874.

Expressioni

Gene expression databases

CollecTFiEXPREG_00000970.

Interactioni

Subunit structurei

Forms a HipA2HipB2 heterotetramer which can interact with DNA.5 Publications

Protein-protein interaction databases

BioGridi4260220. 11 interactors.
DIPiDIP-9898N.
IntActiP23874. 4 interactors.
MINTiMINT-1292260.
STRINGi511145.b1507.

Structurei

Secondary structure

1440
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi3 – 8Combined sources6
Beta strandi11 – 18Combined sources8
Beta strandi24 – 28Combined sources5
Helixi30 – 34Combined sources5
Beta strandi35 – 37Combined sources3
Beta strandi49 – 52Combined sources4
Helixi55 – 62Combined sources8
Beta strandi65 – 67Combined sources3
Helixi69 – 79Combined sources11
Beta strandi82 – 85Combined sources4
Helixi86 – 93Combined sources8
Beta strandi98 – 100Combined sources3
Beta strandi101 – 104Combined sources4
Beta strandi114 – 116Combined sources3
Beta strandi117 – 119Combined sources3
Helixi122 – 130Combined sources9
Turni131 – 133Combined sources3
Helixi137 – 139Combined sources3
Beta strandi149 – 152Combined sources4
Beta strandi153 – 155Combined sources3
Beta strandi158 – 163Combined sources6
Beta strandi166 – 170Combined sources5
Beta strandi178 – 181Combined sources4
Beta strandi185 – 188Combined sources4
Beta strandi189 – 191Combined sources3
Beta strandi193 – 196Combined sources4
Helixi199 – 212Combined sources14
Beta strandi220 – 225Combined sources6
Beta strandi228 – 234Combined sources7
Beta strandi236 – 240Combined sources5
Beta strandi247 – 249Combined sources3
Beta strandi252 – 254Combined sources3
Helixi255 – 258Combined sources4
Helixi263 – 265Combined sources3
Helixi268 – 270Combined sources3
Helixi275 – 282Combined sources8
Helixi288 – 304Combined sources17
Helixi312 – 314Combined sources3
Beta strandi316 – 319Combined sources4
Helixi321 – 323Combined sources3
Beta strandi325 – 327Combined sources3
Helixi337 – 339Combined sources3
Beta strandi342 – 344Combined sources3
Helixi347 – 349Combined sources3
Beta strandi351 – 358Combined sources8
Beta strandi361 – 365Combined sources5
Helixi366 – 368Combined sources3
Helixi371 – 381Combined sources11
Helixi385 – 407Combined sources23
Beta strandi412 – 414Combined sources3
Helixi416 – 434Combined sources19

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2WIUX-ray2.35A/C1-440[»]
3DNTX-ray1.66A/B1-440[»]
3DNUX-ray1.54A1-440[»]
3DNVX-ray2.68A1-440[»]
3FBRX-ray3.50A1-437[»]
3HZIX-ray2.98A1-440[»]
3TPBX-ray1.88A1-440[»]
3TPDX-ray1.50A1-440[»]
3TPEX-ray1.90A1-440[»]
3TPTX-ray2.25A/B1-440[»]
3TPVX-ray2.30B1-440[»]
4YG7X-ray3.77D/K2-437[»]
5K98X-ray3.99A/D2-440[»]
ProteinModelPortaliP23874.
SMRiP23874.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP23874.

Family & Domainsi

Sequence similaritiesi

Belongs to the HipA Ser/Thr kinase family.Curated

Phylogenomic databases

eggNOGiENOG4105CAF. Bacteria.
COG3550. LUCA.
HOGENOMiHOG000188799.
InParanoidiP23874.
KOiK07154.
OMAiSCENEWL.

Family and domain databases

InterProiIPR012893. HipA-like_C.
IPR017508. HipA_N1.
IPR012894. HipA_N2.
[Graphical view]
PfamiPF13657. Couple_hipA. 1 hit.
PF07804. HipA_C. 1 hit.
PF07805. HipA_N. 1 hit.
[Graphical view]
TIGRFAMsiTIGR03071. couple_hipA. 1 hit.

Sequencei

Sequence statusi: Complete.

P23874-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPKLVTWMNN QRVGELTKLA NGAHTFKYAP EWLASRYARP LSLSLPLQRG
60 70 80 90 100
NITSDAVFNF FDNLLPDSPI VRDRIVKRYH AKSRQPFDLL SEIGRDSVGA
110 120 130 140 150
VTLIPEDETV THPIMAWEKL TEARLEEVLT AYKADIPLGM IREENDFRIS
160 170 180 190 200
VAGAQEKTAL LRIGNDWCIP KGITPTTHII KLPIGEIRQP NATLDLSQSV
210 220 230 240 250
DNEYYCLLLA KELGLNVPDA EIIKAGNVRA LAVERFDRRW NAERTVLLRL
260 270 280 290 300
PQEDMCQTFG LPSSVKYESD GGPGIARIMA FLMGSSEALK DRYDFMKFQV
310 320 330 340 350
FQWLIGATDG HAKNFSVFIQ AGGSYRLTPF YDIISAFPVL GGTGIHISDL
360 370 380 390 400
KLAMGLNASK GKKTAIDKIY PRHFLATAKV LRFPEVQMHE ILSDFARMIP
410 420 430 440
AALDNVKTSL PTDFPENVVT AVESNVLRLH GRLSREYGSK
Length:440
Mass (Da):49,276
Last modified:July 19, 2003 - v2
Checksum:i378771C4CAB55319
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti40P → Q in AAA56878 (PubMed:1715862).Curated1
Sequence conflicti214 – 215GL → WV in AAA56878 (PubMed:1715862).Curated2
Sequence conflicti274G → R in AAA56878 (PubMed:1715862).Curated1

Mass spectrometryi

Molecular mass is 49143.80 Da from positions 1 - 440. Determined by MALDI. 1 Publication
Molecular mass is 49223.80 Da from positions 1 - 440. Determined by MALDI. Phosphorylated form.1 Publication

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M61242 Genomic DNA. Translation: AAA56878.1.
U00096 Genomic DNA. Translation: AAC74580.1.
AP009048 Genomic DNA. Translation: BAA15179.2.
PIRiF64904.
RefSeqiNP_416024.1. NC_000913.3.
WP_001125439.1. NZ_CP014272.1.

Genome annotation databases

EnsemblBacteriaiAAC74580; AAC74580; b1507.
BAA15179; BAA15179; BAA15179.
GeneIDi946064.
KEGGiecj:JW1500.
eco:b1507.
PATRICi32118308. VBIEscCol129921_1574.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M61242 Genomic DNA. Translation: AAA56878.1.
U00096 Genomic DNA. Translation: AAC74580.1.
AP009048 Genomic DNA. Translation: BAA15179.2.
PIRiF64904.
RefSeqiNP_416024.1. NC_000913.3.
WP_001125439.1. NZ_CP014272.1.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2WIUX-ray2.35A/C1-440[»]
3DNTX-ray1.66A/B1-440[»]
3DNUX-ray1.54A1-440[»]
3DNVX-ray2.68A1-440[»]
3FBRX-ray3.50A1-437[»]
3HZIX-ray2.98A1-440[»]
3TPBX-ray1.88A1-440[»]
3TPDX-ray1.50A1-440[»]
3TPEX-ray1.90A1-440[»]
3TPTX-ray2.25A/B1-440[»]
3TPVX-ray2.30B1-440[»]
4YG7X-ray3.77D/K2-437[»]
5K98X-ray3.99A/D2-440[»]
ProteinModelPortaliP23874.
SMRiP23874.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi4260220. 11 interactors.
DIPiDIP-9898N.
IntActiP23874. 4 interactors.
MINTiMINT-1292260.
STRINGi511145.b1507.

PTM databases

iPTMnetiP23874.

Proteomic databases

PaxDbiP23874.
PRIDEiP23874.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaiAAC74580; AAC74580; b1507.
BAA15179; BAA15179; BAA15179.
GeneIDi946064.
KEGGiecj:JW1500.
eco:b1507.
PATRICi32118308. VBIEscCol129921_1574.

Organism-specific databases

EchoBASEiEB0438.
EcoGeneiEG10443. hipA.

Phylogenomic databases

eggNOGiENOG4105CAF. Bacteria.
COG3550. LUCA.
HOGENOMiHOG000188799.
InParanoidiP23874.
KOiK07154.
OMAiSCENEWL.

Enzyme and pathway databases

BioCyciEcoCyc:EG10443-MONOMER.
ECOL316407:JW1500-MONOMER.
MetaCyc:EG10443-MONOMER.

Miscellaneous databases

EvolutionaryTraceiP23874.
PROiP23874.

Gene expression databases

CollecTFiEXPREG_00000970.

Family and domain databases

InterProiIPR012893. HipA-like_C.
IPR017508. HipA_N1.
IPR012894. HipA_N2.
[Graphical view]
PfamiPF13657. Couple_hipA. 1 hit.
PF07804. HipA_C. 1 hit.
PF07805. HipA_N. 1 hit.
[Graphical view]
TIGRFAMsiTIGR03071. couple_hipA. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiHIPA_ECOLI
AccessioniPrimary (citable) accession number: P23874
Secondary accession number(s): P76139, P76880, P77507
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1991
Last sequence update: July 19, 2003
Last modified: November 2, 2016
This is version 126 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Miscellaneousi

Caution

Has been reported to phosphorylate EF-Tu in vitro (on 'Thr-383') (PubMed:19150849). According to another report, does not phosphorylate EF-Tu (PubMed:19622872).2 Publications

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Escherichia coli
    Escherichia coli (strain K12): entries and cross-references to EcoGene
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.