Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

P23874

- HIPA_ECOLI

UniProt

P23874 - HIPA_ECOLI

(max 400 entries)x

Your basket is currently empty.

Select item(s) and click on "Add to basket" to create your own collection here
(400 entries max)

Protein

Serine/threonine-protein kinase HipA

Gene

hipA

Organism
Escherichia coli (strain K12)
Status
Reviewed - 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.

Enzyme regulationi

Once phosphorylated no longer has kinase activity.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei181 – 1811ATP1 Publication
Active sitei309 – 3091Proton acceptor1 Publication

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi152 – 1576ATP1 Publication
Nucleotide bindingi234 – 2363ATP1 Publication
Nucleotide bindingi311 – 3144ATP1 Publication
Nucleotide bindingi331 – 3322ATP1 Publication
DNA bindingi379 – 3824

GO - Molecular functioni

  1. ATP binding Source: EcoCyc
  2. DNA binding Source: UniProtKB-KW
  3. magnesium ion binding Source: EcoCyc
  4. protein serine/threonine kinase activity Source: EcoCyc

GO - Biological processi

  1. dormancy process Source: EcoCyc
  2. negative regulation of catalytic activity Source: EcoCyc
  3. peptidyl-serine autophosphorylation Source: EcoCyc
  4. response to antibiotic Source: UniProtKB-KW
  5. 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:2.7.11.1)
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 lineageiBacteriaProteobacteriaGammaproteobacteriaEnterobacterialesEnterobacteriaceaeEscherichia
ProteomesiUP000000318: Chromosome, UP000000625: Chromosome

Organism-specific databases

EcoGeneiEG10443. hipA.

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)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi22 – 221G → 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 Publication
Mutagenesisi88 – 881D → N: Loss of toxicity, still confers high persistence. 1 Publication
Mutagenesisi150 – 1501S → A: No phosphorylation; cells grow normally. 1 Publication
Mutagenesisi291 – 2911D → 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 Publication
Mutagenesisi309 – 3091D → Q: Loss of autophosphorylation; cells grow normally; protein can accumulate to high levels in E.coli. 1 Publication
Mutagenesisi332 – 3321D → Q: Loss of autophosphorylation; cells grow normally. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 440440Serine/threonine-protein kinase HipAPRO_0000083988Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei150 – 1501Phosphoserine; by autocatalysis2 Publications

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

PhosSiteiP0612176.

Expressioni

Gene expression databases

GenevestigatoriP23874.

Interactioni

Subunit structurei

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

Protein-protein interaction databases

DIPiDIP-9898N.
IntActiP23874. 4 interactions.
MINTiMINT-1292260.
STRINGi511145.b1507.

Structurei

Secondary structure

1
440
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi3 – 86Combined sources
Beta strandi11 – 188Combined sources
Beta strandi24 – 285Combined sources
Helixi30 – 345Combined sources
Beta strandi35 – 373Combined sources
Beta strandi49 – 524Combined sources
Helixi55 – 628Combined sources
Beta strandi65 – 673Combined sources
Helixi69 – 7911Combined sources
Beta strandi82 – 854Combined sources
Helixi86 – 938Combined sources
Beta strandi98 – 1003Combined sources
Beta strandi101 – 1044Combined sources
Beta strandi114 – 1163Combined sources
Beta strandi117 – 1193Combined sources
Helixi122 – 1309Combined sources
Turni131 – 1333Combined sources
Helixi137 – 1393Combined sources
Beta strandi149 – 1524Combined sources
Beta strandi153 – 1553Combined sources
Beta strandi158 – 1636Combined sources
Beta strandi166 – 1705Combined sources
Beta strandi178 – 1814Combined sources
Beta strandi185 – 1884Combined sources
Beta strandi189 – 1913Combined sources
Beta strandi193 – 1964Combined sources
Helixi199 – 21214Combined sources
Beta strandi220 – 2256Combined sources
Beta strandi228 – 2347Combined sources
Beta strandi236 – 2405Combined sources
Beta strandi247 – 2493Combined sources
Beta strandi252 – 2543Combined sources
Helixi255 – 2584Combined sources
Helixi263 – 2653Combined sources
Helixi268 – 2703Combined sources
Helixi275 – 2828Combined sources
Helixi288 – 30417Combined sources
Helixi312 – 3143Combined sources
Beta strandi316 – 3194Combined sources
Helixi321 – 3233Combined sources
Beta strandi325 – 3273Combined sources
Helixi337 – 3393Combined sources
Beta strandi342 – 3443Combined sources
Helixi347 – 3493Combined sources
Beta strandi351 – 3588Combined sources
Beta strandi361 – 3655Combined sources
Helixi366 – 3683Combined sources
Helixi371 – 38111Combined sources
Helixi385 – 40723Combined sources
Beta strandi412 – 4143Combined sources
Helixi416 – 43419Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
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[»]
ProteinModelPortaliP23874.
SMRiP23874. Positions 2-437.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP23874.

Family & Domainsi

Sequence similaritiesi

Belongs to the HipA Ser/Thr kinase family.Curated

Phylogenomic databases

eggNOGiCOG3550.
HOGENOMiHOG000188799.
InParanoidiP23874.
KOiK07154.
OMAiSGAKYES.
OrthoDBiEOG6ZSP44.

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti40 – 401P → Q in AAA56878. (PubMed:1715862)Curated
Sequence conflicti214 – 2152GL → WV in AAA56878. (PubMed:1715862)Curated
Sequence conflicti274 – 2741G → R in AAA56878. (PubMed:1715862)Curated

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.
YP_489771.1. NC_007779.1.

Genome annotation databases

EnsemblBacteriaiAAC74580; AAC74580; b1507.
BAA15179; BAA15179; BAA15179.
GeneIDi12931226.
946064.
KEGGiecj:Y75_p1482.
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 .
PIRi F64904.
RefSeqi NP_416024.1. NC_000913.3.
YP_489771.1. NC_007779.1.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2WIU X-ray 2.35 A/C 1-440 [» ]
3DNT X-ray 1.66 A/B 1-440 [» ]
3DNU X-ray 1.54 A 1-440 [» ]
3DNV X-ray 2.68 A 1-440 [» ]
3FBR X-ray 3.50 A 1-437 [» ]
3HZI X-ray 2.98 A 1-440 [» ]
3TPB X-ray 1.88 A 1-440 [» ]
3TPD X-ray 1.50 A 1-440 [» ]
3TPE X-ray 1.90 A 1-440 [» ]
3TPT X-ray 2.25 A/B 1-440 [» ]
3TPV X-ray 2.30 B 1-440 [» ]
ProteinModelPortali P23874.
SMRi P23874. Positions 2-437.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

DIPi DIP-9898N.
IntActi P23874. 4 interactions.
MINTi MINT-1292260.
STRINGi 511145.b1507.

PTM databases

PhosSitei P0612176.

Proteomic databases

PaxDbi P23874.
PRIDEi P23874.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

EnsemblBacteriai AAC74580 ; AAC74580 ; b1507 .
BAA15179 ; BAA15179 ; BAA15179 .
GeneIDi 12931226.
946064.
KEGGi ecj:Y75_p1482.
eco:b1507.
PATRICi 32118308. VBIEscCol129921_1574.

Organism-specific databases

EchoBASEi EB0438.
EcoGenei EG10443. hipA.

Phylogenomic databases

eggNOGi COG3550.
HOGENOMi HOG000188799.
InParanoidi P23874.
KOi K07154.
OMAi SGAKYES.
OrthoDBi EOG6ZSP44.

Enzyme and pathway databases

BioCyci EcoCyc:EG10443-MONOMER.
ECOL316407:JW1500-MONOMER.
MetaCyc:EG10443-MONOMER.

Miscellaneous databases

EvolutionaryTracei P23874.
PROi P23874.

Gene expression databases

Genevestigatori P23874.

Family and domain databases

InterProi IPR012893. HipA-like_C.
IPR017508. HipA_N1.
IPR012894. HipA_N2.
[Graphical view ]
Pfami PF13657. Couple_hipA. 1 hit.
PF07804. HipA_C. 1 hit.
PF07805. HipA_N. 1 hit.
[Graphical view ]
TIGRFAMsi TIGR03071. couple_hipA. 1 hit.
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Structure and organization of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis."
    Black D.S., Kelly A.J., Mardis M.J., Moyed H.S.
    J. Bacteriol. 173:5732-5739(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    Strain: K12.
  2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: K12 / MG1655 / ATCC 47076.
  3. "Highly accurate genome sequences of Escherichia coli K-12 strains MG1655 and W3110."
    Hayashi K., Morooka N., Yamamoto Y., Fujita K., Isono K., Choi S., Ohtsubo E., Baba T., Wanner B.L., Mori H., Horiuchi T.
    Mol. Syst. Biol. 2:E1-E5(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: K12 / W3110 / ATCC 27325 / DSM 5911.
  4. "Kinase activity of overexpressed HipA is required for growth arrest and multidrug tolerance in Escherichia coli."
    Correia F.F., D'Onofrio A., Rejtar T., Li L., Karger B.L., Makarova K., Koonin E.V., Lewis K.
    J. Bacteriol. 188:8360-8367(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 134-157, FUNCTION AS A KINASE, ACTIVE SITE, PHOSPHORYLATION AT SER-150, ANTIBIOTIC TOLERANCE, MUTAGENESIS OF SER-150; ASP-309 AND ASP-332.
    Strain: K12.
  5. "hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis."
    Moyed H.S., Bertrand K.P.
    J. Bacteriol. 155:768-775(1983) [PubMed] [Europe PMC] [Abstract]
    Cited for: MUTANT HIPA7 ISOLATION, ROLE IN ANTIBIOTIC TOLERANCE, ROLE IN PERSISTENCE.
    Strain: K12.
  6. "Autoregulation of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis."
    Black D.S., Irwin B., Moyed H.S.
    J. Bacteriol. 176:4081-4091(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS A TOXIN, DISRUPTION PHENOTYPE.
    Strain: K12.
  7. "Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis."
    Korch S.B., Henderson T.A., Hill T.M.
    Mol. Microbiol. 50:1199-1213(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS A TOXIN, FUNCTION IN PERSISTENCE, REQUIREMENT FOR (P)PPGPP, MUTAGENESIS OF GLY-22; ASP-88 AND ASP-291.
    Strain: K12 / MG1655 / ATCC 47076.
  8. "Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation."
    Korch S.B., Hill T.M.
    J. Bacteriol. 188:3826-3836(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS A TOXIN.
    Strain: K12 / MG1655 / ATCC 47076.
  9. "HipA-triggered growth arrest and beta-lactam tolerance in Escherichia coli are mediated by RelA-dependent ppGpp synthesis."
    Bokinsky G., Baidoo E.E., Akella S., Burd H., Weaver D., Alonso-Gutierrez J., Garcia-Martin H., Lee T.S., Keasling J.D.
    J. Bacteriol. 195:3173-3182(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, ROLE IN PPGPP RESPONSE.
  10. "Interaction investigations of HipA binding to HipB dimer and HipB dimer + DNA complex: a molecular dynamics simulation study."
    Li C., Wang Y., Wang Y., Chen G.
    J. Mol. Recognit. 26:556-567(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBUNIT, MODELING OF INTERACTION.
  11. "Molecular mechanism of bacterial persistence by HipA."
    Germain E., Castro-Roa D., Zenkin N., Gerdes K.
    Mol. Cell 52:248-254(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH HIPB, SUBUNIT, MASS SPECTROMETRY.
    Strain: K12 / MG1655 / ATCC 47076.
  12. "New kinase regulation mechanism found in HipBA: a bacterial persistence switch."
    Evdokimov A., Voznesensky I., Fennell K., Anderson M., Smith J.F., Fisher D.A.
    Acta Crystallogr. D 65:875-879(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) IN COMPLEX WITH HIPB.
    Strain: K12 / DH5-alpha.
  13. "Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB."
    Schumacher M.A., Piro K.M., Xu W., Hansen S., Lewis K., Brennan R.G.
    Science 323:396-401(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS) ALONE AND IN COMPLEX WITH MG-ATP AND HIPB, FUNCTION AS A KINASE, ATP-BINDING, DNA-BINDING, SUBSTRATE, SUBUNIT.
  14. "Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance."
    Schumacher M.A., Min J., Link T.M., Guan Z., Xu W., Ahn Y.H., Soderblom E.J., Kurie J.M., Evdokimov A., Moseley M.A., Lewis K., Brennan R.G.
    Cell Rep. 2:518-525(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) PHOSPHORYLATED AND NON-PHOSPHORYLATED AND IN COMPLEX WITH ATP, ATP-BINDING, ENZYME REGULATION, PHOSPHORYLATION AT SER-150.

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 26, 2014
This is version 113 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

External Data

Dasty 3