Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Basket 0
(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)

P23874

- HIPA_ECOLI

UniProt

P23874 - HIPA_ECOLI

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
    • BLAST
    • Align
    • Format
    • Add to basket
    • History
      Entry version 111 (01 Oct 2014)
      Sequence version 2 (19 Jul 2003)
      Previous versions | rss
    • Help video
    • Feedback
    • Comment

    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 binding Source: EcoCyc
    5. 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

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

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    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.
    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

    MPKLVTWMNN QRVGELTKLA NGAHTFKYAP EWLASRYARP LSLSLPLQRG    50
    NITSDAVFNF FDNLLPDSPI VRDRIVKRYH AKSRQPFDLL SEIGRDSVGA 100
    VTLIPEDETV THPIMAWEKL TEARLEEVLT AYKADIPLGM IREENDFRIS 150
    VAGAQEKTAL LRIGNDWCIP KGITPTTHII KLPIGEIRQP NATLDLSQSV 200
    DNEYYCLLLA KELGLNVPDA EIIKAGNVRA LAVERFDRRW NAERTVLLRL 250
    PQEDMCQTFG LPSSVKYESD GGPGIARIMA FLMGSSEALK DRYDFMKFQV 300
    FQWLIGATDG HAKNFSVFIQ AGGSYRLTPF YDIISAFPVL GGTGIHISDL 350
    KLAMGLNASK GKKTAIDKIY PRHFLATAKV LRFPEVQMHE ILSDFARMIP 400
    AALDNVKTSL PTDFPENVVT AVESNVLRLH GRLSREYGSK 440
    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:
    EMBL
    GenBank
    DDBJ
    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:
    EMBL
    GenBank
    DDBJ
    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:
    PDBe
    RCSB PDB
    PDBj
    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.
    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

    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: October 1, 2014
    This is version 111 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