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Q8VSC3

- IPA9_SHIFL

UniProt

Q8VSC3 - IPA9_SHIFL

Protein

E3 ubiquitin-protein ligase ipaH9.8

Gene

ipaH9.8

Organism
Shigella flexneri
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 69 (01 Oct 2014)
      Sequence version 2 (04 Jan 2005)
      Previous versions | rss
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    Functioni

    Effector proteins function to alter host cell physiology and promote bacterial survival in host tissues. This protein is an E3 ubiquitin ligase that interferes with host's ubiquitination pathway and modulates the acute inflammatory responses, thus facilitating bacterial colonization within the host cell. Interacts with IKBKG (NEMO) and TNIP1 (ABIN-1), a ubiquitin-binding adapter protein, which results in TNIP1-dependent 'Lys-27'-linked polyubiquitination of IKBKG. Consequently, polyubiquitinated IKBKG undergoes proteasome-dependent degradation, which perturbs NF-kappa-B activation during bacterial infection. Uses UBE2D2 (UBCH5B) as an E2 ubiquitin-conjugating enzyme. Mediates polyubiquitination of host U2AF1, leading to its proteasomal degradation.5 Publications

    Enzyme regulationi

    Exists in an autoinhibited state in the absence of substrate protein, probably due to interactions of the leucine-rich repeat domain with the catalytic domain. Is activated upon binding to a substrate protein.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei337 – 3371Glycyl thioester intermediate1 Publication

    GO - Molecular functioni

    1. identical protein binding Source: IntAct
    2. ligase activity Source: UniProtKB-KW
    3. protein binding Source: IntAct
    4. ubiquitin-protein transferase activity Source: UniProtKB

    GO - Biological processi

    1. modulation by symbiont of host I-kappaB kinase/NF-kappaB cascade Source: UniProtKB
    2. pathogenesis Source: UniProtKB
    3. protein K27-linked ubiquitination Source: UniProtKB

    Keywords - Molecular functioni

    Ligase

    Keywords - Biological processi

    Ubl conjugation pathway, Virulence

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    E3 ubiquitin-protein ligase ipaH9.8 (EC:6.3.2.-)
    Alternative name(s):
    Invasion plasmid antigen ipaH9.8
    Gene namesi
    Name:ipaH9.8
    Ordered Locus Names:CP0226
    ORF Names:pWR501_0234, SFLP090
    Encoded oniPlasmid pCP3011 Publication
    Plasmid pWR1004 Publications
    Plasmid pINV_F6_M13821 Publication
    Plasmid pSF51 Publication
    OrganismiShigella flexneri
    Taxonomic identifieri623 [NCBI]
    Taxonomic lineageiBacteriaProteobacteriaGammaproteobacteriaEnterobacterialesEnterobacteriaceaeShigella
    ProteomesiUP000001006: Plasmid pCP301

    Subcellular locationi

    Secreted. Host cytoplasm. Host nucleus
    Note: Secreted via Mxi-Spa type III secretion system (TTSS), and delivered into the host cytoplasm. Transported into the host nucleus. This transport is independent of cytosolic factors, but dependent on temperature and partly on ATP/GTP.

    GO - Cellular componenti

    1. extracellular region Source: UniProtKB
    2. host cell cytosol Source: UniProtKB
    3. host cell nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Host cytoplasm, Host nucleus, Secreted

    Pathology & Biotechi

    Disruption phenotypei

    In murine lung infection model, mutants cause severe inflammatory responses, with increased pro-inflammatory cytokine production levels. Colonization is greatly reduced.1 Publication

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi163 – 1631R → A: Abolishes proteasomal degradation of host proteins; when associated with A-187 and A-210. 1 Publication
    Mutagenesisi187 – 1871F → A: Abolishes proteasomal degradation of host proteins; when associated with A-163 and A-210. 1 Publication
    Mutagenesisi210 – 2101H → A: Abolishes proteasomal degradation of host proteins; when associated with A-163 and A-187. 1 Publication
    Mutagenesisi337 – 3371C → A: Abolishes proteasomal degradation of host proteins. 3 Publications
    Mutagenesisi337 – 3371C → A: Loss of activity. 3 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 545545E3 ubiquitin-protein ligase ipaH9.8PRO_0000395755Add
    BLAST

    Post-translational modificationi

    Autoubiquitinated (in vitro). Ubiquitinated in the presence of host E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and ubiquitin.1 Publication

    Keywords - PTMi

    Ubl conjugation

    Proteomic databases

    PRIDEiQ8VSC3.

    Expressioni

    Inductioni

    Induced upon entry into host epithelial cells.1 Publication

    Interactioni

    Subunit structurei

    Interacts with human IKBKG (NEMO) and TNIP1 (ABIN-1). Interacts also with human and murine U2AF1 (U2AF35).3 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    itself3EBI-6125799,EBI-6125799
    IKBKGQ9Y6K98EBI-6125799,EBI-81279From a different organism.
    TNIP1Q150254EBI-6125799,EBI-357849From a different organism.

    Protein-protein interaction databases

    DIPiDIP-46341N.
    IntActiQ8VSC3. 2 interactions.
    MINTiMINT-7993760.
    STRINGi198214.CP0226.

    Structurei

    Secondary structure

    1
    545
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi254 – 2596
    Helixi264 – 27310
    Helixi274 – 2763
    Helixi283 – 29311
    Helixi305 – 31814
    Helixi320 – 35940
    Helixi366 – 38621
    Turni387 – 3893
    Helixi400 – 4089
    Turni409 – 4146
    Helixi434 – 44815
    Helixi451 – 4555
    Helixi458 – 4669
    Helixi469 – 48416
    Helixi486 – 49813
    Helixi504 – 53027

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    3L3PX-ray3.20A254-545[»]
    ProteinModelPortaliQ8VSC3.
    SMRiQ8VSC3. Positions 254-534.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Repeati57 – 7721LRR 1Add
    BLAST
    Repeati78 – 9922LRR 2Add
    BLAST
    Repeati100 – 11718LRR 3Add
    BLAST
    Repeati118 – 13922LRR 4Add
    BLAST
    Repeati140 – 15718LRR 5Add
    BLAST
    Repeati158 – 17922LRR 6Add
    BLAST
    Repeati182 – 20322LRR 7Add
    BLAST
    Repeati205 – 22824LRR 8Add
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 242242Interaction with target proteinsBy similarityAdd
    BLAST
    Regioni243 – 2508LinkerBy similarity
    Regioni251 – 545295E3 ubiquitin-protein ligase catalytic domainBy similarityAdd
    BLAST

    Domaini

    The LRR (leucine-rich repeat) domain forms a slightly curved solenoid and may mediate interaction with target proteins.By similarity

    Sequence similaritiesi

    Contains 8 LRR (leucine-rich) repeats.Curated

    Keywords - Domaini

    Leucine-rich repeat, Repeat

    Phylogenomic databases

    eggNOGiNOG148478.
    HOGENOMiHOG000264729.
    KOiK13791.
    OMAiISYNEIV.
    OrthoDBiEOG6103XQ.

    Family and domain databases

    InterProiIPR029487. NEL_dom.
    [Graphical view]
    PfamiPF14496. NEL. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q8VSC3-1 [UniParc]FASTAAdd to Basket

    « Hide

    MLPINNNFSL PQNSFYNTIS GTYADYFSAW DKWEKQALPG EERDEAVSRL    50
    KECLINNSDE LRLDRLNLSS LPDNLPAQIT LLNVSYNQLT NLPELPVTLK 100
    KLYSASNKLS ELPVLPPALE SLQVQHNELE NLPALPDSLL TMNISYNEIV 150
    SLPSLPQALK NLRATRNFLT ELPAFSEGNN PVVREYFFDR NQISHIPESI 200
    LNLRNECSIH ISDNPLSSHA LPALQRLTSS PDYHGPRIYF SMSDGQQNTL 250
    HRPLADAVTA WFPENKQSDV SQIWHAFEHE EHANTFSAFL DRLSDTVSAR 300
    NTSGFREQVA AWLEKLSASA ELRQQSFAVA ADATESCEDR VALTWNNLRK 350
    TLLVHQASEG LFDNDTGALL SLGREMFRLE ILEDIARDKV RTLHFVDEIE 400
    VYLAFQTMLA EKLQLSTAVK EMRFYGVSGV TANDLRTAEA MVRSREENEF 450
    TDWFSLWGPW HAVLKRTEAD RWAQAEEQKY EMLENEYPQR VADRLKASGL 500
    SGDADAEREA GAQVMRETEQ QIYRQLTDEV LALRLPENGS QLHHS 545
    Length:545
    Mass (Da):61,979
    Last modified:January 4, 2005 - v2
    Checksum:i5E70042D797B5099
    GO

    Sequence cautioni

    The sequence AAK18544.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.
    The sequence AAW64849.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti7 – 71Missing AA sequence (PubMed:11115111)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti222 – 2221P → Q in plasmid pWR100, plasmid pSF5 and plasmid pINV_F6_M1382.
    Natural varianti474 – 4741Q → L in plasmid pINV_F6_M1382.
    Natural varianti536 – 5361P → F in plasmid pWR100.
    Natural varianti536 – 5361P → S in plasmid pSF5.

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF047365 Genomic DNA. Translation: AAC23714.1.
    AL391753 Genomic DNA. Translation: CAC05853.1.
    AF348706 Genomic DNA. Translation: AAK18544.1. Different initiation.
    AY206445 Genomic DNA. Translation: AAP79029.1.
    AY879342 Genomic DNA. Translation: AAW64849.1. Different initiation.
    AF386526 Genomic DNA. Translation: AAL72345.2.
    RefSeqiNP_858359.2. NC_004851.1.
    WP_010921715.1. NC_019197.1.
    YP_006960318.1. NC_019197.1.

    Genome annotation databases

    EnsemblBacteriaiAAL72345; AAL72345; CP0226.
    GeneIDi1238048.
    13917118.
    KEGGisfl:CP0226.
    PATRICi18722784. VBIShiFle86970_5483.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF047365 Genomic DNA. Translation: AAC23714.1 .
    AL391753 Genomic DNA. Translation: CAC05853.1 .
    AF348706 Genomic DNA. Translation: AAK18544.1 . Different initiation.
    AY206445 Genomic DNA. Translation: AAP79029.1 .
    AY879342 Genomic DNA. Translation: AAW64849.1 . Different initiation.
    AF386526 Genomic DNA. Translation: AAL72345.2 .
    RefSeqi NP_858359.2. NC_004851.1.
    WP_010921715.1. NC_019197.1.
    YP_006960318.1. NC_019197.1.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    3L3P X-ray 3.20 A 254-545 [» ]
    ProteinModelPortali Q8VSC3.
    SMRi Q8VSC3. Positions 254-534.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    DIPi DIP-46341N.
    IntActi Q8VSC3. 2 interactions.
    MINTi MINT-7993760.
    STRINGi 198214.CP0226.

    Proteomic databases

    PRIDEi Q8VSC3.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    EnsemblBacteriai AAL72345 ; AAL72345 ; CP0226 .
    GeneIDi 1238048.
    13917118.
    KEGGi sfl:CP0226.
    PATRICi 18722784. VBIShiFle86970_5483.

    Phylogenomic databases

    eggNOGi NOG148478.
    HOGENOMi HOG000264729.
    KOi K13791.
    OMAi ISYNEIV.
    OrthoDBi EOG6103XQ.

    Family and domain databases

    InterProi IPR029487. NEL_dom.
    [Graphical view ]
    Pfami PF14496. NEL. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Induction of type III secretion in Shigella flexneri is associated with differential control of transcription of genes encoding secreted proteins."
      Demers B., Sansonetti P.J., Parsot C.
      EMBO J. 17:2894-2903(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF 1-12 AND 480-494, INDUCTION.
      Strain: M90T / Serotype 5a.
      Plasmid: pWR100
    2. "The virulence plasmid pWR100 and the repertoire of proteins secreted by the type III secretion apparatus of Shigella flexneri."
      Buchrieser C., Glaser P., Rusniok C., Nedjari H., d'Hauteville H., Kunst F., Sansonetti P.J., Parsot C.
      Mol. Microbiol. 38:760-771(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF 1-9, SUBCELLULAR LOCATION.
      Strain: M90T / Serotype 5a.
      Plasmid: pWR100
    3. "Complete DNA sequence and analysis of the large virulence plasmid of Shigella flexneri."
      Venkatesan M.M., Goldberg M.B., Rose D.J., Grotbeck E.J., Burland V., Blattner F.R.
      Infect. Immun. 69:3271-3285(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: M90T / Serotype 5a.
      Plasmid: pWR100
    4. "Comparison of two major forms of the Shigella virulence plasmid pINV: positive selection is a major force driving the divergence."
      Lan R., Stevenson G., Reeves P.R.
      Infect. Immun. 71:6298-6306(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: M1382 / Serotype 6.
      Plasmid: pINV_F6_M1382
    5. "Comparison of the virulence plasmid genomes of two strains of Shigella which lost the ability to bind Congo red."
      Xiong Z., Tang X., Yang F., Zhang X., Yang J., Chen L., Nie H., Yan Y., Jiang Y., Wang J., Xue Y., Xu X., Zhu Y., Dong J., An L., Wang X., Jin Q.
      Sci. China, Ser. C, Life Sci. 49:141-148(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
      Strain: Serotype 5.
      Plasmid: pSF5
    6. "Genome sequence of Shigella flexneri 2a: insights into pathogenicity through comparison with genomes of Escherichia coli K12 and O157."
      Jin Q., Yuan Z., Xu J., Wang Y., Shen Y., Lu W., Wang J., Liu H., Yang J., Yang F., Zhang X., Zhang J., Yang G., Wu H., Qu D., Dong J., Sun L., Xue Y.
      , Zhao A., Gao Y., Zhu J., Kan B., Ding K., Chen S., Cheng H., Yao Z., He B., Chen R., Ma D., Qiang B., Wen Y., Hou Y., Yu J.
      Nucleic Acids Res. 30:4432-4441(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: 301 / Serotype 2a.
      Plasmid: pCP301
    7. "Shigella protein IpaH(9.8) is secreted from bacteria within mammalian cells and transported to the nucleus."
      Toyotome T., Suzuki T., Kuwae A., Nonaka T., Fukuda H., Imajoh-Ohmi S., Toyofuku T., Hori M., Sasakawa C.
      J. Biol. Chem. 276:32071-32079(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, SECRETION VIA TYPE III SECRETION SYSTEM.
      Strain: YSH6000 / Serotype 2a.
    8. "Shigella effector IpaH9.8 binds to a splicing factor U2AF(35) to modulate host immune responses."
      Okuda J., Toyotome T., Kataoka N., Ohno M., Abe H., Shimura Y., Seyedarabi A., Pickersgill R., Sasakawa C.
      Biochem. Biophys. Res. Commun. 333:531-539(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DISRUPTION PHENOTYPE, INTERACTION WITH MURINE U2AF1.
      Strain: YSH6000 / Serotype 2a.
    9. "Type III secretion effectors of the IpaH family are E3 ubiquitin ligases."
      Rohde J.R., Breitkreutz A., Chenal A., Sansonetti P.J., Parsot C.
      Cell Host Microbe 1:77-83(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS A LIGASE, MUTAGENESIS OF CYS-337.
    10. "A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response."
      Ashida H., Kim M., Schmidt-Supprian M., Ma A., Ogawa M., Sasakawa C.
      Nat. Cell Biol. 12:66-73(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH HOST IKBKG AND TNIP1, MUTAGENESIS OF CYS-337.
      Strain: YSH6000 / Serotype 2a.
    11. "Structure of an SspH1-PKN1 complex reveals the basis for host substrate recognition and mechanism of activation for a bacterial E3 ubiquitin ligase."
      Keszei A.F., Tang X., McCormick C., Zeqiraj E., Rohde J.R., Tyers M., Sicheri F.
      Mol. Cell. Biol. 34:362-373(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: MUTAGENESIS OF ARG-163; PHE-187; HIS-210 AND CYS-337, ACTIVE SITE, FUNCTION.
      Strain: M90T / Serotype 5a.
      Plasmid: pWR100
    12. "A disulfide driven domain swap switches off the activity of Shigella IpaH9.8 E3 ligase."
      Seyedarabi A., Sullivan J.A., Sasakawa C., Pickersgill R.W.
      FEBS Lett. 584:4163-4168(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (3.20 ANGSTROMS) OF 254-545, FUNCTION, INTERACTION WITH HUMAN U2AF1, AUTOUBIQUITINATION, ENZYME REGULATION.
      Strain: YSH6000 / Serotype 2a.

    Entry informationi

    Entry nameiIPA9_SHIFL
    AccessioniPrimary (citable) accession number: Q8VSC3
    Secondary accession number(s): O85159
    , Q2TH74, Q6XVV1, Q9AFM5, Q9AJV1
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 13, 2010
    Last sequence update: January 4, 2005
    Last modified: October 1, 2014
    This is version 69 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

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

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3