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Protein

Exotoxin A

Gene

eta

Organism
Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

An NAD-dependent ADP-ribosyltransferase (ADPRT). Catalyzes the transfer of the ADP ribosyl moiety of oxidized NAD (NAD+) onto eukaryotic elongation factor 2 (eEF-2) thus arresting protein synthesis. Has an LD50 of 65 ng/ml against the human lung epithelial cell line C38.1 Publication

Catalytic activityi

NAD+ + diphthamide-[translation elongation factor 2] = nicotinamide + N-(ADP-D-ribosyl)diphthamide-[translation elongation factor 2].

Enzyme regulationi

Inhibited by 1,8-naphthalimide (NAP) as well as a number of poly(ADP-ribose) polymerase inhibitors and other compounds.1 Publication

Kineticsi

For ADP-ribosyltransferase activity of the catalytic fragment 399-605.

  1. KM=121 µM for NAD

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei474 – 4741NAD1 Publication
    Active sitei578 – 57811 Publication
    Binding sitei578 – 5781NAD1 Publication

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi465 – 4673NAD1 Publication
    Nucleotide bindingi479 – 4857NAD1 Publication

    GO - Molecular functioni

    • NAD+-diphthamide ADP-ribosyltransferase activity Source: CACAO

    GO - Biological processi

    • metabolic process Source: GOC
    Complete GO annotation...

    Keywords - Molecular functioni

    Glycosyltransferase, Toxin, Transferase

    Keywords - Ligandi

    NAD

    Enzyme and pathway databases

    BioCyciMetaCyc:MONOMER-15587.
    BRENDAi2.4.2.36. 5087.
    SABIO-RKP11439.

    Protein family/group databases

    TCDBi1.C.73.1.1. the pseudomonas exotoxin a (p-exoa) family.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Exotoxin A (EC:2.4.2.36)
    Short name:
    ETA
    Alternative name(s):
    NAD(+)--diphthamide ADP-ribosyltransferase
    PE
    Gene namesi
    Name:eta
    Ordered Locus Names:PA1148
    OrganismiPseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
    Taxonomic identifieri208964 [NCBI]
    Taxonomic lineageiBacteriaProteobacteriaGammaproteobacteriaPseudomonadalesPseudomonadaceaePseudomonas
    ProteomesiUP000002438 Componenti: Chromosome

    Organism-specific databases

    PseudoCAPiPA1148.

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi82 – 821K → E: Loss of toxicity, no binding to LRP1 receptor. 1 Publication
    Mutagenesisi481 – 4811R → H: 52-fold decrease in ADPRT activity, 55-fold reduction in GH activity, 31-fold increase in dissociation constant for NAD(+). 1 Publication
    Mutagenesisi571 – 5711E → A: 833-fold decrease in ADPRT activity, 4-fold reduction in GH activity, 2-fold increase in dissociation constant for NAD(+). 1 Publication
    Mutagenesisi576 – 5761R → A: 2-fold decrease in ADPRT activity, 14-fold reduction in GH activity, 3-fold increase in dissociation constant for NAD(+). 1 Publication
    Mutagenesisi578 – 5781E → A: 666-fold decrease in ADPRT activity, 14-fold reduction in GH activity, 2-fold increase in dissociation constant for NAD(+), loss of toxicity against mouse cells. 2 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 25251 PublicationAdd
    BLAST
    Chaini26 – 638613Exotoxin APRO_0000019365Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi290 ↔ 3121 Publication

    Post-translational modificationi

    The 8 cysteines participate in intrachain disulfide bonds.

    Keywords - PTMi

    Disulfide bond

    Interactioni

    Protein-protein interaction databases

    STRINGi208964.PA1148.

    Structurei

    Secondary structure

    1
    638
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi32 – 354Combined sources
    Beta strandi36 – 438Combined sources
    Beta strandi49 – 546Combined sources
    Helixi57 – 604Combined sources
    Beta strandi63 – 7412Combined sources
    Turni76 – 794Combined sources
    Beta strandi80 – 856Combined sources
    Turni86 – 883Combined sources
    Beta strandi89 – 935Combined sources
    Beta strandi95 – 1028Combined sources
    Beta strandi106 – 1083Combined sources
    Beta strandi110 – 1156Combined sources
    Beta strandi117 – 1204Combined sources
    Beta strandi122 – 13110Combined sources
    Beta strandi136 – 14510Combined sources
    Beta strandi151 – 1544Combined sources
    Beta strandi157 – 1615Combined sources
    Helixi164 – 1707Combined sources
    Beta strandi173 – 1808Combined sources
    Beta strandi189 – 20113Combined sources
    Helixi213 – 2164Combined sources
    Helixi218 – 2236Combined sources
    Helixi225 – 2273Combined sources
    Helixi230 – 2356Combined sources
    Helixi243 – 2464Combined sources
    Beta strandi249 – 2557Combined sources
    Beta strandi270 – 2734Combined sources
    Helixi280 – 29011Combined sources
    Helixi294 – 2985Combined sources
    Helixi307 – 3115Combined sources
    Helixi313 – 32513Combined sources
    Helixi330 – 3323Combined sources
    Helixi333 – 34210Combined sources
    Turni344 – 3474Combined sources
    Helixi348 – 3569Combined sources
    Helixi358 – 37619Combined sources
    Helixi384 – 3874Combined sources
    Beta strandi392 – 3965Combined sources
    Beta strandi399 – 4035Combined sources
    Helixi408 – 4103Combined sources
    Beta strandi413 – 4186Combined sources
    Helixi422 – 4243Combined sources
    Beta strandi428 – 4303Combined sources
    Beta strandi433 – 4353Combined sources
    Beta strandi438 – 4403Combined sources
    Helixi444 – 45613Combined sources
    Beta strandi459 – 4679Combined sources
    Helixi469 – 4779Combined sources
    Helixi489 – 4913Combined sources
    Beta strandi493 – 4997Combined sources
    Helixi500 – 5045Combined sources
    Beta strandi522 – 5298Combined sources
    Helixi530 – 5356Combined sources
    Beta strandi536 – 5383Combined sources
    Beta strandi543 – 5453Combined sources
    Helixi548 – 5569Combined sources
    Beta strandi558 – 5614Combined sources
    Beta strandi566 – 5727Combined sources
    Beta strandi577 – 5815Combined sources
    Helixi583 – 5875Combined sources
    Beta strandi590 – 5934Combined sources
    Helixi609 – 6113Combined sources
    Helixi614 – 6174Combined sources
    Beta strandi626 – 6283Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1AERX-ray2.30A/B425-634[»]
    1DMAX-ray2.50A/B425-638[»]
    1IKPX-ray1.45A26-638[»]
    1IKQX-ray1.62A26-638[»]
    1XK9X-ray2.10A/B424-638[»]
    1ZM2X-ray3.07B/D/F424-630[»]
    1ZM3X-ray3.07B/D/F424-630[»]
    1ZM4X-ray2.90B/D/F424-630[»]
    1ZM9X-ray2.80B/D/F424-630[»]
    2ZITX-ray3.00B/D/F425-630[»]
    3B78X-ray2.50B/D/F425-630[»]
    3B82X-ray2.35B/D/F425-630[»]
    3B8HX-ray2.50B/D/F425-630[»]
    ProteinModelPortaliP11439.
    SMRiP11439. Positions 27-631.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP11439.

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni26 – 277252IA (required for target cell recognition)Add
    BLAST
    Regioni278 – 389112II (required for translocation in target cell cytoplasm)Add
    BLAST
    Regioni390 – 42940IBAdd
    BLAST
    Regioni430 – 638209III (required for ADP-ribosyl activity)Add
    BLAST

    Keywords - Domaini

    Signal

    Phylogenomic databases

    HOGENOMiHOG000081585.
    KOiK11020.
    OMAiHESNEMQ.
    OrthoDBiEOG6ZPSVM.

    Family and domain databases

    Gene3Di2.60.120.200. 1 hit.
    3.90.1350.10. 1 hit.
    InterProiIPR013320. ConA-like_dom.
    IPR015185. Exotox-A_bind.
    IPR015099. Exotox-A_cataly_dom.
    IPR015186. Exotox-A_middle_dom.
    [Graphical view]
    PfamiPF09101. Exotox-A_bind. 1 hit.
    PF09009. Exotox-A_cataly. 1 hit.
    PF09102. Exotox-A_target. 1 hit.
    [Graphical view]
    SUPFAMiSSF49899. SSF49899. 1 hit.
    SSF56864. SSF56864. 1 hit.

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P11439-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MHLTPHWIPL VASLGLLAGG SFASAAEEAF DLWNECAKAC VLDLKDGVRS
    60 70 80 90 100
    SRMSVDPAIA DTNGQGVLHY SMVLEGGNDA LKLAIDNALS ITSDGLTIRL
    110 120 130 140 150
    EGGVEPNKPV RYSYTRQARG SWSLNWLVPI GHEKPSNIKV FIHELNAGNQ
    160 170 180 190 200
    LSHMSPIYTI EMGDELLAKL ARDATFFVRA HESNEMQPTL AISHAGVSVV
    210 220 230 240 250
    MAQAQPRREK RWSEWASGKV LCLLDPLDGV YNYLAQQRCN LDDTWEGKIY
    260 270 280 290 300
    RVLAGNPAKH DLDIKPTVIS HRLHFPEGGS LAALTAHQAC HLPLETFTRH
    310 320 330 340 350
    RQPRGWEQLE QCGYPVQRLV ALYLAARLSW NQVDQVIRNA LASPGSGGDL
    360 370 380 390 400
    GEAIREQPEQ ARLALTLAAA ESERFVRQGT GNDEAGAASA DVVSLTCPVA
    410 420 430 440 450
    AGECAGPADS GDALLERNYP TGAEFLGDGG DISFSTRGTQ NWTVERLLQA
    460 470 480 490 500
    HRQLEERGYV FVGYHGTFLE AAQSIVFGGV RARSQDLDAI WRGFYIAGDP
    510 520 530 540 550
    ALAYGYAQDQ EPDARGRIRN GALLRVYVPR SSLPGFYRTG LTLAAPEAAG
    560 570 580 590 600
    EVERLIGHPL PLRLDAITGP EEEGGRLETI LGWPLAERTV VIPSAIPTDP
    610 620 630
    RNVGGDLDPS SIPDKEQAIS ALPDYASQPG KPPREDLK
    Length:638
    Mass (Da):69,284
    Last modified:January 11, 2001 - v2
    Checksum:i7B9AAD56A27C700A
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti4 – 41T → I in AAB59097 (PubMed:6201861).Curated
    Sequence conflicti22 – 221F → S in AAB59097 (PubMed:6201861).Curated
    Sequence conflicti204 – 2041A → T in AAB59097 (PubMed:6201861).Curated
    Sequence conflicti389 – 3891S → N in AAB59097 (PubMed:6201861).Curated
    Sequence conflicti432 – 4321I → V in AAB59097 (PubMed:6201861).Curated
    Sequence conflicti540 – 5401G → S in AAB59097 (PubMed:6201861).Curated

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    K01397 Genomic DNA. Translation: AAB59097.1.
    AE004091 Genomic DNA. Translation: AAG04537.1.
    PIRiA30347.
    C83503.
    RefSeqiNP_249839.1. NC_002516.2.
    WP_003112478.1. NC_002516.2.

    Genome annotation databases

    EnsemblBacteriaiAAG04537; AAG04537; PA1148.
    GeneIDi877850.
    KEGGipae:PA1148.
    PATRICi19836616. VBIPseAer58763_1194.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    K01397 Genomic DNA. Translation: AAB59097.1.
    AE004091 Genomic DNA. Translation: AAG04537.1.
    PIRiA30347.
    C83503.
    RefSeqiNP_249839.1. NC_002516.2.
    WP_003112478.1. NC_002516.2.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1AERX-ray2.30A/B425-634[»]
    1DMAX-ray2.50A/B425-638[»]
    1IKPX-ray1.45A26-638[»]
    1IKQX-ray1.62A26-638[»]
    1XK9X-ray2.10A/B424-638[»]
    1ZM2X-ray3.07B/D/F424-630[»]
    1ZM3X-ray3.07B/D/F424-630[»]
    1ZM4X-ray2.90B/D/F424-630[»]
    1ZM9X-ray2.80B/D/F424-630[»]
    2ZITX-ray3.00B/D/F425-630[»]
    3B78X-ray2.50B/D/F425-630[»]
    3B82X-ray2.35B/D/F425-630[»]
    3B8HX-ray2.50B/D/F425-630[»]
    ProteinModelPortaliP11439.
    SMRiP11439. Positions 27-631.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi208964.PA1148.

    Protein family/group databases

    TCDBi1.C.73.1.1. the pseudomonas exotoxin a (p-exoa) family.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblBacteriaiAAG04537; AAG04537; PA1148.
    GeneIDi877850.
    KEGGipae:PA1148.
    PATRICi19836616. VBIPseAer58763_1194.

    Organism-specific databases

    PseudoCAPiPA1148.

    Phylogenomic databases

    HOGENOMiHOG000081585.
    KOiK11020.
    OMAiHESNEMQ.
    OrthoDBiEOG6ZPSVM.

    Enzyme and pathway databases

    BioCyciMetaCyc:MONOMER-15587.
    BRENDAi2.4.2.36. 5087.
    SABIO-RKP11439.

    Miscellaneous databases

    EvolutionaryTraceiP11439.

    Family and domain databases

    Gene3Di2.60.120.200. 1 hit.
    3.90.1350.10. 1 hit.
    InterProiIPR013320. ConA-like_dom.
    IPR015185. Exotox-A_bind.
    IPR015099. Exotox-A_cataly_dom.
    IPR015186. Exotox-A_middle_dom.
    [Graphical view]
    PfamiPF09101. Exotox-A_bind. 1 hit.
    PF09009. Exotox-A_cataly. 1 hit.
    PF09102. Exotox-A_target. 1 hit.
    [Graphical view]
    SUPFAMiSSF49899. SSF49899. 1 hit.
    SSF56864. SSF56864. 1 hit.
    ProtoNetiSearch...

    Publicationsi

    « Hide 'large scale' publications
    1. "Cloning, nucleotide sequence, and expression in Escherichia coli of the exotoxin A structural gene of Pseudomonas aeruginosa."
      Gray G.L., Smith D.H., Baldridge J.S., Harkins R.N., Vasil M.L., Chen E.Y., Heyneker H.L.
      Proc. Natl. Acad. Sci. U.S.A. 81:2645-2649(1984) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF 26-53.
    2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228.
    3. "Active site of Pseudomonas aeruginosa exotoxin A. Glutamic acid 553 is photolabeled by NAD and shows functional homology with glutamic acid 148 of diphtheria toxin."
      Carroll S.F., Collier R.J.
      J. Biol. Chem. 262:8707-8711(1987) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACTIVE SITE.
    4. "Mutagenesis of Pseudomonas exotoxin in identification of sequences responsible for the animal toxicity."
      Chaudhary V.K., Jinno Y., Galo M.G., Fitzgerald D., Pastan I.
      J. Biol. Chem. 265:16306-16310(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: DOMAINS.
    5. "Biochemical and immunochemical studies of proteolytic fragments of exotoxin A from Pseudomonas aeruginosa."
      Bourdenet S., Vacheron M.-J., Guinand M., Michel G., Arminjon F.
      Eur. J. Biochem. 192:379-385(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: DOMAINS.
    6. "The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A."
      Kounnas M.Z., Morris R.E., Thompson M.R., FitzGerald D.J., Strickland D.K., Saelinger C.B.
      J. Biol. Chem. 267:12420-12423(1992) [PubMed] [Europe PMC] [Abstract]
      Cited for: RECEPTOR-BINDING, MUTAGENESIS OF LYS-82.
    7. "Reduction of furin-nicked Pseudomonas exotoxin A: an unfolding story."
      McKee M.L., FitzGerald D.J.
      Biochemistry 38:16507-16513(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISULFIDE BOND.
    8. Cited for: FUNCTION AS A TOXIN, FUNCTION AS A GLYCOHYDROLASE, FUNCTION AS AN ADP-RIBOSYLTRANSFERASE, MUTAGENESIS OF GLU-578.
    9. "Newly discovered and characterized antivirulence compounds inhibit bacterial mono-ADP-ribosyltransferase toxins."
      Turgeon Z., Jorgensen R., Visschedyk D., Edwards P.R., Legree S., McGregor C., Fieldhouse R.J., Mangroo D., Schapira M., Merrill A.R.
      Antimicrob. Agents Chemother. 55:983-991(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION, LETHAL DOSE.
    10. "The crystal structure of Pseudomonas aeruginosa exotoxin domain III with nicotinamide and AMP: conformational differences with the intact exotoxin."
      Li M., Dyda F., Benhar I., Pastan I., Davies D.R.
      Proc. Natl. Acad. Sci. U.S.A. 92:9308-9312(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 424-638.
    11. "Crystal structure of the catalytic domain of Pseudomonas exotoxin A complexed with a nicotinamide adenine dinucleotide analog: implications for the activation process and for ADP ribosylation."
      Li M., Dyda F., Benhar I., Pastan I., Davies D.R.
      Proc. Natl. Acad. Sci. U.S.A. 93:6902-6906(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 424-638.
    12. "The nature and character of the transition state for the ADP-ribosyltransferase reaction."
      Jorgensen R., Wang Y., Visschedyk D., Merrill A.R.
      EMBO Rep. 9:802-809(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 425-630 IN COMPLEX WITH YEAST EEF2 AND NAD, MUTAGENESIS OF ARG-481; GLU-571; ARG-576 AND GLU-578.

    Entry informationi

    Entry nameiTOXA_PSEAE
    AccessioniPrimary (citable) accession number: P11439
    Secondary accession number(s): Q9I4I7
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1989
    Last sequence update: January 11, 2001
    Last modified: May 27, 2015
    This is version 127 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, Reference proteome

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references

    External Data

    Dasty 3

    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 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.