ID   CHTA_VIBCH              Reviewed;         258 AA.
AC   P01555; Q56634; Q9JPV1;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   23-OCT-1986, sequence version 1.
DT   27-MAR-2024, entry version 165.
DE   RecName: Full=Cholera enterotoxin subunit A;
DE   AltName: Full=Cholera enterotoxin, A chain;
DE   Contains:
DE     RecName: Full=Cholera enterotoxin subunit A1;
DE              EC=2.4.2.-;
DE     AltName: Full=Cholera enterotoxin A1 chain;
DE     AltName: Full=Cholera enterotoxin alpha chain;
DE     AltName: Full=NAD(+)--diphthamide ADP-ribosyltransferase;
DE   Contains:
DE     RecName: Full=Cholera enterotoxin subunit A2;
DE     AltName: Full=Cholera enterotoxin A2 chain;
DE     AltName: Full=Cholera enterotoxin gamma chain;
DE   Flags: Precursor;
GN   Name=ctxA; Synonyms=toxA; OrderedLocusNames=VC_1457;
OS   Vibrio cholerae serotype O1 (strain ATCC 39315 / El Tor Inaba N16961).
OC   Bacteria; Pseudomonadota; Gammaproteobacteria; Vibrionales; Vibrionaceae;
OC   Vibrio.
OX   NCBI_TaxID=243277;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=ATCC 39050 / El Tor Inaba 2125 / Serotype O1;
RX   PubMed=6646234; DOI=10.1038/306551a0;
RA   Mekalanos J.J., Swartz D.J., Pearson G.D.N., Harford N., Groyne F.,
RA   de Wilde M.;
RT   "Cholera toxin genes: nucleotide sequence, deletion analysis and vaccine
RT   development.";
RL   Nature 306:551-557(1983).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=ATCC 25870 / Classical Inaba 569B / Serotype O1;
RX   PubMed=1883840; DOI=10.1016/0167-4781(91)90050-v;
RA   Dams E., de Wolf M., Dierick W.;
RT   "Nucleotide sequence analysis of the CT operon of the Vibrio cholerae
RT   classical strain 569B.";
RL   Biochim. Biophys. Acta 1090:139-141(1991).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=1854 / O139-Bengal;
RA   Yamamoto K., Do V.G.R.F., Xu M., Iida T., Miwatani T., Albert M.J.,
RA   Honda T.;
RL   Submitted (MAY-1994) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=ATCC 39050 / El Tor Inaba 2125 / Serotype O1;
RA   Dams E., de Wolf M., Dierick W.;
RL   Submitted (MAY-1991) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=KNIH002;
RA   Shin H.J., Park Y.C., Kim Y.C.;
RT   "Cloning and nucleotide sequence analysis of the virulence gene cassette
RT   from Vibrio cholerae KNIH002 isolated in Korea.";
RL   Misainmurhag Hoiji 35:205-210(1999).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 39315 / El Tor Inaba N16961;
RX   PubMed=10952301; DOI=10.1038/35020000;
RA   Heidelberg J.F., Eisen J.A., Nelson W.C., Clayton R.A., Gwinn M.L.,
RA   Dodson R.J., Haft D.H., Hickey E.K., Peterson J.D., Umayam L.A., Gill S.R.,
RA   Nelson K.E., Read T.D., Tettelin H., Richardson D.L., Ermolaeva M.D.,
RA   Vamathevan J.J., Bass S., Qin H., Dragoi I., Sellers P., McDonald L.A.,
RA   Utterback T.R., Fleischmann R.D., Nierman W.C., White O., Salzberg S.L.,
RA   Smith H.O., Colwell R.R., Mekalanos J.J., Venter J.C., Fraser C.M.;
RT   "DNA sequence of both chromosomes of the cholera pathogen Vibrio
RT   cholerae.";
RL   Nature 406:477-483(2000).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-212.
RC   STRAIN=ATCC 25870 / Classical Inaba 569B / Serotype O1;
RX   PubMed=6090390; DOI=10.1128/jb.159.3.1086-1089.1984;
RA   Lockman H.A., Galen J.E., Kaper J.B.;
RT   "Vibrio cholerae enterotoxin genes: nucleotide sequence analysis of DNA
RT   encoding ADP-ribosyltransferase.";
RL   J. Bacteriol. 159:1086-1089(1984).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 213-258.
RX   PubMed=6315707; DOI=10.1016/s0021-9258(17)43977-9;
RA   Lockman H., Kaper J.B.;
RT   "Nucleotide sequence analysis of the A2 and B subunits of Vibrio cholerae
RT   enterotoxin.";
RL   J. Biol. Chem. 258:13722-13726(1983).
RN   [9]
RP   PROTEIN SEQUENCE OF 19-27.
RX   PubMed=7238869; DOI=10.1016/0014-5793(81)80238-4;
RA   Duffy L.K., Peterson J.W., Kurosky A.;
RT   "Isolation and characterization of a precursor form of the 'A' subunit of
RT   cholera toxin.";
RL   FEBS Lett. 126:187-190(1981).
RN   [10]
RP   PROTEIN SEQUENCE OF 19-38 AND 213-232.
RX   PubMed=955672; DOI=10.1016/0019-2791(76)90173-7;
RA   Klapper D.G., Finkelstein R.A., Capra J.D.;
RT   "Subunit structure and N-terminal amino acid sequence of the three chains
RT   of cholera enterotoxin.";
RL   Immunochemistry 13:605-611(1976).
RN   [11]
RP   PROTEIN SEQUENCE OF 27-72 AND 111-139.
RX   PubMed=437113; DOI=10.1016/0014-5793(79)81136-9;
RA   Lai C.-Y., Cancedda F., Chang D.;
RT   "Primary structure of cholera toxin subunit A1: isolation, partial
RT   sequences and alignment of the BrCN fragments.";
RL   FEBS Lett. 100:85-89(1979).
RN   [12]
RP   PROTEIN SEQUENCE OF 213-258.
RX   PubMed=7028752; DOI=10.1016/s0021-9258(18)43262-0;
RA   Duffy L.K., Peterson J.W., Kurosky A.;
RT   "Covalent structure of the gamma chain of the A subunit of cholera toxin.";
RL   J. Biol. Chem. 256:12252-12256(1981).
RN   [13]
RP   INTERACTION BETWEEN CHOLERA TOXIN AND ADENYLATE CYCLASE.
RX   PubMed=4323551; DOI=10.1038/229266a0;
RA   Sharp G.W., Hynie S.;
RT   "Stimulation of intestinal adenyl cyclase by cholera toxin.";
RL   Nature 229:266-269(1971).
RN   [14]
RP   SUBUNIT.
RX   PubMed=3214; DOI=10.1021/bi00651a011;
RA   Gill D.M.;
RT   "The arrangement of subunits in cholera toxin.";
RL   Biochemistry 15:1242-1248(1976).
RN   [15]
RP   TRANSPORT OF CHOLERA TOXIN WITHIN THE INTESTINAL CELL.
RX   PubMed=13679513; DOI=10.1091/mbc.e03-06-0354;
RA   Fujinaga Y., Wolf A.A., Rodighiero C., Wheeler H., Tsai B., Allen L.,
RA   Jobling M.G., Rapoport T., Holmes R.K., Lencer W.I.;
RT   "Gangliosides that associate with lipid rafts mediate transport of cholera
RT   and related toxins from the plasma membrane to endoplasmic reticulum.";
RL   Mol. Biol. Cell 14:4783-4793(2003).
RN   [16]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
RX   PubMed=7658473; DOI=10.1006/jmbi.1995.0456;
RA   Zhang R.-G., Scott D.L., Westbrook M.L., Nance S., Spangler B.D.,
RA   Shipley G.G., Westbrook E.M.;
RT   "The three-dimensional crystal structure of cholera toxin.";
RL   J. Mol. Biol. 251:563-573(1995).
RN   [17]
RP   X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 19-210 IN COMPLEX WITH NAD AND
RP   HUMAN ARF6, AND SUBUNIT.
RX   PubMed=16099990; DOI=10.1126/science.1113398;
RA   O'Neal C.J., Jobling M.G., Holmes R.K., Hol W.G.;
RT   "Structural basis for the activation of cholera toxin by human ARF6-GTP.";
RL   Science 309:1093-1096(2005).
CC   -!- FUNCTION: The A1 chain catalyzes the ADP-ribosylation of Gs alpha, a
CC       GTP-binding regulatory protein, to activate the adenylate cyclase. This
CC       leads to an overproduction of cAMP and eventually to a hypersecretion
CC       of chloride and bicarbonate followed by water, resulting in the
CC       characteristic cholera stool. The A2 chain tethers A1 to the pentameric
CC       ring.
CC   -!- SUBUNIT: The holotoxin (choleragen) consists of a pentameric ring of B
CC       subunits whose central pore is occupied by the A subunit. The A subunit
CC       contains two chains, A1 and A2, linked by a disulfide bridge.
CC       Interaction with the host protein ARF6 causes a conformation change so
CC       that the enterotoxin subunit A1 can bind NAD and catalyze the ADP-
CC       ribosylation of the host Gs alpha. {ECO:0000269|PubMed:16099990,
CC       ECO:0000269|PubMed:3214}.
CC   -!- INTERACTION:
CC       P01555; P01556: ctxB; NbExp=5; IntAct=EBI-1038392, EBI-1038383;
CC   -!- DOMAIN: The four C-terminal residues of the A2 chain occupy the central
CC       pore of the holotoxin. Deletion of these residues weakens the
CC       interaction between the A subunit and the B pentamer without impairing
CC       the pentamer formation.
CC   -!- MISCELLANEOUS: After binding to gangliosides GM1 in lipid rafts,
CC       through the subunit B pentamer, the holotoxin and the gangliosides are
CC       internalized. The holotoxin remains bound to GM1 until arrival in the
CC       ER. The A subunit has previously been cleaved in the intestinal lumen
CC       but the A1 and A2 chains have remained associated. In the ER, the A
CC       subunit disulfide bridge is reduced, the A1 chain is unfolded by the
CC       PDI and disassembled from the rest of the toxin. Then, the membrane-
CC       associated ER oxidase ERO1 oxidizes PDI, which releases the unfolded A1
CC       chain. The next step is the retrotranslocation of A1 into the cytosol.
CC       This might be mediated by the protein-conducting pore SEC61. Upon
CC       arrival in the cytosol, A1 refolds and avoids proteasome degradation.
CC       In one way or another, A1 finally reaches its target and induces
CC       toxicity.
CC   -!- SIMILARITY: Belongs to the enterotoxin A family. {ECO:0000305}.
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DR   EMBL; X00171; CAA24995.1; -; Genomic_DNA.
DR   EMBL; X58785; CAA41590.1; -; Genomic_DNA.
DR   EMBL; D30053; BAA06290.1; -; Genomic_DNA.
DR   EMBL; X58786; CAA41592.1; -; Genomic_DNA.
DR   EMBL; K02679; AAA27514.1; -; Genomic_DNA.
DR   EMBL; AF175708; AAD51359.1; -; Genomic_DNA.
DR   EMBL; AE003852; AAF94614.1; -; Genomic_DNA.
DR   EMBL; K01170; AAA27572.1; -; Genomic_DNA.
DR   EMBL; D30052; BAA06288.1; -; Genomic_DNA.
DR   PIR; A05129; XVVCA.
DR   RefSeq; NP_231100.1; NC_002505.1.
DR   RefSeq; WP_001881225.1; NZ_LT906614.1.
DR   PDB; 1S5B; X-ray; 2.13 A; A=19-258.
DR   PDB; 1S5C; X-ray; 2.50 A; A=19-258.
DR   PDB; 1S5D; X-ray; 1.75 A; A=19-258.
DR   PDB; 1S5E; X-ray; 1.90 A; A/B=19-258.
DR   PDB; 1S5F; X-ray; 2.60 A; A=19-258.
DR   PDB; 1XTC; X-ray; 2.40 A; A=19-212, C=213-258.
DR   PDB; 2A5D; X-ray; 1.80 A; B=19-210.
DR   PDB; 2A5F; X-ray; 2.02 A; B=19-210.
DR   PDB; 2A5G; X-ray; 2.66 A; B=19-210.
DR   PDBsum; 1S5B; -.
DR   PDBsum; 1S5C; -.
DR   PDBsum; 1S5D; -.
DR   PDBsum; 1S5E; -.
DR   PDBsum; 1S5F; -.
DR   PDBsum; 1XTC; -.
DR   PDBsum; 2A5D; -.
DR   PDBsum; 2A5F; -.
DR   PDBsum; 2A5G; -.
DR   AlphaFoldDB; P01555; -.
DR   BMRB; P01555; -.
DR   SMR; P01555; -.
DR   ComplexPortal; CPX-2345; Cholera toxin.
DR   DIP; DIP-6255N; -.
DR   ELM; P01555; -.
DR   IntAct; P01555; 2.
DR   STRING; 243277.VC_1457; -.
DR   DNASU; 2613963; -.
DR   EnsemblBacteria; AAF94614; AAF94614; VC_1457.
DR   KEGG; vch:VC_1457; -.
DR   PATRIC; fig|243277.26.peg.1387; -.
DR   eggNOG; ENOG5033C2P; Bacteria.
DR   HOGENOM; CLU_091751_0_0_6; -.
DR   BioCyc; MetaCyc:FY484_RS07330-MONOMER; -.
DR   EvolutionaryTrace; P01555; -.
DR   PHI-base; PHI:698; -.
DR   PRO; PR:P01555; -.
DR   Proteomes; UP000000584; Chromosome 1.
DR   GO; GO:1902494; C:catalytic complex; IMP:CAFA.
DR   GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR   GO; GO:0042597; C:periplasmic space; IMP:CAFA.
DR   GO; GO:0005534; F:galactose binding; IMP:CAFA.
DR   GO; GO:0016757; F:glycosyltransferase activity; IEA:UniProtKB-KW.
DR   GO; GO:0008289; F:lipid binding; IDA:DisProt.
DR   GO; GO:0016779; F:nucleotidyltransferase activity; IEA:UniProtKB-KW.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR   GO; GO:0051179; P:localization; IDA:DisProt.
DR   GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IDA:CACAO.
DR   DisProt; DP00250; -.
DR   Gene3D; 1.20.5.240; -; 1.
DR   Gene3D; 3.90.210.10; Heat-Labile Enterotoxin, subunit A; 1.
DR   InterPro; IPR001144; Enterotoxin_A.
DR   Pfam; PF01375; Enterotoxin_a; 1.
DR   PRINTS; PR00771; ENTEROTOXINA.
DR   SUPFAM; SSF56399; ADP-ribosylation; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Direct protein sequencing; Disulfide bond; Enterotoxin;
KW   Glycosyltransferase; NAD; Nucleotidyltransferase; Reference proteome;
KW   Signal; Toxin; Transferase; Virulence.
FT   SIGNAL          1..18
FT                   /evidence="ECO:0000269|PubMed:7238869,
FT                   ECO:0000269|PubMed:955672"
FT   CHAIN           19..212
FT                   /note="Cholera enterotoxin subunit A1"
FT                   /id="PRO_0000019342"
FT   CHAIN           213..258
FT                   /note="Cholera enterotoxin subunit A2"
FT                   /id="PRO_0000019343"
FT   ACT_SITE        130
FT                   /evidence="ECO:0000250"
FT   BINDING         25..28
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16099990"
FT   BINDING         41..43
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:16099990"
FT   DISULFID        205..217
FT                   /note="Interchain (between A1 and A2 chains)"
FT   CONFLICT        20
FT                   /note="D -> N (in Ref. 9; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        37
FT                   /note="S -> R (in Ref. 10; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        39
FT                   /note="G -> L (in Ref. 11; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        45..46
FT                   /note="QS -> SE (in Ref. 11; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        111
FT                   /note="N -> L (in Ref. 11; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        132
FT                   /note="S -> A (in Ref. 11; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        213
FT                   /note="M -> I (in Ref. 1; CAA24995)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        247..248
FT                   /note="DI -> ID (in Ref. 12; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        256
FT                   /note="D -> N (in Ref. 12; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   STRAND          22..29
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           31..37
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           43..45
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   STRAND          51..53
FT                   /evidence="ECO:0007829|PDB:1XTC"
FT   HELIX           59..64
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   STRAND          70..72
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   STRAND          77..83
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           84..94
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   TURN            95..97
FT                   /evidence="ECO:0007829|PDB:2A5D"
FT   STRAND          99..107
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   STRAND          112..114
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           115..119
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           120..122
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           126..128
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   STRAND          131..134
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           139..141
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   STRAND          142..149
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   STRAND          152..154
FT                   /evidence="ECO:0007829|PDB:1S5B"
FT   STRAND          156..159
FT                   /evidence="ECO:0007829|PDB:1S5B"
FT   HELIX           165..169
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           176..178
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           180..182
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           190..193
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           197..200
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           217..244
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   TURN            245..247
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   TURN            250..252
FT                   /evidence="ECO:0007829|PDB:1S5D"
FT   HELIX           254..257
FT                   /evidence="ECO:0007829|PDB:1XTC"
SQ   SEQUENCE   258 AA;  29336 MW;  0F7EBAE62069A5D0 CRC64;
     MVKIIFVFFI FLSSFSYAND DKLYRADSRP PDEIKQSGGL MPRGQSEYFD RGTQMNINLY
     DHARGTQTGF VRHDDGYVST SISLRSAHLV GQTILSGHST YYIYVIATAP NMFNVNDVLG
     AYSPHPDEQE VSALGGIPYS QIYGWYRVHF GVLDEQLHRN RGYRDRYYSN LDIAPAADGY
     GLAGFPPEHR AWREEPWIHH APPGCGNAPR SSMSNTCDEK TQSLGVKFLD EYQSKVKRQI
     FSGYQSDIDT HNRIKDEL
//