HLA_STAAU
ID HLA_STAAU Reviewed; 319 AA.
AC P09616;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 2.
DT 25-MAY-2022, entry version 145.
DE RecName: Full=Alpha-hemolysin;
DE Short=Alpha-HL;
DE AltName: Full=Alpha-toxin;
DE Flags: Precursor;
GN Name=hly; Synonyms=hla;
OS Staphylococcus aureus.
OC Bacteria; Firmicutes; Bacilli; Bacillales; Staphylococcaceae;
OC Staphylococcus.
OX NCBI_TaxID=1280;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND PROTEIN SEQUENCE OF 27-44.
RC STRAIN=ATCC 10832 / Wood 46;
RX PubMed=6500704; DOI=10.1128/iai.46.2.615-618.1984;
RA Gray G.S., Kehoe M.;
RT "Primary sequence of the alpha-toxin gene from Staphylococcus aureus wood
RT 46.";
RL Infect. Immun. 46:615-618(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND SEQUENCE REVISION.
RC STRAIN=ATCC 10832 / Wood 46;
RA Hedengrahn G.;
RL Submitted (OCT-1992) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 27-319, FUNCTION, SUBUNIT, AND
RP MUTAGENESIS OF 315-GLU--ASN-319.
RC STRAIN=ATCC 10832 / Wood 46;
RX PubMed=1587866; DOI=10.1016/s0021-9258(19)50103-x;
RA Walker B., Krishnasastry M., Zorn L., Kasianowicz J., Bayley H.;
RT "Functional expression of the alpha-hemolysin of Staphylococcus aureus in
RT intact Escherichia coli and in cell lysates. Deletion of five C-terminal
RT amino acids selectively impairs hemolytic activity.";
RL J. Biol. Chem. 267:10902-10909(1992).
RN [4] {ECO:0007744|PDB:7AHL}
RP X-RAY CRYSTALLOGRAPHY (1.89 ANGSTROMS) OF 27-319, SUBUNIT, SUBCELLULAR
RP LOCATION, AND DOMAIN.
RC STRAIN=ATCC 10832 / Wood 46;
RX PubMed=8943190; DOI=10.1126/science.274.5294.1859;
RA Song L., Hobaugh M.R., Shustak C., Cheley S., Bayley H., Gouaux J.E.;
RT "Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane
RT pore.";
RL Science 274:1859-1866(1996).
RN [5]
RP SUBUNIT, AND MUTAGENESIS OF 28-ASP-SER-29; 28-ASP--ASP-39; 28-ASP--GLY-49;
RP 28-ASP--PHE-65; 312-TRP--ASN-319; 315-GLU--ASN-319 AND 317-MET--ASN-319.
RX PubMed=1400487; DOI=10.1016/s0021-9258(19)36680-3;
RA Walker B., Krishnasastry M., Zorn L., Bayley H.;
RT "Assembly of the oligomeric membrane pore formed by Staphylococcal alpha-
RT hemolysin examined by truncation mutagenesis.";
RL J. Biol. Chem. 267:21782-21786(1992).
RN [6]
RP MUTAGENESIS OF HIS-61; HIS-74; HIS-170 AND HIS-285.
RC STRAIN=8325-4;
RX PubMed=8168947; DOI=10.1128/iai.62.5.1843-1847.1994;
RA Menzies B.E., Kernodle D.S.;
RT "Site-directed mutagenesis of the alpha-toxin gene of Staphylococcus
RT aureus: role of histidines in toxin activity in vitro and in a murine
RT model.";
RL Infect. Immun. 62:1843-1847(1994).
RN [7]
RP MUTAGENESIS OF HIS-61; HIS-74; HIS-170 AND HIS-285.
RX PubMed=8188346; DOI=10.1128/iai.62.6.2249-2256.1994;
RA Jursch R., Hildebrand A., Hobom G., Tranum-Jensen J., Ward R., Kehoe M.,
RA Bhakdi S.;
RT "Histidine residues near the N-terminus of staphylococcal alpha-toxin as
RT reporters of regions that are critical for oligomerization and pore
RT formation.";
RL Infect. Immun. 62:2249-2256(1994).
RN [8]
RP MUTAGENESIS.
RX PubMed=7559447; DOI=10.1074/jbc.270.39.23065;
RA Walker B., Bayley H.;
RT "Key residues for membrane binding, oligomerization, and pore forming
RT activity of staphylococcal alpha-hemolysin identified by cysteine scanning
RT mutagenesis and targeted chemical modification.";
RL J. Biol. Chem. 270:23065-23071(1995).
RN [9]
RP FUNCTION, INTERACTION WITH HUMAN ADAM10, AND MUTAGENESIS OF HIS-61.
RX PubMed=20624979; DOI=10.1073/pnas.1001815107;
RA Wilke G.A., Bubeck Wardenburg J.;
RT "Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus
RT alpha-hemolysin-mediated cellular injury.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:13473-13478(2010).
CC -!- FUNCTION: Alpha-toxin binds to the membrane of eukaryotic cells
CC (particularly red blood cells, RBC) forming pores, resulting in
CC hemolysis, with the release of low-molecular weight molecules leading
CC to eventual osmotic RBC lysis (PubMed:1587866, PubMed:20624979). Human
CC RBCs bind much less alpha-toxin than do rabbit RBCs (PubMed:1587866,
CC PubMed:20624979). Heptamer oligomerization and pore formation is
CC required for lytic activity (PubMed:1587866, PubMed:20624979).
CC {ECO:0000269|PubMed:1587866, ECO:0000269|PubMed:20624979}.
CC -!- SUBUNIT: Self-assembles to first form a non-lytic oligomeric
CC intermediate, and then, a mushroom-shaped homoheptamer structure of 100
CC Angstroms in length and up to 100 Angstroms in diameter
CC (PubMed:8943190) (Probable). Interacts with human ADAM10; this
CC interaction is required for toxin pore formation, disruption of focal
CC adhesions, and hly-mediated cytotoxicity (PubMed:20624979).
CC {ECO:0000269|PubMed:20624979, ECO:0000269|PubMed:8943190,
CC ECO:0000305|PubMed:1400487, ECO:0000305|PubMed:1587866}.
CC -!- INTERACTION:
CC P09616; P09616: hly; NbExp=6; IntAct=EBI-15848589, EBI-15848589;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8943190}.
CC Note=Secreted as a monomer (PubMed:8943190). After oligomerization and
CC pore formation, the complex is translocated across the bilayer,
CC probably via the Gly-rich domain of each strand.
CC {ECO:0000269|PubMed:8943190}.
CC -!- DOMAIN: The mushroom-shaped heptamer is composed of a cap domain
CC (comprising 7 beta sandwiches and the amino latches of each protomer),
CC 7 rim regions whose protruding strands may interact with the membrane
CC bilayer, and the stem domain (52 Angstroms in length, 26 Angstroms in
CC diameter) which forms the transmembrane pore.
CC {ECO:0000269|PubMed:8943190}.
CC -!- SIMILARITY: Belongs to the aerolysin family. {ECO:0000305}.
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DR EMBL; X01645; CAA25801.1; -; Genomic_DNA.
DR EMBL; M90536; AAA26598.1; -; Genomic_DNA.
DR PIR; S69209; S69209.
DR PDB; 3M2L; X-ray; 2.10 A; A/B/C/D/E/F/G=27-319.
DR PDB; 3M3R; X-ray; 2.20 A; A/B/C/D/E/F/G=27-319.
DR PDB; 3M4D; X-ray; 1.90 A; A/B/C/D/E/F/G=27-319.
DR PDB; 3M4E; X-ray; 2.30 A; A/B/C/D/E/F/G=27-319.
DR PDB; 4IDJ; X-ray; 3.36 A; A=27-319.
DR PDB; 4YHD; X-ray; 2.80 A; A/B/C/D/E/G=27-319.
DR PDB; 6U3T; X-ray; 2.79 A; A/B=27-319.
DR PDB; 6U49; X-ray; 2.35 A; A/B/C/D/E/F/G=27-319.
DR PDB; 6U4P; X-ray; 2.49 A; A/B/C/D/E/F/G=27-319.
DR PDB; 7AHL; X-ray; 1.89 A; A/B/C/D/E/F/G=27-319.
DR PDB; 7O1Q; EM; 3.40 A; A/B/C/D/E/F/G=27-131, A/B/C/D/E/F/G=174-319.
DR PDBsum; 3M2L; -.
DR PDBsum; 3M3R; -.
DR PDBsum; 3M4D; -.
DR PDBsum; 3M4E; -.
DR PDBsum; 4IDJ; -.
DR PDBsum; 4YHD; -.
DR PDBsum; 6U3T; -.
DR PDBsum; 6U49; -.
DR PDBsum; 6U4P; -.
DR PDBsum; 7AHL; -.
DR PDBsum; 7O1Q; -.
DR AlphaFoldDB; P09616; -.
DR SMR; P09616; -.
DR DIP; DIP-59322N; -.
DR IntAct; P09616; 1.
DR ChEMBL; CHEMBL1075259; -.
DR TCDB; 1.C.3.1.1; the Alpha-hemolysin channel-forming toxin (Alphahl) family.
DR ABCD; P09616; 22 sequenced antibodies.
DR Reactome; R-HSA-844456; The NLRP3 inflammasome.
DR Reactome; R-HSA-9660826; Purinergic signaling in leishmaniasis infection.
DR EvolutionaryTrace; P09616; -.
DR PRO; PR:P09616; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0090729; F:toxin activity; IMP:UniProtKB.
DR GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR InterPro; IPR005831; Aerolysin/haemolysin_CS.
DR InterPro; IPR003963; Bi-component_toxin_staph.
DR InterPro; IPR016183; Leukocidin/Hemolysin_toxin.
DR InterPro; IPR036435; Leukocidin/porin_MspA_sf.
DR Pfam; PF07968; Leukocidin; 1.
DR PRINTS; PR01468; BICOMPNTOXIN.
DR SUPFAM; SSF56959; SSF56959; 1.
DR TIGRFAMs; TIGR01002; hlyII; 1.
DR PROSITE; PS00274; AEROLYSIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytolysis; Direct protein sequencing; Hemolysis; Secreted;
KW Signal; Toxin; Virulence.
FT SIGNAL 1..26
FT /evidence="ECO:0000269|PubMed:6500704"
FT CHAIN 27..319
FT /note="Alpha-hemolysin"
FT /id="PRO_0000035636"
FT MUTAGEN 28..65
FT /note="Missing: Binds host red blood cells, complete loss
FT of hemolytic activity, no longer oligomerizes."
FT /evidence="ECO:0000269|PubMed:1400487"
FT MUTAGEN 28..49
FT /note="Missing: Binds host red blood cells, complete loss
FT of hemolytic activity, forms hexamers."
FT /evidence="ECO:0000269|PubMed:1400487"
FT MUTAGEN 28..39
FT /note="Missing: Binds host red blood cells, complete loss
FT of hemolytic activity, mainly forms pentamers."
FT /evidence="ECO:0000269|PubMed:1400487"
FT MUTAGEN 28..29
FT /note="Missing: Binds host red blood cells, complete loss
FT of hemolytic activity, mainly forms pentamers."
FT /evidence="ECO:0000269|PubMed:1400487"
FT MUTAGEN 61
FT /note="H->I,L,P,R,S,T: No oligomerization nor hemolytic
FT activity, wild-type target cell-binding."
FT /evidence="ECO:0000269|PubMed:8188346"
FT MUTAGEN 61
FT /note="H->L: No hemolytic activity, reduced
FT oligomerization, not toxic in mice, no effect on ADAM10
FT binding."
FT /evidence="ECO:0000269|PubMed:20624979,
FT ECO:0000269|PubMed:8168947"
FT MUTAGEN 74
FT /note="H->I,R,T: No oligomerization, altered hemolysis,
FT near wild-type target cell binding."
FT /evidence="ECO:0000269|PubMed:8188346"
FT MUTAGEN 74
FT /note="H->L: 7% of normal hemolytic activity, reduced
FT toxicity in mice."
FT /evidence="ECO:0000269|PubMed:8168947"
FT MUTAGEN 170
FT /note="H->L,P,R: Decreased hemolysis, wild-type
FT oligomerization and target cell binding."
FT /evidence="ECO:0000269|PubMed:8188346"
FT MUTAGEN 170
FT /note="H->L: 16% of normal hemolytic activity."
FT /evidence="ECO:0000269|PubMed:8168947"
FT MUTAGEN 285
FT /note="H->I,P,R,S: Nearly wild-type oligomerization,
FT hemolysis and target cell binding."
FT /evidence="ECO:0000269|PubMed:8188346"
FT MUTAGEN 285
FT /note="H->L: 46% of normal hemolytic activity, slowly toxic
FT in mice."
FT /evidence="ECO:0000269|PubMed:8168947"
FT MUTAGEN 312..319
FT /note="Missing: Binds host red blood cells, complete loss
FT of hemolytic activity, no longer oligomerizes."
FT /evidence="ECO:0000269|PubMed:1400487"
FT MUTAGEN 315..319
FT /note="Missing: Binds host red blood cells, almost complete
FT loss of hemolytic activity, greatly reduced
FT oligomerization."
FT /evidence="ECO:0000269|PubMed:1400487,
FT ECO:0000269|PubMed:1587866"
FT MUTAGEN 317..319
FT /note="Missing: Binds host red blood cells, almost complete
FT loss of hemolytic activity, greatly reduced
FT oligomerization."
FT /evidence="ECO:0000269|PubMed:1400487"
FT HELIX 28..31
FT /evidence="ECO:0007829|PDB:7AHL"
FT TURN 35..38
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 40..43
FT /evidence="ECO:0007829|PDB:4IDJ"
FT STRAND 47..55
FT /evidence="ECO:0007829|PDB:7AHL"
FT TURN 56..59
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 60..69
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 74..87
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 92..95
FT /evidence="ECO:0007829|PDB:3M4D"
FT TURN 98..100
FT /evidence="ECO:0007829|PDB:6U3T"
FT STRAND 101..115
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 123..129
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 135..153
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 158..184
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 188..197
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 200..202
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 205..208
FT /evidence="ECO:0007829|PDB:7AHL"
FT TURN 215..217
FT /evidence="ECO:0007829|PDB:7AHL"
FT HELIX 232..234
FT /evidence="ECO:0007829|PDB:7AHL"
FT HELIX 239..241
FT /evidence="ECO:0007829|PDB:7AHL"
FT HELIX 244..247
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 254..260
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 268..286
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 288..311
FT /evidence="ECO:0007829|PDB:7AHL"
FT TURN 312..315
FT /evidence="ECO:0007829|PDB:7AHL"
FT STRAND 316..318
FT /evidence="ECO:0007829|PDB:7AHL"
SQ SEQUENCE 319 AA; 35904 MW; 6711C415DF7EBF30 CRC64;
MKTRIVSSVT TTLLLGSILM NPVAGAADSD INIKTGTTDI GSNTTVKTGD LVTYDKENGM
HKKVFYSFID DKNHNKKLLV IRTKGTIAGQ YRVYSEEGAN KSGLAWPSAF KVQLQLPDNE
VAQISDYYPR NSIDTKEYMS TLTYGFNGNV TGDDTGKIGG LIGANVSIGH TLKYVQPDFK
TILESPTDKK VGWKVIFNNM VNQNWGPYDR DSWNPVYGNQ LFMKTRNGSM KAADNFLDPN
KASSLLSSGF SPDFATVITM DRKASKQQTN IDVIYERVRD DYQLHWTSTN WKGTNTKDKW
TDRSSERYKI DWEKEEMTN
