LTXA_AGGAC
ID LTXA_AGGAC Reviewed; 1055 AA.
AC P16462; Q43892;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 07-JAN-2015, sequence version 2.
DT 25-MAY-2022, entry version 114.
DE RecName: Full=Leukotoxin;
DE Short=Lkt;
GN Name=ltxA {ECO:0000303|PubMed:8300209};
GN Synonyms=AaLta {ECO:0000303|PubMed:2670940},
GN lktA {ECO:0000303|PubMed:2318535};
OS Aggregatibacter actinomycetemcomitans (Actinobacillus
OS actinomycetemcomitans) (Haemophilus actinomycetemcomitans).
OC Bacteria; Proteobacteria; Gammaproteobacteria; Pasteurellales;
OC Pasteurellaceae; Aggregatibacter.
OX NCBI_TaxID=714;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=JP2;
RX PubMed=2670940; DOI=10.1016/s0021-9258(19)84850-0;
RA Lally E.T., Golub E.E., Kieba I.R., Taichman N.S., Rosenbloom J.,
RA Rosenbloom J.C., Gibson C.W., Demuth D.R.;
RT "Analysis of the Actinobacillus actinomycetemcomitans leukotoxin gene.
RT Delineation of unique features and comparison to homologous toxins.";
RL J. Biol. Chem. 264:15451-15456(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=JP2;
RX PubMed=2318535; DOI=10.1128/iai.58.4.920-929.1990;
RA Kraig E., Dailey T., Kolodrubetz D.;
RT "Nucleotide sequence of the leukotoxin gene from Actinobacillus
RT actinomycetemcomitans: homology to the alpha-hemolysin/leukotoxin gene
RT family.";
RL Infect. Immun. 58:920-929(1990).
RN [3]
RP FUNCTION.
RX PubMed=3258584; DOI=10.1128/iai.56.5.1162-1166.1988;
RA Simpson D.L., Berthold P., Taichman N.S.;
RT "Killing of human myelomonocytic leukemia and lymphocytic cell lines by
RT Actinobacillus actinomycetemcomitans leukotoxin.";
RL Infect. Immun. 56:1162-1166(1988).
RN [4]
RP SUBCELLULAR LOCATION.
RC STRAIN=301-b / Serotype a;
RX PubMed=1937819; DOI=10.1128/iai.59.12.4599-4605.1991;
RA Ohta H., Kato K., Kokeguchi S., Hara H., Fukui K., Murayama Y.;
RT "Nuclease-sensitive binding of an Actinobacillus actinomycetemcomitans
RT leukotoxin to the bacterial cell surface.";
RL Infect. Immun. 59:4599-4605(1991).
RN [5]
RP INDUCTION, AND GENE NAME.
RC STRAIN=652, and JP2;
RX PubMed=8300209; DOI=10.1128/iai.62.2.501-508.1994;
RA Brogan J.M., Lally E.T., Poulsen K., Kilian M., Demuth D.R.;
RT "Regulation of Actinobacillus actinomycetemcomitans leukotoxin expression:
RT analysis of the promoter regions of leukotoxic and minimally leukotoxic
RT strains.";
RL Infect. Immun. 62:501-508(1994).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=11035711; DOI=10.1128/iai.68.11.6094-6100.2000;
RA Kachlany S.C., Fine D.H., Figurski D.H.;
RT "Secretion of RTX leukotoxin by Actinobacillus actinomycetemcomitans.";
RL Infect. Immun. 68:6094-6100(2000).
RN [7]
RP FUNCTION AS A HEMOLYSIN, AND DISRUPTION PHENOTYPE.
RX PubMed=16552030; DOI=10.1128/iai.74.4.2015-2021.2006;
RA Balashova N.V., Crosby J.A., Al Ghofaily L., Kachlany S.C.;
RT "Leukotoxin confers beta-hemolytic activity to Actinobacillus
RT actinomycetemcomitans.";
RL Infect. Immun. 74:2015-2021(2006).
RN [8]
RP REGULATION BY IRON.
RX PubMed=17041062; DOI=10.1128/jb.01253-06;
RA Balashova N.V., Diaz R., Balashov S.V., Crosby J.A., Kachlany S.C.;
RT "Regulation of Aggregatibacter (Actinobacillus) actinomycetemcomitans
RT leukotoxin secretion by iron.";
RL J. Bacteriol. 188:8658-8661(2006).
RN [9]
RP INTERACTION WITH SUPEROXIDE DISMUTASE.
RX PubMed=17635874; DOI=10.1128/iai.00288-07;
RA Balashova N.V., Park D.H., Patel J.K., Figurski D.H., Kachlany S.C.;
RT "Interaction between leukotoxin and Cu,Zn superoxide dismutase in
RT Aggregatibacter actinomycetemcomitans.";
RL Infect. Immun. 75:4490-4497(2007).
RN [10]
RP FUNCTION, AND INTERACTION WITH HUMAN LFA-1.
RX PubMed=17635865; DOI=10.1128/iai.00314-07;
RA Dileepan T., Kachlany S.C., Balashova N.V., Patel J., Maheswaran S.K.;
RT "Human CD18 is the functional receptor for Aggregatibacter
RT actinomycetemcomitans leukotoxin.";
RL Infect. Immun. 75:4851-4856(2007).
RN [11]
RP ACYLATION.
RC STRAIN=JP2N;
RX PubMed=19450669; DOI=10.1016/j.gene.2009.05.002;
RA Balashova N.V., Shah C., Patel J.K., Megalla S., Kachlany S.C.;
RT "Aggregatibacter actinomycetemcomitans LtxC is required for leukotoxin
RT activity and initial interaction between toxin and host cells.";
RL Gene 443:42-47(2009).
RN [12]
RP ACYLATION, AND MUTAGENESIS OF LYS-562 AND LYS-687.
RX PubMed=21729247; DOI=10.1111/j.2041-1014.2011.00617.x;
RA Fong K.P., Tang H.Y., Brown A.C., Kieba I.R., Speicher D.W.,
RA Boesze-Battaglia K., Lally E.T.;
RT "Aggregatibacter actinomycetemcomitans leukotoxin is post-translationally
RT modified by addition of either saturated or hydroxylated fatty acyl
RT chains.";
RL Mol. Oral. Microbiol. 26:262-276(2011).
RN [13]
RP FUNCTION, BINDING TO CHOLESTEROL, AND MUTAGENESIS OF TYR-337 AND TYR-504.
RX PubMed=23792963; DOI=10.1074/jbc.m113.486654;
RA Brown A.C., Balashova N.V., Epand R.M., Epand R.F., Bragin A.,
RA Kachlany S.C., Walters M.J., Du Y., Boesze-Battaglia K., Lally E.T.;
RT "Aggregatibacter actinomycetemcomitans leukotoxin utilizes a cholesterol
RT recognition/amino acid consensus site for membrane association.";
RL J. Biol. Chem. 288:23607-23621(2013).
CC -!- FUNCTION: Virulence factor that plays an important role in immune
CC evasion. Lyses human lymphocytes and monocytes. Binds to the LFA-1
CC integrin on the surface of the host cell and to cholesterol-containing
CC membranes, which probably results in large LtxA-LFA-1 clusters in lipid
CC rafts. Shows also beta-hemolytic activity on certain types of growth
CC media. {ECO:0000269|PubMed:16552030, ECO:0000269|PubMed:17635865,
CC ECO:0000269|PubMed:23792963, ECO:0000269|PubMed:3258584}.
CC -!- SUBUNIT: Interacts specifically with the superoxide dismutase [Cu-Zn].
CC This interaction may protect LtxA from reactive oxygen species and
CC reactive nitrogen species produced by host inflammatory cells during
CC disease (PubMed:17635874). Interacts with the human leukocyte adhesion
CC glycoprotein LFA-1 (ITGAL-ITGB2) (PubMed:17635865).
CC {ECO:0000269|PubMed:17635865, ECO:0000269|PubMed:17635874}.
CC -!- SUBCELLULAR LOCATION: Cell outer membrane {ECO:0000269|PubMed:1937819};
CC Peripheral membrane protein {ECO:0000269|PubMed:1937819}; Extracellular
CC side {ECO:0000269|PubMed:1937819}. Secreted
CC {ECO:0000269|PubMed:11035711}. Note=Leukotoxin expressed by the rough,
CC adherent, clinical isolate CU1000N is cell associated. However, smooth,
CC nonadherent strains, including Y4, JP2 and CU1060N, secrete an
CC abundance of leukotoxin into the culture supernatants during early
CC stages of growth (PubMed:11035711). Secretion is inhibited by free iron
CC (PubMed:17041062). {ECO:0000269|PubMed:11035711,
CC ECO:0000269|PubMed:17041062}.
CC -!- INDUCTION: Levels of toxin expression vary greatly among strains.
CC Highly leukotoxic strains (JP2-type strains) produce more LtxA protein
CC and ltx mRNA than minimally leukotoxic strains (652-type strains).
CC Variations are probably due to different types of promoters
CC (PubMed:8300209). Expression is not affected by iron (PubMed:17041062).
CC {ECO:0000269|PubMed:17041062, ECO:0000269|PubMed:8300209}.
CC -!- DOMAIN: The Gly-rich region is probably involved in binding calcium,
CC which is required for target cell-binding or cytolytic activity.
CC {ECO:0000250}.
CC -!- PTM: Acylated at Lys-562 and Lys-687 by LtxC. This modification is
CC required for full activity. Isolated methyl esters contain palmitoyl
CC and palmitolyl fatty acyl groups with smaller quantities of myristic
CC and stearic fatty acids. {ECO:0000269|PubMed:19450669,
CC ECO:0000269|PubMed:21729247}.
CC -!- DISRUPTION PHENOTYPE: Mutation completely abolishes the beta-hemolytic
CC activity of A.actinomycetemcomitans. {ECO:0000269|PubMed:16552030}.
CC -!- SIMILARITY: Belongs to the RTX prokaryotic toxin (TC 1.C.11) family.
CC {ECO:0000305}.
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DR EMBL; M27399; AAA21922.1; -; Genomic_DNA.
DR EMBL; X16829; CAA34731.1; -; Genomic_DNA.
DR PIR; A37205; A37205.
DR RefSeq; WP_005567703.1; NZ_CP065604.1.
DR AlphaFoldDB; P16462; -.
DR SMR; P16462; -.
DR STRING; 714.ACT75_09605; -.
DR TCDB; 1.C.11.1.7; the pore-forming rtx toxin (rtx-toxin) family.
DR eggNOG; COG2931; Bacteria.
DR GO; GO:0009279; C:cell outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR Gene3D; 2.150.10.10; -; 3.
DR InterPro; IPR018511; Hemolysin-typ_Ca-bd_CS.
DR InterPro; IPR001343; Hemolysn_Ca-bd.
DR InterPro; IPR013550; RTX_C.
DR InterPro; IPR018504; RTX_N.
DR InterPro; IPR003995; RTX_toxin_determinant-A.
DR InterPro; IPR011049; Serralysin-like_metalloprot_C.
DR Pfam; PF00353; HemolysinCabind; 3.
DR Pfam; PF02382; RTX; 1.
DR Pfam; PF08339; RTX_C; 1.
DR PRINTS; PR01488; RTXTOXINA.
DR SUPFAM; SSF51120; SSF51120; 2.
DR PROSITE; PS00330; HEMOLYSIN_CALCIUM; 5.
PE 1: Evidence at protein level;
KW Calcium; Cell outer membrane; Coiled coil; Cytolysis; Hemolysis; Membrane;
KW Repeat; Secreted; Toxin; Virulence.
FT CHAIN 1..1055
FT /note="Leukotoxin"
FT /id="PRO_0000196216"
FT REPEAT 721..738
FT /note="Hemolysin-type calcium-binding 1"
FT REPEAT 739..756
FT /note="Hemolysin-type calcium-binding 2"
FT REPEAT 757..774
FT /note="Hemolysin-type calcium-binding 3"
FT REPEAT 775..792
FT /note="Hemolysin-type calcium-binding 4"
FT REPEAT 793..810
FT /note="Hemolysin-type calcium-binding 5"
FT REPEAT 811..828
FT /note="Hemolysin-type calcium-binding 6"
FT REPEAT 829..846
FT /note="Hemolysin-type calcium-binding 7"
FT REGION 334..340
FT /note="Cholesterol recognition/amino acid consensus (CRAC)
FT region"
FT /evidence="ECO:0000269|PubMed:23792963"
FT REGION 502..506
FT /note="Cholesterol recognition/amino acid consensus (CRAC)
FT region"
FT /evidence="ECO:0000269|PubMed:23792963"
FT REGION 795..815
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 990..1009
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 11..49
FT /evidence="ECO:0000255"
FT COMPBIAS 991..1009
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 337
FT /note="Y->P: Loss of cytotoxicity."
FT /evidence="ECO:0000269|PubMed:23792963"
FT MUTAGEN 504
FT /note="Y->P: Decreases cytotoxicity."
FT /evidence="ECO:0000269|PubMed:23792963"
FT MUTAGEN 562
FT /note="K->R: Loss of cytotoxicity."
FT /evidence="ECO:0000269|PubMed:21729247"
FT MUTAGEN 687
FT /note="K->R: Loss of cytotoxicity."
FT /evidence="ECO:0000269|PubMed:21729247"
FT CONFLICT 240
FT /note="L -> Y (in Ref. 1; AAA21922)"
FT /evidence="ECO:0000305"
FT CONFLICT 260
FT /note="D -> H (in Ref. 1; AAA21922)"
FT /evidence="ECO:0000305"
FT CONFLICT 336
FT /note="E -> A (in Ref. 1; AAA21922)"
FT /evidence="ECO:0000305"
FT CONFLICT 416
FT /note="F -> S (in Ref. 1; AAA21922)"
FT /evidence="ECO:0000305"
FT CONFLICT 439
FT /note="F -> S (in Ref. 1; AAA21922)"
FT /evidence="ECO:0000305"
FT CONFLICT 724
FT /note="T -> N (in Ref. 1; AAA21922)"
FT /evidence="ECO:0000305"
FT CONFLICT 927..1055
FT /note="RARLKRQFELQRGKVDKSLNNKVEEIIGKDGERITSQDIDNLFDKSGNKKTI
FT SPQELAGLIKNKGKSSSLMSSSRSSSMLTQKSGLSNDISRIISATSGFGSSGKALSASP
FT LQTNNNFNSYANSLATTA -> VHDLRDNLSYSEVKSTNHSIIKLKKLSVKMGSGLLRK
FT TLIIFLIRVGTKRQFHLKSLPDLLRIKVSQVALCLLLVRQVCLHKSPVCQMILVVLFQQ
FT PVVLVHPVKRYPLRHCRPIITLTLTQIR (in Ref. 1; AAA21922)"
SQ SEQUENCE 1055 AA; 113854 MW; 5331C396FA76669E CRC64;
MATTTLPNTK QQAAQFANSV ADRAKENIDA AKEQLQKALD KLGKTGKKLT LYIPKNYKKG
NGLTALIKAA QKLGIEVYHE GKDGPALTNG ILNTGKKLLG LTERGLTLFA PELDKWIQGN
KHLSNSVGST GNLTKAIDKV QSVLGTLQAF LNTAFSGMDL DALIKARQNG KNVTDVQLAK
ASLNLINELI GTISSITNNV DTFSKQLNKL GEALGQVKHF GSFGDKLKNL PKLGNLGKGL
GALSGVLSAI SAALLLANKD ADTATKAAAA AELTNKVLGN IGKAITQYLI AQRAAAGLST
TGPVAGLIAS VVSLAISPLS FLGIAKQFDR ARMLEEYSKR FKKFGYNGDS LLGQFYKNTG
IADAAITTIN TVLSAIAAGV GAASAGSLVG APIGLLVSAI TSLISGILDA SKQAVFEHIA
NQLADKIKAW ENKYGKNYFE NGYDARHSAF LEDSLKLFNE LREKYKTENI LSITQQGWDQ
RIGELAGITR NGDRIQSGKA YVDYLKKGEE LAKHSDKFTK QILDPIKGNI DLSGIKGSTT
LTFLNPLLTA GKEERKTRQS GKYEFITELK VKGRTDWKVK GVPNSNGVYD FSNLIQHAVT
RDNKVLEARL IANLGAKDDY VFVGSGSTIV NAGDGYDVVD YSKGRTGALT IDGRNATKAG
QYKVERDLSG TQVLQETVSK QETKRGKVTD LLEYRNYKLD YYYTNKGFKA HDELNSVEEI
IGSTLRDKFY GSKFNDVFHG HDGDDLIYGY DGDDRLYGDN GNDEIHGGQG NDKLYGGAGN
DRLFGEYGNN YLDGGEGDDH LEGGNGSDIL RGGSGNDKLF GNQGDDLLDG GEGDDQLAGG
EGNDIYVYRK EYGHHTITEH SGDKDKLSLA NINLKDVSFE RNGNDLLLKT NNRTAVTFKG
WFSKPNSSAG LDEYQRKLLE YAPEKDRARL KRQFELQRGK VDKSLNNKVE EIIGKDGERI
TSQDIDNLFD KSGNKKTISP QELAGLIKNK GKSSSLMSSS RSSSMLTQKS GLSNDISRII
SATSGFGSSG KALSASPLQT NNNFNSYANS LATTA
