ID   LKA1B_MANHA             Reviewed;         953 AA.
AC   Q7BHI8;
DT   16-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT   10-MAY-2005, sequence version 1.
DT   25-MAY-2022, entry version 73.
DE   RecName: Full=Leukotoxin;
DE            Short=Lkt;
GN   Name=lktA;
OS   Mannheimia haemolytica (Pasteurella haemolytica).
OC   Bacteria; Proteobacteria; Gammaproteobacteria; Pasteurellales;
OC   Pasteurellaceae; Mannheimia.
OX   NCBI_TaxID=75985;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=Serotype A1 / PH2;
RX   PubMed=11157953; DOI=10.1128/jb.183.4.1394-1404.2001;
RA   Davies R.L., Whittam T.S., Selander R.K.;
RT   "Sequence diversity and molecular evolution of the leukotoxin (lktA) gene
RT   in bovine and ovine strains of Mannheimia (Pasteurella) haemolytica.";
RL   J. Bacteriol. 183:1394-1404(2001).
RN   [2]
RP   FUNCTION.
RC   STRAIN=Serotype A1;
RX   PubMed=2463967; DOI=10.1128/iai.57.2.420-425.1989;
RA   Clinkenbeard K.D., Mosier D.A., Confer A.W.;
RT   "Transmembrane pore size and role of cell swelling in cytotoxicity caused
RT   by Pasteurella haemolytica leukotoxin.";
RL   Infect. Immun. 57:420-425(1989).
RN   [3]
RP   FUNCTION.
RC   STRAIN=Serotype A1 / D153;
RX   PubMed=9596757; DOI=10.1128/iai.66.6.2836-2844.1998;
RA   Hsuan S.L., Kannan M.S., Jeyaseelan S., Prakash Y.S., Sieck G.C.,
RA   Maheswaran S.K.;
RT   "Pasteurella haemolytica A1-derived leukotoxin and endotoxin induce
RT   intracellular calcium elevation in bovine alveolar macrophages by different
RT   signaling pathways.";
RL   Infect. Immun. 66:2836-2844(1998).
RN   [4]
RP   INTERACTION WITH LFA-1.
RC   STRAIN=Serotype A1 / D153;
RX   PubMed=10603370; DOI=10.1128/iai.68.1.72-79.2000;
RA   Jeyaseelan S., Hsuan S.L., Kannan M.S., Walcheck B., Wang J.F.,
RA   Kehrli M.E., Lally E.T., Sieck G.C., Maheswaran S.K.;
RT   "Lymphocyte function-associated antigen 1 is a receptor for Pasteurella
RT   haemolytica leukotoxin in bovine leukocytes.";
RL   Infect. Immun. 68:72-79(2000).
RN   [5]
RP   FUNCTION.
RC   STRAIN=Serotype A1 / D153;
RX   PubMed=11553552; DOI=10.1128/iai.69.10.6131-6139.2001;
RA   Jeyaseelan S., Kannan M.S., Briggs R.E., Thumbikat P., Maheswaran S.K.;
RT   "Mannheimia haemolytica leukotoxin activates a nonreceptor tyrosine kinase
RT   signaling cascade in bovine leukocytes, which induces biological effects.";
RL   Infect. Immun. 69:6131-6139(2001).
RN   [6]
RP   REVIEW.
RX   PubMed=11750142; DOI=10.1016/s0378-1135(01)00467-9;
RA   Narayanan S.K., Nagaraja T.G., Chengappa M.M., Stewart G.C.;
RT   "Leukotoxins of Gram-negative bacteria.";
RL   Vet. Microbiol. 84:337-356(2002).
RN   [7]
RP   FUNCTION.
RX   PubMed=12732470; DOI=10.1016/s0882-4010(03)00033-0;
RA   Thumbikat P., Briggs R.E., Kannan M.S., Maheswaran S.K.;
RT   "Biological effects of two genetically defined leukotoxin mutants of
RT   Mannheimia haemolytica.";
RL   Microb. Pathog. 34:217-226(2003).
RN   [8]
RP   FUNCTION.
RC   STRAIN=Serotype A1 / D153;
RX   PubMed=15797811; DOI=10.1016/j.micpath.2005.01.002;
RA   Thumbikat P., Dileepan T., Kannan M.S., Maheswaran S.K.;
RT   "Mechanisms underlying Mannheimia haemolytica leukotoxin-induced oncosis
RT   and apoptosis of bovine alveolar macrophages.";
RL   Microb. Pathog. 38:161-172(2005).
RN   [9]
RP   FUNCTION.
RC   STRAIN=Serotype A1 / D153;
RX   PubMed=15925274; DOI=10.1016/j.micpath.2005.02.005;
RA   Dileepan T., Thumbikat P., Walcheck B., Kannan M.S., Maheswaran S.K.;
RT   "Recombinant expression of bovine LFA-1 and characterization of its role as
RT   a receptor for Mannheimia haemolytica leukotoxin.";
RL   Microb. Pathog. 38:249-257(2005).
CC   -!- FUNCTION: Pasteurella leukotoxins are exotoxins that attack host
CC       leukocytes and especially polymorphonuclear cells, by causing cell
CC       rupture. The leukotoxin binds to the host LFA-1 integrin and induces a
CC       signaling cascade leading to many biological effects, including
CC       tyrosine phosphorylation of the CD18 tail, elevation of the
CC       intracellular Ca(2+) and lysis of the host cell. This leukotoxin is a
CC       major contributor to the pathogenesis of lung injury in bovine
CC       pneumonic pasteurellosis. It has also week hemolytic activity.
CC       {ECO:0000269|PubMed:11553552, ECO:0000269|PubMed:12732470,
CC       ECO:0000269|PubMed:15797811, ECO:0000269|PubMed:15925274,
CC       ECO:0000269|PubMed:2463967, ECO:0000269|PubMed:9596757}.
CC   -!- INTERACTION:
CC       Q7BHI8; P61625: ITGAL; Xeno; NbExp=2; IntAct=EBI-11580242, EBI-11616611;
CC       Q7BHI8; P32592: ITGB2; Xeno; NbExp=3; IntAct=EBI-11580242, EBI-11509482;
CC   -!- SUBCELLULAR LOCATION: Secreted. Host cell membrane {ECO:0000305};
CC       Multi-pass membrane protein {ECO:0000305}.
CC   -!- DOMAIN: The transmembrane domains are believed to be involved in pore
CC       formation in target cells.
CC   -!- DOMAIN: The Gly-rich region is probably involved in calcium binding,
CC       which is required for target cell-binding and cytolytic activity.
CC   -!- DOMAIN: The C-terminal domain contains an export signal that is
CC       recognized by the ABC transporter complex LktBD.
CC   -!- PTM: Acylated by LktC. The toxin only becomes active when modified
CC       (PubMed:12732470). {ECO:0000269|PubMed:12732470}.
CC   -!- MISCELLANEOUS: The lktCABD operon has a complex mosaic structure that
CC       has been derived by extensive inter- and intraspecies horizontal DNA
CC       transfer and intragenic recombination events.
CC   -!- SIMILARITY: Belongs to the RTX prokaryotic toxin (TC 1.C.11) family.
CC       {ECO:0000305}.
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DR   EMBL; AF314503; AAG40287.1; -; Genomic_DNA.
DR   RefSeq; WP_006248023.1; NZ_VAJK01000035.1.
DR   AlphaFoldDB; Q7BHI8; -.
DR   SMR; Q7BHI8; -.
DR   IntAct; Q7BHI8; 2.
DR   GeneID; 67370328; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR   GO; GO:0090729; F:toxin activity; IDA:GO_Central.
DR   GO; GO:0001897; P:cytolysis by symbiont of host cells; IMP:GO_Central.
DR   GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR   GO; GO:1902512; P:positive regulation of apoptotic DNA fragmentation; IDA:AgBase.
DR   GO; GO:0070230; P:positive regulation of lymphocyte apoptotic process; IDA:AgBase.
DR   Gene3D; 2.150.10.10; -; 1.
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; 1.
DR   PROSITE; PS00330; HEMOLYSIN_CALCIUM; 4.
PE   1: Evidence at protein level;
KW   Calcium; Cytolysis; Hemolysis; Host cell membrane; Host membrane;
KW   Lipoprotein; Membrane; Repeat; Secreted; Toxin; Transmembrane;
KW   Transmembrane helix; Virulence.
FT   CHAIN           1..953
FT                   /note="Leukotoxin"
FT                   /id="PRO_0000196220"
FT   TRANSMEM        229..249
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        297..317
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        359..379
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        381..401
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   REPEAT          715..732
FT                   /note="Hemolysin-type calcium-binding 1"
FT   REPEAT          733..750
FT                   /note="Hemolysin-type calcium-binding 2"
FT   REPEAT          751..768
FT                   /note="Hemolysin-type calcium-binding 3"
FT   REPEAT          769..786
FT                   /note="Hemolysin-type calcium-binding 4"
FT   REPEAT          789..806
FT                   /note="Hemolysin-type calcium-binding 5"
SQ   SEQUENCE   953 AA;  101997 MW;  7F93D113A118C05F CRC64;
     MGTRLTTLSN GLKNTLTATK SGLHKAGQSL TQAGSSLKTG AKKIILYIPQ NYQYDTEQGN
     GLQDLVKAAE ELGIEVQREE RNNIATAQTS LGTIQTAIGL TERGIVLSAP QIDKLLQKTK
     AGQALGSAES IVQNANKAKT VLSGIQSILG SVLAGMDLDE ALQNNSNQHA LAKAGLELTN
     SLIENIANSV KTLDEFGEQI SQFGSKLQNI KGLGTLGDKL KNIGGLDKAG LGLDVISGLL
     SGATAALVLA DKNASTAKKV GAGFELANQV VGNITKAVSS YILAQRVAAG LSSTGPVAAL
     IASTVSLAIS PLAFAGIADK FNHAKSLESY AERFKKLGYD GDNLLAEYQR GTGTIDASVT
     AINTALAAIA GGVSAAAAGS VIASPIALLV SGITGVISTI LQYSKQAMFE HVANKIHNKI
     VEWEKNNHGK NYFENGYDAR YLANLQDNMK FLLNLNKELQ AERVIAITQQ QWDNNIGDLA
     GISRLGEKVL SGKAYVDAFE EGKHIKADKL VQLDSANGII DVSNSGKAKT QHILFRTPLL
     TPGTEHRERV QTGKYEYITK LNINRVDSWK ITDGAASSTF DLTNVVQRIG IELDNAGNVT
     KTKETKIIAK LGEGDDNVFV GSGTTEIDGG EGYDRVHYSR GNYGALTIDA TKETEQGSYT
     VNRFVETGKA LHEVTSTHTA LVGNREEKIE YRHSNNQHHA GYYTKDTLKA VEEIIGTSHN
     DIFKGSKFND AFNGGDGVDT IDGNDGNDRL FGGKGDDILD GGNGDDFIDG GKGNDLLHGG
     KGDDIFVHRK GDGNDIITDS DGNDKLSFSD SNLKDLTFEK VKHNLVITNS KKEKVTIQNW
     FREADFAKEV PNYKATKDEK IEEIIGQNGE RITSKQVDDL IAKGNGKITQ DELSKVVDNY
     ELLKHSKNVT NSLDKLISSV SAFTSSNDSR NVLVAPTSML DQSLSSLQFA RAA