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P15917 (LEF_BACAN) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 136. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Lethal factor

Short name=LF
EC=3.4.24.83
Alternative name(s):
Anthrax lethal toxin endopeptidase component
Gene names
Name:lef
Ordered Locus Names:pXO1-107, BXA0172, GBAA_pXO1_0172
Encoded onPlasmid pXO1
OrganismBacillus anthracis [Reference proteome] [HAMAP]
Taxonomic identifier1392 [NCBI]
Taxonomic lineageBacteriaFirmicutesBacilliBacillalesBacillaceaeBacillusBacillus cereus group

Protein attributes

Sequence length809 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. LF is the lethal factor that, when associated with PA, causes death. LF is not toxic by itself. It is a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5). Cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of LF involved in cytotoxicity. The proteasome may mediate a toxic process initiated by LF in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or other putative substrates. Ref.7 Ref.8 Ref.9 Ref.10 Ref.11

Catalytic activity

Preferred amino acids around the cleavage site can be denoted BBBBxHx-|-H, in which B denotes Arg or Lys, H denotes a hydrophobic amino acid, and x is any amino acid. The only known protein substrates are mitogen-activated protein (MAP) kinase kinases.

Cofactor

Binds 1 zinc ion per subunit.

Subunit structure

Anthrax toxins are composed of three distinct proteins, a protective antigen (PA), a lethal factor (LF) and an edema factor (EF). None of these is toxic by itself. PA+LF forms the lethal toxin (LeTx); PA+EF forms the edema toxin (EdTx).

Subcellular location

Secreted.

Induction

Positively transcriptionally regulated by AtxA, which, in turn, is induced by bicarbonate and high temperatures (37 degrees Celsius). Ref.14

Domain

It comprises four domains: domain I binds the membrane-translocating component (PA); domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK before cleavage. Domain IV contains the catalytic center.

The PA-binding region is found in both B.anthracis EF and LF.

Miscellaneous

LF binds to the heptamer formed by cleaved PA on the host cell membrane. This step is followed by internalization of the hetero-oligomeric complex by receptor-mediated endocytosis. LeTx requires passage through an acidic vesicle for activity; at acidic pH, as the pore is inserted into the membrane, LF is translocated and reaches its cytosolic targets. LF is probably directly involved in its routing, by interacting with the lipid membrane. This interaction could involve a conformational change of LF and/or an oligomerization of the protein. LF may have the capability of partially unfolding in order to cross the membrane.

Sequence similarities

Belongs to the peptidase M34 family.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

pagAP134235EBI-456923,EBI-456868

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3333 Ref.1
Chain34 – 809776Lethal factor
PRO_0000029233

Regions

Repeat315 – 333191
Repeat342 – 357162
Repeat360 – 378193
Repeat380 – 397184
Repeat399 – 416185
Region34 – 293260PA-binding region Potential
Region60 – 295236I; PA-binding region Potential
Region296 – 33035IIA
Region315 – 4161025 X approximate repeats
Region336 – 41681III
Region420 – 583164IIB
Region585 – 809225IV

Sites

Active site7201
Metal binding7191Zinc; catalytic
Metal binding7231Zinc; catalytic
Metal binding7681Zinc; catalytic

Natural variations

Natural variant2991A → S in strain: Sterne.

Experimental info

Mutagenesis1801V → A: No effect on PA-binding ability. Ref.16
Mutagenesis1811Y → A: Loss of ability to bind to PA. Ref.16
Mutagenesis1821Y → A: Loss of ability to bind to PA. Ref.16
Mutagenesis1831E → A: No effect on PA-binding ability. Ref.16
Mutagenesis1841I → A: Loss of ability to bind to PA. Ref.16
Mutagenesis1851G → A: No effect on PA-binding ability. Ref.16
Mutagenesis1861K → A: Loss of ability to bind to PA. Ref.16
Mutagenesis2201D → A: Loss of ability to bind to PA and loss of toxicity. Ref.17
Mutagenesis2211L → A: No effect on PA-binding ability and fully toxic. Ref.17
Mutagenesis2221L → A: No effect on PA-binding ability and fully toxic. Ref.17
Mutagenesis2231F → A: Loss of ability to bind to PA and non-toxic. Ref.17
Mutagenesis7191H → A: Loss of activity and zinc binding. Ref.15
Mutagenesis7201E → C or D: Loss of activity. No effect on zinc binding. Ref.15
Mutagenesis7231H → A: Loss of activity and zinc binding. Ref.15

Secondary structure

.................................................................................................................................................. 809
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P15917 [UniParc].

Last modified July 5, 2004. Version 2.
Checksum: 2076B4D7277317EE

FASTA80993,770
        10         20         30         40         50         60 
MNIKKEFIKV ISMSCLVTAI TLSGPVFIPL VQGAGGHGDV GMHVKEKEKN KDENKRKDEE 

        70         80         90        100        110        120 
RNKTQEEHLK EIMKHIVKIE VKGEEAVKKE AAEKLLEKVP SDVLEMYKAI GGKIYIVDGD 

       130        140        150        160        170        180 
ITKHISLEAL SEDKKKIKDI YGKDALLHEH YVYAKEGYEP VLVIQSSEDY VENTEKALNV 

       190        200        210        220        230        240 
YYEIGKILSR DILSKINQPY QKFLDVLNTI KNASDSDGQD LLFTNQLKEH PTDFSVEFLE 

       250        260        270        280        290        300 
QNSNEVQEVF AKAFAYYIEP QHRDVLQLYA PEAFNYMDKF NEQEINLSLE ELKDQRMLAR 

       310        320        330        340        350        360 
YEKWEKIKQH YQHWSDSLSE EGRGLLKKLQ IPIEPKKDDI IHSLSQEEKE LLKRIQIDSS 

       370        380        390        400        410        420 
DFLSTEEKEF LKKLQIDIRD SLSEEEKELL NRIQVDSSNP LSEKEKEFLK KLKLDIQPYD 

       430        440        450        460        470        480 
INQRLQDTGG LIDSPSINLD VRKQYKRDIQ NIDALLHQSI GSTLYNKIYL YENMNINNLT 

       490        500        510        520        530        540 
ATLGADLVDS TDNTKINRGI FNEFKKNFKY SISSNYMIVD INERPALDNE RLKWRIQLSP 

       550        560        570        580        590        600 
DTRAGYLENG KLILQRNIGL EIKDVQIIKQ SEKEYIRIDA KVVPKSKIDT KIQEAQLNIN 

       610        620        630        640        650        660 
QEWNKALGLP KYTKLITFNV HNRYASNIVE SAYLILNEWK NNIQSDLIKK VTNYLVDGNG 

       670        680        690        700        710        720 
RFVFTDITLP NIAEQYTHQD EIYEQVHSKG LYVPESRSIL LHGPSKGVEL RNDSEGFIHE 

       730        740        750        760        770        780 
FGHAVDDYAG YLLDKNQSDL VTNSKKFIDI FKEEGSNLTS YGRTNEAEFF AEAFRLMHST 

       790        800 
DHAERLKVQK NAPKTFQFIN DQIKFIINS 

« Hide

References

« Hide 'large scale' references
[1]"Nucleotide sequence and analysis of the lethal factor gene (lef) from Bacillus anthracis."
Bragg T.S., Robertson D.L.
Gene 81:45-54(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF 34-49.
[2]"A comparison of Bacillus anthracis sequences."
Lowe J.
Submitted (APR-1990) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Sequence and organization of pXO1, the large Bacillus anthracis plasmid harboring the anthrax toxin genes."
Okinaka R.T., Cloud K., Hampton O., Hoffmaster A.R., Hill K.K., Keim P., Koehler T.M., Lamke G., Kumano S., Mahillon J., Manter D., Martinez Y., Ricke D., Svensson R., Jackson P.J.
J. Bacteriol. 181:6509-6515(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: Sterne.
[4]"Comparative genome sequencing for discovery of novel polymorphisms in Bacillus anthracis."
Read T.D., Salzberg S.L., Pop M., Shumway M.F., Umayam L., Jiang L., Holtzapple E., Busch J.D., Smith K.L., Schupp J.M., Solomon D., Keim P., Fraser C.M.
Science 296:2028-2033(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Strain: Ames / isolate Florida / A2012.
[5]"The complete genome sequence of Bacillus anthracis Ames 'Ancestor'."
Ravel J., Jiang L., Stanley S.T., Wilson M.R., Decker R.S., Read T.D., Worsham P., Keim P.S., Salzberg S.L., Fraser-Liggett C.M., Rasko D.A.
J. Bacteriol. 191:445-446(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: Ames ancestor.
[6]"Sequence analysis of the genes encoding for the major virulence factors of Bacillus anthracis vaccine strain 'Carbosap'."
Adone R., Pasquali P., La Rosa G., Marianelli C., Muscillo M., Fasanella A., Francia M., Ciuchini F.
J. Appl. Microbiol. 93:117-121(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 29-809.
Strain: Carbosap and Ferrara.
[7]"Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor."
Duesbery N.S., Webb C.P., Leppla S.H., Gordon V.M., Klimpel K.R., Copeland T.D., Ahn N.G., Oskarsson M.K., Fukasawa K., Paull K.D., Vande Woude G.F.
Science 280:734-737(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages."
Vitale G., Pellizzari R., Recchi C., Napolitani G., Mock M., Montecucco C.
Biochem. Biophys. Res. Commun. 248:706-711(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[9]"Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase."
Duesbery N.S., Vande Woude G.F.
J. Appl. Microbiol. 87:289-293(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[10]"Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor."
Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.
Biochem. J. 352:739-745(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[11]"Proteasome activity is required for anthrax lethal toxin to kill macrophages."
Tang G., Leppla S.H.
Infect. Immun. 67:3055-3060(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[12]"Secondary structure of anthrax lethal toxin proteins and their interaction with large unilamellar vesicles: a Fourier-transform infrared spectroscopy approach."
Wang X.-M., Mock M., Ruysschaert J.-M., Cabiaux V.
Biochemistry 35:14939-14946(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[13]"Zinc content of the Bacillus anthracis lethal factor."
Kochi S.K., Schiavo G., Mock M., Montecucco C.
FEMS Microbiol. Lett. 124:343-348(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: ZINC-BINDING.
[14]"The three Bacillus anthracis toxin genes are coordinately regulated by bicarbonate and temperature."
Sirard J.-C., Mock M., Fouet A.
J. Bacteriol. 176:5188-5192(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: REGULATION OF TOXIN EXPRESSION.
Strain: Sterne.
[15]"Lethal factor active-site mutations affect catalytic activity in vitro."
Hammond S.E., Hanna P.C.
Infect. Immun. 66:2374-2378(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF HIS-719; GLU-720 AND HIS-723.
Strain: Sterne.
[16]"Involvement of residues 147VYYEIGK153 in binding of lethal factor to protective antigen of Bacillus anthracis."
Gupta P., Singh A., Chauhan V., Bhatnagar R.
Biochem. Biophys. Res. Commun. 280:158-163(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF VAL-180; TYR-181; TYR-182; GLU-183; ILE-184; GLY-185 AND LYS-186.
Strain: Sterne.
[17]"Asp 187 and Phe 190 residues in lethal factor are required for the expression of anthrax lethal toxin activity."
Singh A., Chauhan V., Sodhi A., Bhatnagar R.
FEMS Microbiol. Lett. 212:183-186(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ASP-220; LEU-221; LEU-222 AND PHE-223.
Strain: Sterne.
[18]"Toxins of Bacillus anthracis."
Brossier F., Mock M.
Toxicon 39:1747-1755(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[19]"Crystal structure of the anthrax lethal factor."
Pannifer A.D., Wong T.Y., Schwarzenbacher R., Renatus M., Petosa C., Bienkowska J., Lacy D.B., Collier R.J., Park S., Leppla S.H., Hanna P.C., Liddington R.C.
Nature 414:229-233(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH ZINC IONS AND MAP2K2.
[20]"The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor."
Turk B.E., Wong T.Y., Schwarzenbacher R., Jarrell E.T., Leppla S.H., Collier R.J., Liddington R.C., Cantley L.C.
Nat. Struct. Mol. Biol. 11:60-66(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.52 ANGSTROMS) OF 34-809 IN COMPLEX WITH ZINC IONS AND PEPTIDE SUBSTRATE ANALOG.
[21]"Anthrax lethal factor inhibition."
Shoop W.L., Xiong Y., Wiltsie J., Woods A., Guo J., Pivnichny J.V., Felcetto T., Michael B.F., Bansal A., Cummings R.T., Cunningham B.R., Friedlander A.M., Douglas C.M., Patel S.B., Wisniewski D., Scapin G., Salowe S.P., Zaller D.M. expand/collapse author list , Chapman K.T., Scolnick E.M., Schmatz D.M., Bartizal K., MacCoss M., Hermes J.D.
Proc. Natl. Acad. Sci. U.S.A. 102:7958-7963(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 297-809 IN COMPLEX WITH ZINC IONS AND PROTEASE INHIBITOR.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M29081 Genomic DNA. Translation: AAA79216.1.
M30210 Genomic DNA. Translation: AAA22569.1.
AF065404 Genomic DNA. Translation: AAD32411.1.
AE011190 Genomic DNA. Translation: AAM26117.1.
AE017336 Genomic DNA. Translation: AAT28913.2.
AJ413934 Genomic DNA. Translation: CAC93932.1.
AJ413935 Genomic DNA. Translation: CAC93933.1.
PIRJQ0032.
RefSeqNP_052803.1. NC_001496.1.
NP_652928.1. NC_003980.1.
YP_016503.2. NC_007322.2.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1J7NX-ray2.30A/B34-809[»]
1JKYX-ray3.90A34-809[»]
1PWPX-ray2.90A/B34-809[»]
1PWQX-ray3.52A/B34-809[»]
1PWUX-ray2.70A/B34-809[»]
1PWVX-ray2.85A/B34-809[»]
1PWWX-ray2.80A/B34-809[»]
1YQYX-ray2.30A297-809[»]
1ZXVX-ray2.67A/B34-809[»]
2L0RNMR-A705-809[»]
3KWVX-ray3.10C/F34-296[»]
4DV8X-ray1.63A296-809[»]
ProteinModelPortalP15917.
SMRP15917. Positions 62-809.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-29871N.
IntActP15917. 1 interaction.
MINTMINT-7014731.
STRING261594.GBAA_pXO1_0172.

Chemistry

BindingDBP15917.
ChEMBLCHEMBL4372.

Protein family/group databases

MEROPSM34.001.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaAAT28913; AAT28913; GBAA_pXO1_0172.
GeneID1158731.
2820148.
3361711.
KEGGbar:GBAA_pXO1_0172.
PATRIC24662141. VBIBacAnt106580_0160.

Phylogenomic databases

eggNOGNOG45846.
HOGENOMHOG000034565.
KOK08645.
OMARMMARYE.
OrthoDBEOG62ZHV6.

Enzyme and pathway databases

BioCycANTHRA:GBAA_PXO1_0172-MONOMER.
BANT261594:GJ7F-5757-MONOMER.

Family and domain databases

Gene3D1.10.2030.10. 1 hit.
3.40.390.10. 2 hits.
InterProIPR015239. Anthrax_tox_lethal-fac_cen.
IPR003541. Anthrax_toxin_lethal/edema.
IPR014781. Anthrax_toxin_lethal/edema_N/C.
IPR024079. MetalloPept_cat_dom.
[Graphical view]
PfamPF09156. Anthrax-tox_M. 1 hit.
PF07737. ATLF. 2 hits.
[Graphical view]
PRINTSPR01392. ANTHRAXTOXNA.
PROSITEPS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP15917.

Entry information

Entry nameLEF_BACAN
AccessionPrimary (citable) accession number: P15917
Secondary accession number(s): Q8KYJ6, Q933F6
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: July 5, 2004
Last modified: June 11, 2014
This is version 136 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references