Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Lethal factor

Gene

lef

Organism
Bacillus anthracis
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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. Also cleaves mouse Nlrp1b allele 1, leading to NLRP1 inflammasome activation, IL1B release and eventually host inflammatory response (PubMed:19651869).6 Publications

Catalytic activityi

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.

Cofactori

Zn2+4 PublicationsNote: Binds 1 zinc ion per subunit.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi719Zinc; catalytic3 Publications1
Active sitei7202 Publications1
Metal bindingi723Zinc; catalytic3 Publications1
Metal bindingi768Zinc; catalytic3 Publications1

GO - Molecular functioni

GO - Biological processi

  • negative regulation of gene expression Source: UniProtKB
  • negative regulation of MAPK cascade Source: UniProtKB
  • negative regulation of protein phosphorylation Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • pathogenesis Source: CACAO
  • positive regulation of apoptotic process in other organism Source: UniProtKB
  • proteolysis Source: CACAO
  • proteolysis in other organism Source: UniProtKB
  • regulation of establishment of endothelial barrier Source: UniProtKB
  • regulation of proteasomal protein catabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Metalloprotease, Protease, Toxin

Keywords - Biological processi

Virulence

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BioCyciANTHRA:GBAA_PXO1_0172-MONOMER.
BRENDAi3.4.24.83. 634.
ReactomeiR-HSA-5210891. Uptake and function of anthrax toxins.

Protein family/group databases

MEROPSiM34.001.

Names & Taxonomyi

Protein namesi
Recommended name:
Lethal factor (EC:3.4.24.83)
Short name:
LF
Alternative name(s):
Anthrax lethal toxin endopeptidase component
Gene namesi
Name:lef
Ordered Locus Names:pXO1-107, BXA0172, GBAA_pXO1_0172
Encoded oniPlasmid pXO10 Publication
OrganismiBacillus anthracis
Taxonomic identifieri1392 [NCBI]
Taxonomic lineageiBacteriaFirmicutesBacilliBacillalesBacillaceaeBacillusBacillus cereus group
Proteomesi
  • UP000000594 Componenti: Plasmid pXO1

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi180V → A: No effect on PA-binding ability. 1 Publication1
Mutagenesisi181Y → A: Loss of ability to bind to PA. 1 Publication1
Mutagenesisi182Y → A: Loss of ability to bind to PA. 1 Publication1
Mutagenesisi183E → A: No effect on PA-binding ability. 1 Publication1
Mutagenesisi184I → A: Loss of ability to bind to PA. 1 Publication1
Mutagenesisi185G → A: No effect on PA-binding ability. 1 Publication1
Mutagenesisi186K → A: Loss of ability to bind to PA. 1 Publication1
Mutagenesisi220D → A: Loss of ability to bind to PA and loss of toxicity. 1 Publication1
Mutagenesisi221L → A: No effect on PA-binding ability and fully toxic. 1 Publication1
Mutagenesisi222L → A: No effect on PA-binding ability and fully toxic. 1 Publication1
Mutagenesisi223F → A: Loss of ability to bind to PA and non-toxic. 1 Publication1
Mutagenesisi719H → A: Loss of activity and zinc binding. 1 Publication1
Mutagenesisi720E → C or D: Loss of activity. No effect on zinc binding. 2 Publications1
Mutagenesisi723H → A: Loss of activity and zinc binding. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL4372.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 331 PublicationAdd BLAST33
ChainiPRO_000002923334 – 809Lethal factorAdd BLAST776

Expressioni

Inductioni

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

Interactioni

Subunit structurei

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).3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
pagAP134235EBI-456923,EBI-456868

Protein-protein interaction databases

DIPiDIP-29871N.
IntActiP15917. 1 interactor.
MINTiMINT-7014731.

Chemistry databases

BindingDBiP15917.

Structurei

Secondary structure

1809
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni62 – 65Combined sources4
Helixi66 – 76Combined sources11
Beta strandi77 – 80Combined sources4
Helixi87 – 97Combined sources11
Helixi101 – 109Combined sources9
Beta strandi113 – 119Combined sources7
Helixi121 – 123Combined sources3
Helixi125 – 127Combined sources3
Helixi132 – 135Combined sources4
Beta strandi136 – 138Combined sources3
Beta strandi144 – 146Combined sources3
Helixi147 – 149Combined sources3
Beta strandi151 – 155Combined sources5
Beta strandi157 – 159Combined sources3
Beta strandi161 – 165Combined sources5
Turni170 – 172Combined sources3
Helixi174 – 190Combined sources17
Helixi193 – 196Combined sources4
Helixi201 – 211Combined sources11
Beta strandi213 – 216Combined sources4
Helixi217 – 222Combined sources6
Helixi225 – 228Combined sources4
Helixi236 – 240Combined sources5
Helixi243 – 258Combined sources16
Helixi260 – 269Combined sources10
Helixi271 – 282Combined sources12
Helixi284 – 293Combined sources10
Helixi300 – 310Combined sources11
Helixi312 – 317Combined sources6
Helixi320 – 330Combined sources11
Helixi337 – 342Combined sources6
Helixi346 – 354Combined sources9
Helixi357 – 359Combined sources3
Beta strandi361 – 363Combined sources3
Helixi365 – 379Combined sources15
Beta strandi381 – 383Combined sources3
Helixi384 – 389Combined sources6
Turni390 – 392Combined sources3
Turni393 – 396Combined sources4
Helixi403 – 412Combined sources10
Helixi413 – 415Combined sources3
Helixi421 – 428Combined sources8
Beta strandi435 – 437Combined sources3
Helixi439 – 455Combined sources17
Beta strandi458 – 460Combined sources3
Helixi461 – 464Combined sources4
Turni465 – 467Combined sources3
Beta strandi470 – 474Combined sources5
Helixi476 – 478Combined sources3
Helixi481 – 484Combined sources4
Beta strandi486 – 488Combined sources3
Helixi498 – 505Combined sources8
Beta strandi510 – 515Combined sources6
Beta strandi518 – 522Combined sources5
Beta strandi532 – 537Combined sources6
Beta strandi543 – 547Combined sources5
Turni548 – 550Combined sources3
Beta strandi551 – 554Combined sources4
Beta strandi556 – 570Combined sources15
Beta strandi573 – 583Combined sources11
Helixi585 – 607Combined sources23
Beta strandi616 – 619Combined sources4
Helixi625 – 642Combined sources18
Helixi645 – 657Combined sources13
Beta strandi662 – 667Combined sources6
Helixi669 – 671Combined sources3
Helixi673 – 676Combined sources4
Helixi682 – 684Combined sources3
Beta strandi688 – 693Combined sources6
Helixi694 – 696Combined sources3
Beta strandi698 – 705Combined sources8
Turni709 – 711Combined sources3
Helixi713 – 733Combined sources21
Beta strandi735 – 737Combined sources3
Helixi741 – 743Combined sources3
Helixi745 – 754Combined sources10
Turni755 – 757Combined sources3
Helixi761 – 763Combined sources3
Helixi766 – 777Combined sources12
Helixi782 – 791Combined sources10
Helixi793 – 807Combined sources15

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
4PKQX-ray2.20A298-809[»]
4PKRX-ray2.20A298-809[»]
4PKSX-ray2.30A298-809[»]
4PKTX-ray2.40A298-809[»]
4PKUX-ray2.40A298-809[»]
4PKVX-ray2.50A298-809[»]
4PKWX-ray1.75A298-809[»]
4WF6X-ray2.65A298-809[»]
4XM6X-ray2.35A298-809[»]
4XM7X-ray2.70A298-809[»]
4XM8X-ray2.70A298-809[»]
5D1SX-ray2.10A298-809[»]
5D1TX-ray2.20A298-809[»]
5D1UX-ray2.85A298-809[»]
ProteinModelPortaliP15917.
SMRiP15917.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP15917.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati315 – 3331Add BLAST19
Repeati342 – 3572Add BLAST16
Repeati360 – 3783Add BLAST19
Repeati380 – 3974Add BLAST18
Repeati399 – 4165Add BLAST18

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni34 – 293PA-binding regionSequence analysisAdd BLAST260
Regioni60 – 295I; PA-binding regionSequence analysisAdd BLAST236
Regioni296 – 330IIAAdd BLAST35
Regioni315 – 4165 X approximate repeatsAdd BLAST102
Regioni336 – 416IIIAdd BLAST81
Regioni420 – 583IIBAdd BLAST164
Regioni585 – 809IVAdd BLAST225

Domaini

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.

Sequence similaritiesi

Belongs to the peptidase M34 family.Curated

Keywords - Domaini

Repeat, Signal

Phylogenomic databases

HOGENOMiHOG000034565.
KOiK08645.
OMAiRMMARYE.

Family and domain databases

Gene3Di1.10.2030.10. 1 hit.
3.40.390.10. 2 hits.
InterProiIPR015239. Anthrax_tox_lethal-fac_cen.
IPR003541. Anthrax_toxin_lethal/edema.
IPR014781. Anthrax_toxin_lethal/edema_N/C.
IPR024079. MetalloPept_cat_dom.
[Graphical view]
PfamiPF09156. Anthrax-tox_M. 1 hit.
PF07737. ATLF. 2 hits.
[Graphical view]
PRINTSiPR01392. ANTHRAXTOXNA.
PROSITEiPS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P15917-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNIKKEFIKV ISMSCLVTAI TLSGPVFIPL VQGAGGHGDV GMHVKEKEKN
60 70 80 90 100
KDENKRKDEE RNKTQEEHLK EIMKHIVKIE VKGEEAVKKE AAEKLLEKVP
110 120 130 140 150
SDVLEMYKAI GGKIYIVDGD ITKHISLEAL SEDKKKIKDI YGKDALLHEH
160 170 180 190 200
YVYAKEGYEP VLVIQSSEDY VENTEKALNV YYEIGKILSR DILSKINQPY
210 220 230 240 250
QKFLDVLNTI KNASDSDGQD LLFTNQLKEH PTDFSVEFLE QNSNEVQEVF
260 270 280 290 300
AKAFAYYIEP QHRDVLQLYA PEAFNYMDKF NEQEINLSLE ELKDQRMLAR
310 320 330 340 350
YEKWEKIKQH YQHWSDSLSE EGRGLLKKLQ IPIEPKKDDI IHSLSQEEKE
360 370 380 390 400
LLKRIQIDSS DFLSTEEKEF LKKLQIDIRD SLSEEEKELL NRIQVDSSNP
410 420 430 440 450
LSEKEKEFLK KLKLDIQPYD INQRLQDTGG LIDSPSINLD VRKQYKRDIQ
460 470 480 490 500
NIDALLHQSI GSTLYNKIYL YENMNINNLT ATLGADLVDS TDNTKINRGI
510 520 530 540 550
FNEFKKNFKY SISSNYMIVD INERPALDNE RLKWRIQLSP DTRAGYLENG
560 570 580 590 600
KLILQRNIGL EIKDVQIIKQ SEKEYIRIDA KVVPKSKIDT KIQEAQLNIN
610 620 630 640 650
QEWNKALGLP KYTKLITFNV HNRYASNIVE SAYLILNEWK NNIQSDLIKK
660 670 680 690 700
VTNYLVDGNG RFVFTDITLP NIAEQYTHQD EIYEQVHSKG LYVPESRSIL
710 720 730 740 750
LHGPSKGVEL RNDSEGFIHE FGHAVDDYAG YLLDKNQSDL VTNSKKFIDI
760 770 780 790 800
FKEEGSNLTS YGRTNEAEFF AEAFRLMHST DHAERLKVQK NAPKTFQFIN

DQIKFIINS
Length:809
Mass (Da):93,770
Last modified:July 5, 2004 - v2
Checksum:i2076B4D7277317EE
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti299A → S in strain: Sterne. 1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
PIRiJQ0032.
RefSeqiNP_052803.1. NC_001496.1.
WP_001022097.1. NZ_LHUO01000026.1.
WP_010890024.1. NZ_JTAE01000006.1.

Genome annotation databases

EnsemblBacteriaiAAM26117; AAM26117; BX_A0172.
AAT28913; AAT28913; GBAA_pXO1_0172.
GeneIDi3361711.
KEGGibar:GBAA_pXO1_0172.
PATRICi24662141. VBIBacAnt106580_0160.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
PIRiJQ0032.
RefSeqiNP_052803.1. NC_001496.1.
WP_001022097.1. NZ_LHUO01000026.1.
WP_010890024.1. NZ_JTAE01000006.1.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
4PKQX-ray2.20A298-809[»]
4PKRX-ray2.20A298-809[»]
4PKSX-ray2.30A298-809[»]
4PKTX-ray2.40A298-809[»]
4PKUX-ray2.40A298-809[»]
4PKVX-ray2.50A298-809[»]
4PKWX-ray1.75A298-809[»]
4WF6X-ray2.65A298-809[»]
4XM6X-ray2.35A298-809[»]
4XM7X-ray2.70A298-809[»]
4XM8X-ray2.70A298-809[»]
5D1SX-ray2.10A298-809[»]
5D1TX-ray2.20A298-809[»]
5D1UX-ray2.85A298-809[»]
ProteinModelPortaliP15917.
SMRiP15917.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-29871N.
IntActiP15917. 1 interactor.
MINTiMINT-7014731.

Chemistry databases

BindingDBiP15917.
ChEMBLiCHEMBL4372.

Protein family/group databases

MEROPSiM34.001.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaiAAM26117; AAM26117; BX_A0172.
AAT28913; AAT28913; GBAA_pXO1_0172.
GeneIDi3361711.
KEGGibar:GBAA_pXO1_0172.
PATRICi24662141. VBIBacAnt106580_0160.

Phylogenomic databases

HOGENOMiHOG000034565.
KOiK08645.
OMAiRMMARYE.

Enzyme and pathway databases

BioCyciANTHRA:GBAA_PXO1_0172-MONOMER.
BRENDAi3.4.24.83. 634.
ReactomeiR-HSA-5210891. Uptake and function of anthrax toxins.

Miscellaneous databases

EvolutionaryTraceiP15917.
PROiP15917.

Family and domain databases

Gene3Di1.10.2030.10. 1 hit.
3.40.390.10. 2 hits.
InterProiIPR015239. Anthrax_tox_lethal-fac_cen.
IPR003541. Anthrax_toxin_lethal/edema.
IPR014781. Anthrax_toxin_lethal/edema_N/C.
IPR024079. MetalloPept_cat_dom.
[Graphical view]
PfamiPF09156. Anthrax-tox_M. 1 hit.
PF07737. ATLF. 2 hits.
[Graphical view]
PRINTSiPR01392. ANTHRAXTOXNA.
PROSITEiPS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiLEF_BACAN
AccessioniPrimary (citable) accession number: P15917
Secondary accession number(s): Q8KYJ6, Q933F6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: July 5, 2004
Last modified: November 30, 2016
This is version 158 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Miscellaneousi

Miscellaneous

LF binds to the heptamer formed by cleaved PA on the host cell membrane. This step is followed by internalization of the heterooligomeric 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.

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Plasmid, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. Peptidase families
    Classification of peptidase families and list of entries
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.