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Protein

Lethal factor

Gene

lef

Organism
Bacillus anthracis
Status
Reviewed-Annotation score: -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

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.

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

Keywordsi

Molecular functionHydrolase, Metalloprotease, Protease, Toxin
Biological processVirulence
LigandMetal-binding, Zinc

Enzyme and pathway databases

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

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
DrugBankiDB07290 (2R)-2-{[(4-FLUORO-3-METHYLPHENYL)SULFONYL]AMINO}-N-HYDROXY-2-TETRAHYDRO-2H-PYRAN-4-YLACETAMIDE
DB08177 (E)-3-(5((5-(4-CHLOROPHENYL)FURAN-2-YL)METHYLENE)-4-OXO-2-THIOXOTHIAZOLIDIN-3-YL)PROPANOIC ACID
DB02255 GM6001
DB01883 N-(Sulfanylacetyl)Tyrosylprolylmethioninamide

PTM / Processingi

Molecule processing

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

Proteomic databases

PRIDEiP15917

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
pagAP1342328EBI-456923,EBI-456868

Protein-protein interaction databases

DIPiDIP-29871N
IntActiP15917, 6 interactors
MINTiP15917

Chemistry databases

BindingDBiP15917

Structurei

Secondary structure

1809
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

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

Gene3Di3.40.390.10, 2 hits
InterProiView protein in InterPro
IPR015239 Anthrax_LF_cen
IPR003541 Anthrax_toxin_lethal/edema
IPR014781 Anthrax_toxin_lethal/edema_N/C
IPR024079 MetalloPept_cat_dom_sf
PfamiView protein in Pfam
PF09156 Anthrax-tox_M, 1 hit
PF07737 ATLF, 2 hits
PRINTSiPR01392 ANTHRAXTOXNA
PROSITEiView protein in PROSITE
PS00142 ZINC_PROTEASE, 1 hit

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_QANP01000007.1
WP_010890024.1, NZ_NRIZ01000019.1

Genome annotation databases

EnsemblBacteriaiAAM26117; AAM26117; BX_A0172
AAT28913; AAT28913; GBAA_pXO1_0172
GeneIDi3361711
KEGGibar:GBAA_pXO1_0172

Similar proteinsi

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_QANP01000007.1
WP_010890024.1, NZ_NRIZ01000019.1

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, 6 interactors
MINTiP15917

Chemistry databases

BindingDBiP15917
ChEMBLiCHEMBL4372
DrugBankiDB07290 (2R)-2-{[(4-FLUORO-3-METHYLPHENYL)SULFONYL]AMINO}-N-HYDROXY-2-TETRAHYDRO-2H-PYRAN-4-YLACETAMIDE
DB08177 (E)-3-(5((5-(4-CHLOROPHENYL)FURAN-2-YL)METHYLENE)-4-OXO-2-THIOXOTHIAZOLIDIN-3-YL)PROPANOIC ACID
DB02255 GM6001
DB01883 N-(Sulfanylacetyl)Tyrosylprolylmethioninamide

Protein family/group databases

MEROPSiM34.001

Proteomic databases

PRIDEiP15917

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaiAAM26117; AAM26117; BX_A0172
AAT28913; AAT28913; GBAA_pXO1_0172
GeneIDi3361711
KEGGibar:GBAA_pXO1_0172

Phylogenomic databases

HOGENOMiHOG000034565
KOiK08645
OMAiRMMARYE

Enzyme and pathway databases

BRENDAi3.4.24.83 634
ReactomeiR-HSA-5210891 Uptake and function of anthrax toxins

Miscellaneous databases

EvolutionaryTraceiP15917
PROiPR:P15917

Family and domain databases

Gene3Di3.40.390.10, 2 hits
InterProiView protein in InterPro
IPR015239 Anthrax_LF_cen
IPR003541 Anthrax_toxin_lethal/edema
IPR014781 Anthrax_toxin_lethal/edema_N/C
IPR024079 MetalloPept_cat_dom_sf
PfamiView protein in Pfam
PF09156 Anthrax-tox_M, 1 hit
PF07737 ATLF, 2 hits
PRINTSiPR01392 ANTHRAXTOXNA
PROSITEiView protein in PROSITE
PS00142 ZINC_PROTEASE, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiLEF_BACAN
AccessioniPrimary (citable) accession number: P15917
Secondary accession number(s): Q8KYJ6, Q933F6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: July 5, 2004
Last modified: July 18, 2018
This is version 171 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

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

Documents

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