| IED ID | IndEnz0002006566 |
| Enzyme Type ID | protease006566 |
| Protein Name |
Lethal factor LF EC 3.4.24.83 Anthrax lethal toxin endopeptidase component |
| Gene Name | lef pXO1-107 BXA0172 GBAA_pXO1_0172 |
| Organism | Bacillus anthracis |
| Taxonomic Lineage | cellular organisms Bacteria Terrabacteria group Firmicutes Bacilli Bacillales Bacillaceae Bacillus Bacillus cereus group Bacillus anthracis |
| Enzyme Sequence | MNIKKEFIKVISMSCLVTAITLSGPVFIPLVQGAGGHGDVGMHVKEKEKNKDENKRKDEERNKTQEEHLKEIMKHIVKIEVKGEEAVKKEAAEKLLEKVPSDVLEMYKAIGGKIYIVDGDITKHISLEALSEDKKKIKDIYGKDALLHEHYVYAKEGYEPVLVIQSSEDYVENTEKALNVYYEIGKILSRDILSKINQPYQKFLDVLNTIKNASDSDGQDLLFTNQLKEHPTDFSVEFLEQNSNEVQEVFAKAFAYYIEPQHRDVLQLYAPEAFNYMDKFNEQEINLSLEELKDQRMLARYEKWEKIKQHYQHWSDSLSEEGRGLLKKLQIPIEPKKDDIIHSLSQEEKELLKRIQIDSSDFLSTEEKEFLKKLQIDIRDSLSEEEKELLNRIQVDSSNPLSEKEKEFLKKLKLDIQPYDINQRLQDTGGLIDSPSINLDVRKQYKRDIQNIDALLHQSIGSTLYNKIYLYENMNINNLTATLGADLVDSTDNTKINRGIFNEFKKNFKYSISSNYMIVDINERPALDNERLKWRIQLSPDTRAGYLENGKLILQRNIGLEIKDVQIIKQSEKEYIRIDAKVVPKSKIDTKIQEAQLNINQEWNKALGLPKYTKLITFNVHNRYASNIVESAYLILNEWKNNIQSDLIKKVTNYLVDGNGRFVFTDITLPNIAEQYTHQDEIYEQVHSKGLYVPESRSILLHGPSKGVELRNDSEGFIHEFGHAVDDYAGYLLDKNQSDLVTNSKKFIDIFKEEGSNLTSYGRTNEAEFFAEAFRLMHSTDHAERLKVQKNAPKTFQFINDQIKFIINS |
| Enzyme Length | 809 |
| Uniprot Accession Number | P15917 |
| Absorption | |
| Active Site | ACT_SITE 720; /evidence="ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:9573135" |
| Activity Regulation | ACTIVITY REGULATION: Inhibited by NSC-12155 (1,3-Bis(2-methyl-4-aminoquinoline-6-yl)ure) (PubMed:14718925). Inhibited by phenoxyacetic acid bearing alpha-benzyl substituents on the C2-side chain (PubMed:22342144). Inhibited by sulfonamide hydroxamate with benzylic additions at the sulfonamide nitrogen (PubMed:25372673). Also inhibited by sulfonamide hydroxamates with alkylation at the sulfonamide nitrogen (PubMed:26492514). Inhibited by hydroxamic acid inhibitors (PubMed:26578066). {ECO:0000269|PubMed:14718925, ECO:0000269|PubMed:22342144, ECO:0000269|PubMed:25372673, ECO:0000269|PubMed:26492514, ECO:0000269|PubMed:26578066}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=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.; EC=3.4.24.83; Evidence={ECO:0000269|PubMed:14718925, ECO:0000269|PubMed:9563949}; |
| DNA Binding | |
| EC Number | 3.4.24.83 |
| Enzyme Function | FUNCTION: Lethal factor (LF), which constitutes one of the three proteins composing the anthrax toxin, is able to trigger rapid cell death in macrophages (PubMed:3711080, PubMed:8380282, PubMed:9563949, PubMed:10475971, PubMed:11104681, PubMed:9703991). Acts as 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 (PubMed:9563949, PubMed:10475971, PubMed:11104681, PubMed:9703991, PubMed:14718925). Also cleaves mouse Nlrp1b: host Nlrp1b cleavage promotes ubiquitination and degradation of the N-terminal part of Nlrp1b by the proteasome, thereby releasing the cleaved C-terminal part of Nlrp1b, which polymerizes and forms the Nlrp1b inflammasome followed by host cell pyroptosis (PubMed:10338520, PubMed:19651869, PubMed:31268597, PubMed:30872531). Able to cleave mouse Nlrp1b alleles 1 and 5, while it is not able to cleave Nlrp1b alleles 2, 3 and 4 (PubMed:16429160, PubMed:19651869). In contrast, does not cleave NLRP1 human ortholog (PubMed:19651869). LF is not toxic by itself and only acts as a lethal factor when associated with protective antigen (PA) to form the lethal toxin (LeTx): PA is required for LF translocation into the host cytosol (PubMed:9563949, PubMed:10475971, PubMed:11104681, PubMed:9703991). {ECO:0000269|PubMed:10338520, ECO:0000269|PubMed:10475971, ECO:0000269|PubMed:11104681, ECO:0000269|PubMed:14718925, ECO:0000269|PubMed:16429160, ECO:0000269|PubMed:19651869, ECO:0000269|PubMed:30872531, ECO:0000269|PubMed:31268597, ECO:0000269|PubMed:3711080, ECO:0000269|PubMed:8380282, ECO:0000269|PubMed:9563949, ECO:0000269|PubMed:9703991}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (1); Beta strand (26); Chain (1); Compositional bias (1); Domain (2); Helix (47); Metal binding (3); Mutagenesis (21); Natural variant (1); Region (7); Repeat (5); Signal peptide (1); Turn (8) |
| Keywords | 3D-structure;Direct protein sequencing;Host cytoplasm;Hydrolase;Metal-binding;Metalloprotease;Plasmid;Protease;Reference proteome;Repeat;Secreted;Signal;Toxin;Virulence;Zinc |
| Interact With | P13423 |
| Induction | INDUCTION: Positively transcriptionally regulated by AtxA, which, in turn, is induced by bicarbonate and high temperatures (37 degrees Celsius). {ECO:0000269|PubMed:8051039}. |
| Subcellular Location | SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:2509294}. Host cytoplasm, host cytosol {ECO:0000269|PubMed:1512256}. Note=Translocation into host cytosol is mediated via interaction with the cleaved form of protective antigen (PA-63): following secretion, LF binds via its N-terminal region to the upper rim of the ring-shaped homooligomer formed by PA-63 on the host cell membrane (PubMed:21037566, PubMed:32810181). In this PA-63 pre-pore state, the N-terminal segment of LF refolds into an alpha helix engaged in the alpha-clamp of the PA-63 pre-pore (PubMed:32047164, PubMed:32521227). Loaded complexes are then endocytosed, followed by a conformational change of oligomerized PA-63 from the pre-pore to pore state, which is triggered by the low pH in the endosome (PubMed:3711080, PubMed:8380282, PubMed:10085027, PubMed:12551953). LF is then unfolded to pass through the PA-63 pore and translocate into the host cytosol (PubMed:21037566, PubMed:32047164, PubMed:32521227). {ECO:0000269|PubMed:10085027, ECO:0000269|PubMed:12551953, ECO:0000269|PubMed:21037566, ECO:0000269|PubMed:32047164, ECO:0000269|PubMed:32521227, ECO:0000269|PubMed:32810181, ECO:0000269|PubMed:3711080, ECO:0000269|PubMed:8380282}. |
| Modified Residue | |
| Post Translational Modification | |
| Signal Peptide | SIGNAL 1..33; /evidence=ECO:0000269|PubMed:2509294 |
| Structure 3D | NMR spectroscopy (1); Electron microscopy (6); X-ray crystallography (25) |
| Cross Reference PDB | 1J7N; 1JKY; 1PWP; 1PWQ; 1PWU; 1PWV; 1PWW; 1YQY; 1ZXV; 2L0R; 3KWV; 4DV8; 4PKQ; 4PKR; 4PKS; 4PKT; 4PKU; 4PKV; 4PKW; 4WF6; 4XM6; 4XM7; 4XM8; 5D1S; 5D1T; 5D1U; 6PSN; 6WJJ; 6ZXJ; 6ZXK; 6ZXL; 7KXR; |
| Mapped Pubmed ID | 11790132; 15983377; 16293620; 16338135; 19332063; 23313942; 34158520; |
| Motif | |
| Gene Encoded By | Plasmid pXO1 |
| Mass | 93,770 |
| Kinetics | |
| Metal Binding | METAL 719; /note="Zinc; via tele nitrogen"; /evidence="ECO:0000269|PubMed:11700563, ECO:0000269|PubMed:14718924, ECO:0000269|PubMed:14718925, ECO:0000269|PubMed:15911756, ECO:0000269|PubMed:22342144, ECO:0000269|PubMed:25372673, ECO:0000269|PubMed:26492514, ECO:0000269|PubMed:26578066, ECO:0007744|PDB:1J7N, ECO:0007744|PDB:1PWP, ECO:0007744|PDB:1PWQ, ECO:0007744|PDB:1PWU, ECO:0007744|PDB:1PWW, ECO:0007744|PDB:1YQY, ECO:0007744|PDB:4DV8, ECO:0007744|PDB:4PKQ, ECO:0007744|PDB:4PKR, ECO:0007744|PDB:4PKS, ECO:0007744|PDB:4PKT, ECO:0007744|PDB:4PKV, ECO:0007744|PDB:4PKW, ECO:0007744|PDB:4WF6, ECO:0007744|PDB:4XM6, ECO:0007744|PDB:4XM7, ECO:0007744|PDB:5D1S, ECO:0007744|PDB:5D1T"; METAL 723; /note="Zinc; via tele nitrogen"; /evidence="ECO:0000269|PubMed:11700563, ECO:0000269|PubMed:14718924, ECO:0000269|PubMed:14718925, ECO:0000269|PubMed:15911756, ECO:0000269|PubMed:22342144, ECO:0000269|PubMed:25372673, ECO:0000269|PubMed:26492514, ECO:0000269|PubMed:26578066, ECO:0007744|PDB:1J7N, ECO:0007744|PDB:1PWP, ECO:0007744|PDB:1PWQ, ECO:0007744|PDB:1PWU, ECO:0007744|PDB:1PWW, ECO:0007744|PDB:1YQY, ECO:0007744|PDB:4DV8, ECO:0007744|PDB:4PKQ, ECO:0007744|PDB:4PKR, ECO:0007744|PDB:4PKS, ECO:0007744|PDB:4PKT, ECO:0007744|PDB:4PKV, ECO:0007744|PDB:4PKW, ECO:0007744|PDB:4WF6, ECO:0007744|PDB:4XM6, ECO:0007744|PDB:4XM7, ECO:0007744|PDB:5D1S, ECO:0007744|PDB:5D1T"; METAL 768; /note="Zinc"; /evidence="ECO:0000269|PubMed:11700563, ECO:0000269|PubMed:14718924, ECO:0000269|PubMed:14718925, ECO:0000269|PubMed:15911756, ECO:0000269|PubMed:22342144, ECO:0000269|PubMed:25372673, ECO:0000269|PubMed:26492514, ECO:0000269|PubMed:26578066, ECO:0007744|PDB:1J7N, ECO:0007744|PDB:1PWP, ECO:0007744|PDB:1PWQ, ECO:0007744|PDB:1PWU, ECO:0007744|PDB:1PWW, ECO:0007744|PDB:1YQY, ECO:0007744|PDB:4DV8, ECO:0007744|PDB:4PKQ, ECO:0007744|PDB:4PKR, ECO:0007744|PDB:4PKS, ECO:0007744|PDB:4PKT, ECO:0007744|PDB:4PKV, ECO:0007744|PDB:4PKW, ECO:0007744|PDB:4WF6, ECO:0007744|PDB:4XM6, ECO:0007744|PDB:4XM7, ECO:0007744|PDB:5D1S, ECO:0007744|PDB:5D1T" |
| Rhea ID | |
| Cross Reference Brenda | 3.4.24.83; |