Protein: Lethal factor (LF) (EC 3.4.24.83) (Anthrax lethal toxin endopeptidase component) (P15917)
Organism: Bacillus anthracis
Function: Lethal factor (LF), which constitutes one of the three proteins composing the anthrax toxin, is able to trigger rapid cell death in macrophages. 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. 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. Able to cleave mouse Nlrp1b alleles 1 and 5, while it is not able to cleave Nlrp1b alleles 2, 3 and 4. In contrast, does not cleave NLRP1 human ortholog. 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.
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:10085027, PubMed:12551953, PubMed:3711080, PubMed:8380282). 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}.
Interaction partners:
Sequence:
MNIKKEFIKVISMSCLVTAITLSGPVFIPLVQGAGGHGDVGMHVKEKEKNKDENKRKDEERNKTQEEHLKEIMKHIVKIEVKGEEAVKKEAAEKLLEKVPSDVLEMYKAIGGKIYIVDGDITKHISLEALSEDKKKIKDIYGKDALLHEHYVYAKEGYEPVLVIQSSEDYVENTEKALNVYYEIGKILSRDILSKINQPYQKFLDVLNTIKNASDSDGQDLLFTNQLKEHPTDFSVEFLEQNSNEVQEVFAKAFAYYIEPQHRDVLQLYAPEAFNYMDKFNEQEINLSLEELKDQRMLARYEKWEKIKQHYQHWSDSLSEEGRGLLKKLQIPIEPKKDDIIHSLSQEEKELLKRIQIDSSDFLSTEEKEFLKKLQIDIRDSLSEEEKELLNRIQVDSSNPLSEKEKEFLKKLKLDIQPYDINQRLQDTGGLIDSPSINLDVRKQYKRDIQNIDALLHQSIGSTLYNKIYLYENMNINNLTATLGADLVDSTDNTKINRGIFNEFKKNFKYSISSNYMIVDINERPALDNERLKWRIQLSPDTRAGYLENGKLILQRNIGLEIKDVQIIKQSEKEYIRIDAKVVPKSKIDTKIQEAQLNINQEWNKALGLPKYTKLITFNVHNRYASNIVESAYLILNEWKNNIQSDLIKKVTNYLVDGNGRFVFTDITLPNIAEQYTHQDEIYEQVHSKGLYVPESRSILLHGPSKGVELRNDSEGFIHEFGHAVDDYAGYLLDKNQSDLVTNSKKFIDIFKEEGSNLTSYGRTNEAEFFAEAFRLMHSTDHAERLKVQKNAPKTFQFINDQIKFIINS