Lethal factor

Details

Name
Lethal factor
Synonyms
  • 3.4.24.83
  • Anthrax lethal toxin endopeptidase component
  • LF
Gene Name
lef
Organism
Bacillus anthracis
Amino acid sequence
>lcl|BSEQ0016400|Lethal factor
MNIKKEFIKVISMSCLVTAITLSGPVFIPLVQGAGGHGDVGMHVKEKEKNKDENKRKDEE
RNKTQEEHLKEIMKHIVKIEVKGEEAVKKEAAEKLLEKVPSDVLEMYKAIGGKIYIVDGD
ITKHISLEALSEDKKKIKDIYGKDALLHEHYVYAKEGYEPVLVIQSSEDYVENTEKALNV
YYEIGKILSRDILSKINQPYQKFLDVLNTIKNASDSDGQDLLFTNQLKEHPTDFSVEFLE
QNSNEVQEVFAKAFAYYIEPQHRDVLQLYAPEAFNYMDKFNEQEINLSLEELKDQRMLAR
YEKWEKIKQHYQHWSDSLSEEGRGLLKKLQIPIEPKKDDIIHSLSQEEKELLKRIQIDSS
DFLSTEEKEFLKKLQIDIRDSLSEEEKELLNRIQVDSSNPLSEKEKEFLKKLKLDIQPYD
INQRLQDTGGLIDSPSINLDVRKQYKRDIQNIDALLHQSIGSTLYNKIYLYENMNINNLT
ATLGADLVDSTDNTKINRGIFNEFKKNFKYSISSNYMIVDINERPALDNERLKWRIQLSP
DTRAGYLENGKLILQRNIGLEIKDVQIIKQSEKEYIRIDAKVVPKSKIDTKIQEAQLNIN
QEWNKALGLPKYTKLITFNVHNRYASNIVESAYLILNEWKNNIQSDLIKKVTNYLVDGNG
RFVFTDITLPNIAEQYTHQDEIYEQVHSKGLYVPESRSILLHGPSKGVELRNDSEGFIHE
FGHAVDDYAGYLLDKNQSDLVTNSKKFIDIFKEEGSNLTSYGRTNEAEFFAEAFRLMHST
DHAERLKVQKNAPKTFQFINDQIKFIINS
Number of residues
809
Molecular Weight
93769.58
Theoretical pI
5.69
GO Classification
Functions
metal ion binding / metallopeptidase activity
Processes
negative regulation of gene expression / negative regulation of MAPK cascade / negative regulation of protein phosphorylation / negative regulation of transcription from RNA polymerase II promoter / pathogenesis / positive regulation of apoptotic process in other organism / proteolysis / proteolysis in other organism / regulation of establishment of endothelial barrier / regulation of proteasomal protein catabolic process
Components
cytosol / endosome membrane / extracellular region / plasma membrane
General Function
Metallopeptidase activity
Specific 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. Also cleaves mouse Nlrp1b allele 1, leading to NLRP1 inflammasome activation, IL1B release and eventually host inflammatory response (PubMed:19651869).
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Secreted
Gene sequence
>lcl|BSEQ0016401|Lethal factor (lef)
ATGAATATAAAAAAAGAATTTATAAAAGTAATTAGTATGTCATGTTTAGTAACAGCAATT
ACTTTGAGTGGTCCCGTCTTTATCCCCCTTGTACAGGGGGCGGGCGGTCATGGTGATGTA
GGTATGCACGTAAAAGAGAAAGAGAAAAATAAAGATGAGAATAAGAGAAAAGATGAAGAA
CGAAATAAAACACAGGAAGAGCATTTAAAGGAAATCATGAAACACATTGTAAAAATAGAA
GTAAAAGGGGAGGAAGCTGTTAAAAAAGAGGCAGCAGAAAAGCTACTTGAGAAAGTACCA
TCTGATGTTTTAGAGATGTATAAAGCAATTGGAGGAAAGATATATATTGTGGATGGTGAT
ATTACAAAACATATATCTTTAGAAGCATTATCTGAAGATAAGAAAAAAATAAAAGACATT
TATGGGAAAGATGCTTTATTACATGAACATTATGTATATGCAAAAGAAGGATATGAACCC
GTACTTGTAATCCAATCTTCGGAAGATTATGTAGAAAATACTGAAAAGGCACTGAACGTT
TATTATGAAATAGGTAAGATATTATCAAGGGATATTTTAAGTAAAATTAATCAACCATAT
CAGAAATTTTTAGATGTATTAAATACCATTAAAAATGCATCTGATTCAGATGGACAAGAT
CTTTTATTTACTAATCAGCTTAAGGAACATCCCACAGACTTTTCTGTAGAATTCTTGGAA
CAAAATAGCAATGAGGTACAAGAAGTATTTGCGAAAGCTTTTGCATATTATATCGAGCCA
CAGCATCGTGATGTTTTACAGCTTTATGCACCGGAAGCTTTTAATTACATGGATAAATTT
AACGAACAAGAAATAAATCTATCCTTGGAAGAACTTAAAGATCAACGGATGCTGGCAAGA
TATGAAAAATGGGAAAAGATAAAACAGCACTATCAACACTGGAGCGATTCTTTATCTGAA
GAAGGAAGAGGACTTTTAAAAAAGCTGCAGATTCCTATTGAGCCAAAGAAAGATGACATA
ATTCATTCTTTATCTCAAGAAGAAAAAGAGCTTCTAAAAAGAATACAAATTGATAGTAGT
GATTTTTTATCTACTGAGGAAAAAGAGTTTTTAAAAAAGCTACAAATTGATATTCGTGAT
TCTTTATCTGAAGAAGAAAAAGAGCTTTTAAATAGAATACAGGTGGATAGTAGTAATCCT
TTATCTGAAAAAGAAAAAGAGTTTTTAAAAAAGCTGAAACTTGATATTCAACCATATGAT
ATTAATCAAAGGTTGCAAGATACAGGAGGGTTAATTGATAGTCCGTCAATTAATCTTGAT
GTAAGAAAGCAGTATAAAAGGGATATTCAAAATATTGATGCTTTATTACATCAATCCATT
GGAAGTACCTTGTACAATAAAATTTATTTGTATGAAAATATGAATATCAATAACCTTACA
GCAACCCTAGGTGCGGATTTAGTTGATTCCACTGATAATACTAAAATTAATAGAGGTATT
TTCAATGAATTCAAAAAAAATTTCAAATATAGTATTTCTAGTAACTATATGATTGTTGAT
ATAAATGAAAGGCCTGCATTAGATAATGAGCGTTTGAAATGGAGAATCCAATTATCACCA
GATACTCGAGCAGGATATTTAGAAAATGGAAAGCTTATATTACAAAGAAACATCGGTCTG
GAAATAAAGGATGTACAAATAATTAAGCAATCCGAAAAAGAATATATAAGGATTGATGCG
AAAGTAGTGCCAAAGAGTAAAATAGATACAAAAATTCAAGAAGCACAGTTAAATATAAAT
CAGGAATGGAATAAAGCATTAGGGTTACCAAAATATACAAAGCTTATTACATTCAACGTG
CATAATAGATATGCATCCAATATTGTAGAAAGTGCTTATTTAATATTGAATGAATGGAAA
AATAATATTCAAAGTGATCTTATAAAAAAGGTAACAAATTACTTAGTTGATGGTAATGGA
AGATTTGTTTTTACCGATATTACTCTCCCTAATATAGCTGAACAATATACACATCAAGAT
GAGATATATGAGCAAGTTCATTCAAAAGGGTTATATGTTCCAGAATCCCGTTCTATATTA
CTCCATGGACCTTCAAAAGGTGTAGAATTAAGGAATGATAGTGAGGGTTTTATACACGAA
TTTGGACATGCTGTGGATGATTATGCTGGATATCTATTAGATAAGAACCAATCTGATTTA
GTTACAAATTCTAAAAAATTCATTGATATTTTTAAGGAAGAAGGGAGTAATTTAACTTCG
TATGGGAGAACAAATGAAGCGGAATTTTTTGCAGAAGCCTTTAGGTTAATGCATTCTACG
GACCATGCTGAACGTTTAAAAGTTCAAAAAAATGCTCCGAAAACTTTCCAATTTATTAAC
GATCAGATTAAGTTCATTATTAACTCATAA
Chromosome Location
Not Available
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDP15917
UniProtKB Entry NameLEF_BACAN
GenBank Protein ID143144
GenBank Gene IDM29081
General References
  1. Bragg TS, Robertson DL: Nucleotide sequence and analysis of the lethal factor gene (lef) from Bacillus anthracis. Gene. 1989 Sep 1;81(1):45-54. [Article]
  2. Okinaka RT, Cloud K, Hampton O, Hoffmaster AR, Hill KK, Keim P, Koehler TM, Lamke G, Kumano S, Mahillon J, Manter D, Martinez Y, Ricke D, Svensson R, Jackson PJ: Sequence and organization of pXO1, the large Bacillus anthracis plasmid harboring the anthrax toxin genes. J Bacteriol. 1999 Oct;181(20):6509-15. [Article]
  3. Read TD, Salzberg SL, Pop M, Shumway M, Umayam L, Jiang L, Holtzapple E, Busch JD, Smith KL, Schupp JM, Solomon D, Keim P, Fraser CM: Comparative genome sequencing for discovery of novel polymorphisms in Bacillus anthracis. Science. 2002 Jun 14;296(5575):2028-33. Epub 2002 May 9. [Article]
  4. Ravel J, Jiang L, Stanley ST, Wilson MR, Decker RS, Read TD, Worsham P, Keim PS, Salzberg SL, Fraser-Liggett CM, Rasko DA: The complete genome sequence of Bacillus anthracis Ames "Ancestor". J Bacteriol. 2009 Jan;191(1):445-6. doi: 10.1128/JB.01347-08. Epub 2008 Oct 24. [Article]
  5. Adone R, Pasquali P, La Rosa G, Marianelli C, Muscillo M, Fasanella A, Francia M, Ciuchini F: Sequence analysis of the genes encoding for the major virulence factors of Bacillus anthracis vaccine strain 'Carbosap'. J Appl Microbiol. 2002;93(1):117-21. [Article]
  6. Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR, Copeland TD, Ahn NG, Oskarsson MK, Fukasawa K, Paull KD, Vande Woude GF: Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science. 1998 May 1;280(5364):734-7. [Article]
  7. Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M, Montecucco C: Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun. 1998 Jul 30;248(3):706-11. [Article]
  8. Duesbery NS, Vande Woude GF: Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase. J Appl Microbiol. 1999 Aug;87(2):289-93. [Article]
  9. Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C: Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J. 2000 Dec 15;352 Pt 3:739-45. [Article]
  10. Tang G, Leppla SH: Proteasome activity is required for anthrax lethal toxin to kill macrophages. Infect Immun. 1999 Jun;67(6):3055-60. [Article]
  11. Wang XM, Mock M, Ruysschaert JM, Cabiaux V: Secondary structure of anthrax lethal toxin proteins and their interaction with large unilamellar vesicles: a fourier-transform infrared spectroscopy approach. Biochemistry. 1996 Nov 26;35(47):14939-46. [Article]
  12. Kochi SK, Schiavo G, Mock M, Montecucco C: Zinc content of the Bacillus anthracis lethal factor. FEMS Microbiol Lett. 1994 Dec 15;124(3):343-8. [Article]
  13. Sirard JC, Mock M, Fouet A: The three Bacillus anthracis toxin genes are coordinately regulated by bicarbonate and temperature. J Bacteriol. 1994 Aug;176(16):5188-92. [Article]
  14. Hammond SE, Hanna PC: Lethal factor active-site mutations affect catalytic activity in vitro. Infect Immun. 1998 May;66(5):2374-8. [Article]
  15. Gupta P, Singh A, Chauhan V, Bhatnagar R: Involvement of residues 147VYYEIGK153 in binding of lethal factor to protective antigen of Bacillus anthracis. Biochem Biophys Res Commun. 2001 Jan 12;280(1):158-63. [Article]
  16. Singh A, Chauhan V, Sodhi A, Bhatnagar R: Asp 187 and Phe 190 residues in lethal factor are required for the expression of anthrax lethal toxin activity. FEMS Microbiol Lett. 2002 Jul 2;212(2):183-6. [Article]
  17. Brossier F, Mock M: Toxins of Bacillus anthracis. Toxicon. 2001 Nov;39(11):1747-55. [Article]
  18. Liao KC, Mogridge J: Expression of Nlrp1b inflammasome components in human fibroblasts confers susceptibility to anthrax lethal toxin. Infect Immun. 2009 Oct;77(10):4455-62. doi: 10.1128/IAI.00276-09. Epub 2009 Aug 3. [Article]
  19. Pannifer AD, Wong TY, Schwarzenbacher R, Renatus M, Petosa C, Bienkowska J, Lacy DB, Collier RJ, Park S, Leppla SH, Hanna P, Liddington RC: Crystal structure of the anthrax lethal factor. Nature. 2001 Nov 8;414(6860):229-33. [Article]
  20. Turk BE, Wong TY, Schwarzenbacher R, Jarrell ET, Leppla SH, Collier RJ, Liddington RC, Cantley LC: The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor. Nat Struct Mol Biol. 2004 Jan;11(1):60-6. Epub 2003 Dec 29. [Article]
  21. Shoop WL, Xiong Y, Wiltsie J, Woods A, Guo J, Pivnichny JV, Felcetto T, Michael BF, Bansal A, Cummings RT, Cunningham BR, Friedlander AM, Douglas CM, Patel SB, Wisniewski D, Scapin G, Salowe SP, Zaller DM, Chapman KT, Scolnick EM, Schmatz DM, Bartizal K, MacCoss M, Hermes JD: Anthrax lethal factor inhibition. Proc Natl Acad Sci U S A. 2005 May 31;102(22):7958-63. Epub 2005 May 23. [Article]

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