Family M34


Summary Holotypes Alignment Tree Genomes Structure Literature

Summary for family M34

NamePeptidase family M34 (anthrax lethal factor family)
Family type peptidaseM34.001 - anthrax lethal factor (Bacillus anthracis), MEROPS Accession MER0001345 (peptidase unit: 585-809)
Content of familyPeptidase family M34 contains a highly-selective bacterial endopeptidase.
History Identifier created: Proteolysis in Cell Function, pp13-21, IOS Press, Amsterdam (1997)
Catalytic typeMetallo
Active site residuesH719 E720 H723 Y761 E768 
Active siteAnthrax lethal factor (M34.001) is one of the HEXXH motif" metallopeptidases in clan MA. In these, the two histidines of the HEXXH motif are ligands of a single zinc atom, and the glutamate has a catalytic role. A more C-terminal glutamate acts as the third ligand of the zinc atom, and a tyrosine residue contributes to catalysis (Tonello et al., 2004).
Activities and specificitiesLethal factor is an endopeptidase with highly restricted specificity, the only known protein substrates being mitogen-activated protein kinase kinases (MAPKKs; Vitale et al., 2000). The proteins are cleaved near their N-termini, which inactivates them. An approximate consensus sequence for cleavage has been defined as Xbb-Xbb-Xbb-Xbb-Xaa-Xcc-XaaXcc, in which Xaa is any amino acid, Xbb is Lys or Arg, and Xcc is a hydrophobic amino acid, but it is clear that selectivity for the MAPKK proteins must also depend upon recognition of some structural element more remote from the site of cleavage (Leppla, 2004). Laboratory methods for the assay of lethal factor have been described by Min et al. (2004).
InhibitorsInhibitors with potency in the micromolar Ki range have been described (Min et al., 2004; Panchal et al., 2004; Turk et al., 2004).
Molecular structureThe crystal structure shows that lethal factor is formed of four domains. Domain IV is the peptidase unit, which shows limited similarities to the N-terminal domain of thermolysin (M04.001). The active-site cleft lies between domains III and IV, and the zinc ion is ligated by two histidines and a glutamate. An additional glutamate forms the third ligand of the zinc, and a tyrosine residue has a catalytic function (Pannifer et al., 2001; Tonello et al., 2004).
Basis of clan assignmentPredicted active site residues for members of this family and thermolysin, the type example for clan MA, occur in the motif HEXXH
Distribution of family Bacteria details  
Archaea -  
Protozoa -  
Fungi -  
Plants -  
Animals -  
Viruses -  
Biological functionsThe anthrax toxin is a complex of three proteins, of which lethal factor is one, and the others are protective factor and oedema factor (an adenylate cyclase). Lethal factor is toxic only when in combination with protective factor (Leppla, 2004). Like the tetanus and botulism toxins (in peptidase family M27), lethal factor enters the endosomes of host cells, but in this case the cells are macrophages. Lethal factor acts by disrupting intracellular signalling, specifically by cleaving MAPKKs so as to prevent them from binding mitogen-activated protein kinase. As a result, the immune response is either reduced or delayed, mitogen-activated protein kinase kinase 3 is cleaved, and release of the proinflammatory mediators nitric oxide and tumor necrosis factor alpha is prevented (Dang et al., 2004).
Pharmaceutical and biotech relevanceLethal factor can be used in the laboratory selectively to block MAPKK-dependent pathways in intact cells.
Statistics for family M34Sequences:72
Identifiers with PDB entries:2
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
anthrax lethal factorM34.001Yes
Zmp1 peptidase (Clostridium difficile-type)M34.002Yes
family M34 non-peptidase homologuesnon-peptidase homologue-
family M34 unassigned peptidasesunassigned-