|Name||Peptidase family M41 (FtsH endopeptidase family)|
|Family type peptidase||M41.001 - FtsH peptidase (Escherichia coli), MEROPS Accession MER0001620 (peptidase unit: 365-647)|
|Content of family||Peptidase family M41 contains ATP-dependent metalloendopeptidases.|
Identifier created: Proteolysis in Cell Function, pp13-21, IOS Press, Amsterdam (1997)|
The most fully characterised peptidase in family M41 is the bacterial FtsH peptidase (M41.001, reviewed by Akiyama et al. (2004)), but the eukaryotic homologues are also of great interest.
|Active site residues||E418 |
|Active site||The peptidases of family M41 contain the HEXXH motif in which the glutamate is expected to have a catalytic role and the two histidines to be ligands of a single zinc atom. Ftsh (M41.001) was inactivated by mutations E415Q and H418Y in the "HEXXH" motif (Karata et al., 1999) (see the Alignment). Low activity of the E476Q mutant suggests that Glu476 is the third zinc ligand (Saikawa et al., 2002).|
|Activities and specificities||Peptidase activity of FtsH is ATP-dependent (Bruckner et al., 2003), and the other members of the family also contain the ATP-ase domains. Natural substrates are membrane-embedded and soluble proteins. FtsH acts "processively", degrading a given substrate molecule progressively from either N-terminus or C-terminus (Akiyama & Ito, 2003; Chiba et al., 2002). |
An in vitro assay with the sigma32 protein as substrate has been described (Okuno et al., 2004).
|Inhibitors||FtsH activity of Escherichia coli is regulated during infection with bacteriophage lambda by the cIII peptide, which is both a substrate and an inhibitor of the peptidase (Herman et al., 1997). It is also reported that a function of SpoVM protein in Bacillus subtilis is to inhibit the proteolytic activity of FtsH (Prajapati et al., 2000. Synthetic inhibitors have not been described.|
|Molecular structure||The molecule of Ftsh contains (from the N-terminus) two transmembrane domains, Walker A and B ATP-ase domains, an SRH domain commonly associated with Walker domains, the HEXXH active site motif, the probable third ligand, and a coiled-coil domain near the C-terminus (Shotland et al., 2000). No three-dimensional structure is available for the peptidase unit. The part of the molecule containing the ATPase and peptidase units is cytoplasmic. Active FtsH in vivo is not only membrane-bound but also oligomeric, probably as a homohexamer associated with a second protein, HflKC (Niwa et al., 2002; Saikawa et al., 2004). The structures of the other peptidases in the family are generally similar to that of FtsH.|
|Basis of clan assignment||Predicted active site residues for members of this family and thermolysin, the type example for clan MA, occur in the motif HEXXH|
|Biological functions||The physiological substrates of peptidases in family M41 are generally membrane proteins. Substrates of FtsH peptidase in Escherichia coli include the proteins sigma32 (Okuno et al., 2004), YccA and SecY (Kihara et al., 1999). |
The eukaryote homologues of the FtsH endopeptidase include the mitochondrial m- and i-AAA peptidases (M41.003, M41.004), and in yeast there is a third homologue: AFG3 (M41.002). The m-AAA protease has a chaperone function important for the correct assembly of protein complexes in the mitochondrion, including elements of the respiratory chain and ATP-dependent enzymes. Both m-AAA and i-AAA endopeptidases are essential for the breakdown of uncomplexed components. Mutations in any of the three genes lead to mitochondrial dysfunction.
The mitochondrial protein paraplegin (M41.006) is a third mammalian homolog, and mutations in the paraplegin gene are associated with an autosomal form of hereditary spastic paraplegia (Atorino et al., 2003).
|Statistics for family M41||Sequences:||11574|
|Identifiers with PDB entries:||7|
Sequence library (FastA format)|
|Sequence alignment (FastA format)|
|Phylogenetic tree (Newick format)|