Family M41


Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

Summary for family M41

NamePeptidase family M41 (FtsH endopeptidase family)
Family type peptidaseM41.001 - FtsH peptidase (Escherichia coli), MEROPS Accession MER0001620 (peptidase unit: 365-647)
Content of familyPeptidase family M41 contains ATP-dependent metalloendopeptidases.
History 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.
Catalytic typeMetallo
Active site residuesH417 E418 H421 D495 
Active siteThe 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 specificitiesPeptidase 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).
InhibitorsFtsH 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 structureThe 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 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 details  
Protozoa details  
Fungi -  
Plants details  
Animals details  
Viruses details  
Biological functionsThe 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 M41Sequences:11574
Identifiers with PDB entries:7
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Other databases INTERPRO IPR000642
PFAM PF01434
SCOP 82419
Peptidases and Homologues MEROPS ID Structure
FtsH peptidaseM41.001Yes
AFG3 peptidaseM41.002-
m-AAA peptidaseM41.003-
i-AAA peptidaseM41.004Yes
AtFtsH2 peptidaseM41.005-
Afg3-like protein 2M41.007Yes
FtsH-2 peptidaseM41.009-
Ftsh peptidase (Thermus-type)M41.013Yes
Mername-AA223 peptidaseM41.015-
Afg3-like protein 1AM41.016-
FtsH-SLR0228 peptidaseM41.017-
AtFtsH11 peptidaseM41.018-
AtFtsH6 peptidaseM41.019-
AtFtsH1 peptidaseM41.020-
FtsH peptidase (Thermotoga-type)M41.021Yes
AtFtsH3 peptidaseM41.022-
AtFtsH10 peptidaseM41.023-
AtFtsH5 peptidaseM41.024-
AtFtsH8 peptidaseM41.025-
YME1L1 g.p. (Homo sapiens) and similarM41.026-
AtFtsH9 peptidaseM41.A03-
AtFtsH7 peptidaseM41.A04-
At1g79560 (Arabidopsis thaliana)-type peptidaseM41.A06-
CG6512 protein (Drosophila melanogaster)M41.A09-
spg-7 g.p. (Caenorhabditis elegans)M41.A10-
ymel-1 g.p. (Caenorhabditis elegans)M41.A11-
ppgn-1 g.p. (Caenorhabditis elegans)M41.A12-
PF11_0203 g.p. (Plasmodium falciparum)M41.A13-
SPBC543.09 (Schizosaccharomyces pombe)M41.A14-
rcaA g.p. (Dictyostelium discoideum)M41.A15-
DDB_G0293388 g.p. (Dictyostelium discoideum)M41.A16-
DDB_G0284249 g.p. (Dictyostelium discoideum)M41.A17-
DDB_G0267492 g.p. (Dictyostelium discoideum)M41.A18-
hCG2041332 (Homo sapiens)M41.A19-
PF14_0616 g.p. (Plasmodium falciparum)M41.A21-
family M41 non-peptidase homologuesnon-peptidase homologue-
family M41 unassigned peptidasesunassignedYes