Summary: Peptidase family M48
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Peptidase family M48 Provide feedback
Peptidase_M48 is the largely extracellular catalytic region of CAAX prenyl protease homologues such as Human FACE-1 protease. These are metallopeptidases, with the characteristic HExxH motif giving the two histidine-zinc-ligands and an adjacent glutamate on the next helix being the third. The whole molecule folds to form a deep groove/cleft into which the substrate can fit [1,2].
Pryor EE Jr, Horanyi PS, Clark KM, Fedoriw N, Connelly SM, Koszelak-Rosenblum M, Zhu G, Malkowski MG, Wiener MC, Dumont ME;, Science. 2013;339:1600-1604.: Structure of the integral membrane protein CAAX protease Ste24p. PUBMED:23539602 EPMC:23539602
Quigley A, Dong YY, Pike AC, Dong L, Shrestha L, Berridge G, Stansfeld PJ, Sansom MS, Edwards AM, Bountra C, von Delft F, Bullock AN, Burgess-Brown NA, Carpenter EP;, Science. 2013;339:1604-1607.: The structural basis of ZMPSTE24-dependent laminopathies. PUBMED:23539603 EPMC:23539603
Internal database links
|SCOOP:||Pox_Rif BSP Peptidase_M56 DUF955 DUF2268 SprT-like DUF2201_N DUF4157|
|Similarity to PfamA using HHSearch:||Peptidase_M56|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001915
In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:
- Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.
- Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases.
In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.
Metalloproteases are the most diverse of the four main types of protease, with more than 50 families identified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site [PUBMED:7674922]. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [PUBMED:7674922].
This group of metallopeptidases belong to MEROPS peptidase family M48 (Ste24 endopeptidase family, clan M-); members of both subfamily are represented. The members of this set of proteins are mostly described as probable protease htpX homologue (EC) or CAAX prenyl protease 1, which proteolytically removes the C-terminal three residues of farnesylated proteins. They are integral membrane proteins associated with the endoplasmic reticulum and Golgi, binding one zinc ion per subunit.
In Saccharomyces cerevisiae (Baker's yeast) Ste24p is required for the first NH2-terminal proteolytic processing event within the a-factor precursor, which takes place after COOH-terminal CAAX modification is complete. The Ste24p contains multiple predicted membrane spans, a zinc metalloprotease motif (HEXXH), and a COOH-terminal ER retrieval signal (KKXX). The HEXXH protease motif is critical for Ste24p activity, since Ste24p fails to function when conserved residues within this motif are mutated.
The Ste24p homologues occur in a diverse group of organisms, including Escherichia coli, Schizosaccharomyces pombe (Fission yeast), Haemophilus influenzae, and Homo sapiens (Human), which indicates that the gene is highly conserved throughout evolution. Ste24p and the proteins related to it define a subfamily of proteins that are likely to function as intracellular, membrane-associated zinc metalloproteases [PUBMED:9015299].
HtpX is a zinc-dependent endoprotease member of the membrane-localized proteolytic system in E. coli, which participates in the proteolytic quality control of membrane proteins in conjunction with FtsH, a membrane-bound and ATP-dependent protease. Biochemical characterisation revealed that HtpX undergoes self-degradation upon cell disruption or membrane solubilization. It can also degraded casein and cleaves solubilized membrane proteins, for example, SecY [PUBMED:16076848]. Expression of HtpX in the plasma membrane is under the control of CpxR, with the metalloproteinase active site of HtpX located on the cytosolic side of the membrane. This suggests a potential role for HtpX in the response to mis-folded proteins [PUBMED:12081643].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
|Molecular function||metalloendopeptidase activity (GO:0004222)|
|Biological process||proteolysis (GO:0006508)|
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Clan MA is one of two zinc-dependent metallopeptidases that contain the HEXXH motif. The two histidines are zinc ligands. The structures of this clan show the active site is between its two sub-domains.
The clan contains the following 58 members:Aspzincin_M35 Astacin BSP DUF1570 DUF2201_N DUF2268 DUF3152 DUF3267 DUF3633 DUF3810 DUF4157 DUF4344 DUF45 DUF4953 DUF955 HRXXH Peptidase_M1 Peptidase_M10 Peptidase_M11 Peptidase_M13 Peptidase_M2 Peptidase_M27 Peptidase_M3 Peptidase_M30 Peptidase_M32 Peptidase_M35 Peptidase_M36 Peptidase_M4 Peptidase_M41 Peptidase_M43 Peptidase_M48 Peptidase_M4_C Peptidase_M50 Peptidase_M50B Peptidase_M54 Peptidase_M56 Peptidase_M57 Peptidase_M6 Peptidase_M60 Peptidase_M61 Peptidase_M64 Peptidase_M66 Peptidase_M7 Peptidase_M8 Peptidase_M9 Peptidase_M91 Peptidase_Mx Peptidase_Mx1 Peptidase_U49 Reprolysin Reprolysin_2 Reprolysin_3 Reprolysin_4 Reprolysin_5 SprT-like WLM Zn_peptidase Zn_peptidase_2
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Curation and family details
|Number in seed:||21|
|Number in full:||42051|
|Average length of the domain:||189.80 aa|
|Average identity of full alignment:||23 %|
|Average coverage of the sequence by the domain:||55.47 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Peptidase_M48 domain has been found. There are 14 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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