Summary

Glycoprotease family

The Peptidase M22 proteins are part of the HSP70-actin superfamily ([1]). The region represented here is an insert into the fold and is not found in the rest of the family (beyond the Peptidase M22 family). Included in this family are the Rhizobial NodU proteins and the HypF regulator. This region also contains the histidine dyad believed to coordinate the metal ion and hence provide catalytic activity. Interestingly the histidines are not well conserved, and there is a lack of experimental evidence to support peptidase activity as a general property of this family. There also appear to be instances of this domain outside of the HSP70-actin superfamily (e.g. Q9ZM49).

Literature references

Aravind L, Koonin EV; , J Mol Biol 1999;287:1023-1040.: Gleaning non-trivial structural, functional and evolutionary information about proteins by iterative database searches. PUBMED:10222208

InterPro entry IPR000905

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.

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-, 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; 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 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.

This group of metallopeptidases belong to MEROPS peptidase family M22 (clan MK). The type example being O-sialoglycoprotein endopeptidase () from Pasteurella haemolytica (Mannheimia haemolytica).

O-Sialoglycoprotein endopeptidase is secreted by the bacterium P. haemolytica, and digests only proteins that are heavily sialylated, in particular those with sialylated serine and threonine residues PUBMED:7674959. Substrate proteins include glycophorin A and leukocyte surface antigens CD34, CD43, CD44 and CD45 PUBMED:7674922, PUBMED:7674959. Removal of glycosylation, by treatment with neuraminidase, completely negates susceptibility to O-sialoglycoprotein endopeptidase digestion PUBMED:7674922, PUBMED:7674959.

Sequence similarity searches have revealed other members of the M22 family, from yeast, Mycobacterium, Haemophilus influenzae and the cyanobacterium Synechocystis PUBMED:7674922. The zinc-binding and catalytic residues of this family have not been determined, although the motif HMEGH may be a zinc-binding region PUBMED:7674922.

Clan

This family is a member of clan Actin_ATPase (CL0108), which contains the following 26 members:

Acetate_kinase Actin BcrAD_BadFG Bvg_acc_factor CmcH_NodU DDR DUF1464 DUF1786 EutA FGGY_C FGGY_N FtsA Fumble GDA1_CD39 Glucokinase Hexokinase_1 Hexokinase_2 HSP70 Hydant_A_N Hydantoinase_A MreB_Mbl Peptidase_M22 Ppx-GppA ROK StbA UPF0075

Gene Ontology

Molecular function	metalloendopeptidase activity (GO:0004222)
Biological process	proteolysis (GO:0006508)

External database links

MEROPS:	M22
PANDIT:	PF00814
PROSITE:	PDOC00779
SYSTERS:	Peptidase_M22

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (114) Full (3459) NCBI (7931) Metagenomics (5495)
Viewer:

Formatting options

Alignment:	Seed (114) Full (3459)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (114) Full (3459) NCBI (7931) Metagenomics (5495)
Full length sequences	Full-sequences (3459)

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER2.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

Pfam-B_1670 (release 2.1) & Pfam-B_4550 (Release 7.5)

Previous IDs:

Glycoprotease;

Type:

Family

Author:

Bateman A

Number in seed:

114

Number in full:

3459

Average length of the domain:

230.60 aa

Average identity of full alignment:

25 %

Average coverage of the sequence by the domain:

74.58 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 9421015 -E 1000 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	21.8	21.8
Trusted cut-off	21.8	21.8
Noise cut-off	21.7	21.7

Model length:

268

Family (HMM) version:

18

Download:

download the raw HMM for this family

Species distribution

Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Interactions

There is 1 interaction for this family. More...

Peptidase_M22

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the MSD 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_M22 domain has been found.

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Family: Peptidase_M22 (PF00814)

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