Summary: Subtilase family

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Wikipedia: Subtilase
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Subtilase

Subtilase family

Structure of the complex formed between subtilisin Carlsberg and eglin c, an elastase inhibitor from the leech Hirudo medicinalis.^[1]

Identifiers

Symbol

Peptidase_S8

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Subtilases are a family of subtilisin-like serine proteases. They appear to have independently and convergently evolved an Asp/Ser/His catalytic triad, like in the trypsin serine proteases. The structure of proteins in this family shows that they have an alpha/beta fold containing a 7-stranded parallel beta sheet.

The subtilisin family is the second largest serine protease family characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence.^[2] Subtilase is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses.^[3] The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase.^[3]^[4] Structures have been determined for several members of the subtilisin family showing that subtilisins exploit the same catalytic triad as the chymotrypsins although the residues occur in a different order (His/Asp/Ser in chymotrypsin and Asp/His/Ser in subtilisin); otherwise the structures show similarity to no other proteins.^[3]^[4] Some subtilisins are mosaic proteins, whereas others contain N- and C-terminal extensions that show no sequence similarity to any other known protein.^[3] Based on sequence homology, a subdivision into six families has been proposed.^[2]

The proprotein-processing endopeptidases kexin, furin and related enzymes form a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site.^[3]^[4] Members of the kexin family, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of Cys-173 near to the active histidine.^[4]Only 1 viral member of the subtilisin family is known, a 56-kDa protease from herpes virus 1, which infects the channel catfish.^[3]

Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser/Glu/Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101, as well as for kumamolisin from a thermophilic bacterium, Bacillus novo sp. MN-32. Mutations in the human gene leads to a fatal neurodegenerative disease.^[5]

[edit] Human proteins containing this domain

FURIN; MBTPS1; PCSK1; PCSK2; PCSK4; PCSK5; PCSK6; PCSK7; PCSK9; TPP2;

[edit] References

^ Bode W, Papamokos E, Musil D (August 1987). "The high-resolution X-ray crystal structure of the complex formed between subtilisin Carlsberg and eglin c, an elastase inhibitor from the leech Hirudo medicinalis. Structural analysis, subtilisin structure and interface geometry". Eur. J. Biochem. 166 (3): 673–92. doi:10.1111/j.1432-1033.1987.tb13566.x. PMID 3301348.
^ ^a ^b Siezen RJ, Leunissen JA (1997). "Subtilases: the superfamily of subtilisin-like serine proteases". Protein Sci. 6 (3): 501–523. doi:10.1002/pro.5560060301. PMID 9070434.
^ ^a ^b ^c ^d ^e ^f Rawlings ND, Barrett AJ (1994). "Families of serine peptidases". Meth. Enzymol. 244: 19–61. doi:10.1016/0076-6879(94)44004-2. PMID 7845208.
^ ^a ^b ^c ^d Rawlings ND, Barrett AJ (1993). "Evolutionary families of peptidases". Biochem. J. 290: 205–218. PMC 1132403. PMID 8439290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1132403.
^ Wlodawer A, Oda K, Li M, Gustchina A, Dunn BM, Oyama H (2003). "Structural and enzymatic properties of the sedolisin family of serine-carboxyl peptidases". Acta Biochim. Pol. 50 (1): 81–102. PMID 12673349.

[edit] External links

Eukaryotic Linear Motif resource motif class CLV_PCSK_FUR_1
Eukaryotic Linear Motif resource motif class CLV_PCSK_PC1ET2_1
Eukaryotic Linear Motif resource motif class CLV_PCSK_PC7_1
Eukaryotic Linear Motif resource motif class CLV_PCSK_SKI1_1

This article incorporates text from the public domain Pfam and InterPro IPR000209

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Subtilase family

Subtilases are a family of serine proteases. They appear to have independently and convergently evolved an Asp/Ser/His catalytic triad, like that found in the trypsin serine proteases (see PF00089). Structure is an alpha/beta fold containing a 7-stranded parallel beta sheet, order 2314567.

Internal database links

SCOOP:

PA

External database links

HOMSTRAD:	subt
MEROPS:	S53 S8
PANDIT:	PF00082
PRINTS:	PR00723
PROSITE:	PDOC00125
Pseudofam:	PF00082
SCOP:	1cse
SYSTERS:	Peptidase_S8

This tab holds annotation information from the InterPro database.

InterPro entry IPR000209

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.

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [PUBMED:7845208]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Over 20 families (denoted S1 - S66) of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence [PUBMED:7845208]. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [PUBMED:7845208].

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [PUBMED:7845208]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds [PUBMED:7845208]. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [PUBMED:7845208, PUBMED:8439290].

This group of serine peptidases belong to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin)) and S53 (sedolisin) both of which are members of clan SB.

The subtilisin family is the second largest serine protease family characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence [PUBMED:9070434]. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses [PUBMED:7845208]. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [PUBMED:7845208, PUBMED:8439290]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [PUBMED:7845208, PUBMED:8439290]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [PUBMED:7845208]. Based on sequence homology, a subdivision into six families has been proposed [PUBMED:9070434].

The proprotein-processing endopeptidases kexin, furin and related enzymes form a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site [PUBMED:7845208, PUBMED:8439290]. Members of the kexin family, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of Cys-173 near to the active histidine [PUBMED:8439290].Only 1 viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish [PUBMED:7845208].

Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101, as well as for kumamolisin from a thermophilic bacterium, Bacillus sp. MN-32. Mutations in the human gene leads to a fatal neurodegenerative disease [PUBMED:12673349].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Molecular function	serine-type endopeptidase activity (GO:0004252)
Biological process	proteolysis (GO:0006508)

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 (63) Full (10741) NCBI (11260) Metagenomics (3381)
Viewer:

Formatting options

Alignment:	Seed (63) Full (10741)
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 (63) Full (10741) NCBI (11260) Metagenomics (3381)
Full length sequences	Full-sequences (10741)

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 HMMER3.

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:

Overington

Previous IDs:

subtilase;

Type:

Domain

Author:

Eddy SR, Sonnhammer ELL

Number in seed:

63

Number in full:

10741

Average length of the domain:

297.30 aa

Average identity of full alignment:

20 %

Average coverage of the sequence by the domain:

42.31 %

HMM information

HMM build commands:

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

search method: hmmsearch -Z 15929002 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	21.5	21.5
Trusted cut-off	21.5	21.5
Noise cut-off	21.4	21.4

Model length:

282

Family (HMM) version:

17

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

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number of species

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Colour assignments

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab if you need to select sub-trees and view sequence alignments. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, it's distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 11 interactions for this family. More...

potato_inhibit Kazal_1 Peptidase_S8 SSI P_proprotein PA Prot_inhib_II PPC Inhibitor_I9 DUF1034 Pro-kuma_activ

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 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_S8 domain has been found. There are 180 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.

Loading structure mapping...

Family: Peptidase_S8 (PF00082)

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Summary: Subtilase family

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Subtilase

[edit] Human proteins containing this domain

[edit] References

[edit] External links

Subtilase family

Internal database links

External database links

InterPro entry IPR000209

Gene Ontology

Domain organisation

Alignments

Viewing

Downloading

View options

Formatting options

Download options

External links

HMM logo

Trees

Curation and family details

Curation

HMM information

Species distribution

Sunburst controls

Weight segments by...

Change the size of the sunburst

Colour assignments

How the sunburst is generated

Colouring and labels

Anomalies in the taxonomy tree

Missing taxonomic levels

Unmapped species names

Sub-species

Too many species/sequences

Tree controls

Annotation

Download tree

Selected sequences

Species trees

Interactive tree

Interactions

Structures