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324  structures 3631  species 11  interactions 15113  sequences 580  architectures

Family: Peptidase_S8 (PF00082)

Summary: Subtilase family

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This is the Wikipedia entry entitled "Subtilase". More...

Subtilase Edit Wikipedia article

Subtilase family
PDB 1cse EBI.jpg
Structure of the complex formed between subtilisin Carlsberg and eglin c, an elastase inhibitor from the leech Hirudo medicinalis.[1]
Identifiers
Symbol Peptidase_S8
Pfam PF00082
InterPro IPR000209
PROSITE PDOC00125
MEROPS S8
SCOP 1cse
SUPERFAMILY 1cse
CDD cd00306

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 subtilases 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]

Human proteins containing this domain

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

References

  1. ^ 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. 
  2. ^ 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. PMC 2143677. PMID 9070434. 
  3. ^ 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. 
  4. ^ a b c d Rawlings ND, Barrett AJ (1993). "Evolutionary families of peptidases". Biochem. J. 290: 205–218. PMC 1132403. PMID 8439290. 
  5. ^ 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. 

External links

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

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Subtilase family Provide feedback

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.

External database links

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. Many families 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.

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

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(63)
Full
(15113)
Representative proteomes NCBI
(14631)
Meta
(3376)
RP15
(2244)
RP35
(4178)
RP55
(5504)
RP75
(6420)
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Format an alignment

  Seed
(63)
Full
(15113)
Representative proteomes NCBI
(14631)
Meta
(3376)
RP15
(2244)
RP35
(4178)
RP55
(5504)
RP75
(6420)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(63)
Full
(15113)
Representative proteomes NCBI
(14631)
Meta
(3376)
RP15
(2244)
RP35
(4178)
RP55
(5504)
RP75
(6420)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

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

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's seed alignment. 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 alignment.

Note: You can also download the data file for the tree.

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 View help on the curation process

Seed source: Overington
Previous IDs: subtilase;
Type: Domain
Author: Eddy SR, Sonnhammer ELL
Number in seed: 63
Number in full: 15113
Average length of the domain: 299.50 aa
Average identity of full alignment: 19 %
Average coverage of the sequence by the domain: 44.44 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 23193494 -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

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Interactions

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

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

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 324 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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