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167  structures 4110  species 0  interactions 25301  sequences 738  architectures

Family: PA (PF02225)

Summary: PA domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "PA clan of proteases". More...

PA clan of proteases Edit Wikipedia article

PA protease clan
Identifiers
Symbol?
PfamCL0124
InterProIPR009003
SCOP250494 / SCOPe / SUPFAM

The PA clan (proteases of mixed nucleophile, superfamily A) is the largest group of proteases with common ancestry. Members have a chymotrypsin-like fold and similar proteolysis mechanisms but sequence identity of <10%. The clan contains both cysteine and serine proteases (different nucleophiles)[1][2]. PA clan proteases can be found in plants[3] , animals[3], fungi[3], eubacteria[4], archaea[5][6] and viruses[7].

Structure

Cartoon structure of TEV protease. The double β-barrels that define the superfamily are highlighted in red. (PDB 1lvm)
Surface structure of TEV protease. The C-terminal extension only present in viral members of the PA clan of chymotrypsin-like proteases as (a) surface with loop in blue (b) secondary structure and (c) b-factor putty (wider regions indicate greater flexibility) for the structure of TEV protease C151A (PDB 1lvb). Substrate in black, active site triad in red. The final 15 amino acids (222-236) of the enzyme C-terminus are not visible in the structure as they are too flexible.

Despite retaining as little as 10% sequence identity, PA clan members isolated from viruses, prokaryotes and eukaryotes show structural homology and can be aligned by structural similarity (e.g. with DALI).

Double β-barrel

PA clan proteases all share a core motif of two β-barrels with covalent catalysis performed by an acid-histidine-nucleophile catalytic triad motif. The triad residues are split between the two barrels so that catalysis takes place at their interface[8].

Viral protease loop

In addition to the double β-barrel core, some viral proteases (such as TEV protease have a long, flexible C-terminal loop that forms a lid to which completely covers the substrate and create a binding tunnel. This tunnel contains a set of tight binding pockets such that each side chain of the substrate peptide (P6 to P1’) is bound in a complementary site (S6 to S1’)[9] and specificity is endowed by the large contact area between enzyme and substrate. Conversely, cellular proteases that lack this loop, such as trypsin have broader specificity.

Evolution and function

The PA clan contains a diverse array of proteases from eukaryotes, prokaryotes and viruses. It also encompasses varied functions including blood clotting (e.g. thrombin), digestion (e.g. trypsin), snake venoms (e.g. pit viper haemotoxin), bacterial toxins (e.g. exfoliative toxin) and viral polyprotein processing (e.g. polio, norovirus, and TEV proteases).

All cellular PA clan proteases are serine proteases, however there are both serine and cysteine protease families of viral proteases. This indicates that the nucleophile must have exchanged at some point by divergent evolution.

Families

Family Stereotype example Known structure?
C03 poliovirus-type picornain 3C (human poliovirus 1) Yes
C04 nuclear-inclusion-a peptidase (plum pox virus) (plum pox virus) Yes
C24 rabbit hemorrhagic disease virus 3C-like peptidase (rabbit hemorrhagic disease virus) No
C30 porcine transmissible gastroenteritis virus-type main peptidase (transmissible gastroenteritis virus) Yes
C37 calicivirin (Southampton virus) Yes
C62 gill-associated virus 3C-like peptidase (gill-associated virus) No
C74 pestivirus NS2 peptidase (bovine viral diarrhea virus 1) No
C99 iflavirus processing peptidase (Ectropis obliqua picorna-like virus) No
S01 chymotrypsin A (cattle-type) (Bos taurus) Yes
S03 togavirin (Sindbis virus) Yes
S06 IgA1-specific serine peptidase ({Neisseria}-type) (Neisseria gonorrhoeae) Yes
S07 flavivirin (yellow fever virus) No
S29 hepacivirin (hepatitis C virus) Yes
S30 potyvirus P1 peptidase (plum pox virus) No
S31 pestivirus NS3 polyprotein peptidase (bovine viral diarrhea virus 1) No
S32 equine arteritis virus serine peptidase (equine arteritis virus) Yes
S39 sobemovirus peptidase (cocksfoot mottle virus) Yes
S46 dipeptidyl-peptidase 7 ({Porphyromonas gingivalis}-type) (Porphyromonas gingivalis) No
S55 SpoIVB peptidase (Bacillus subtilis) No
S64 Ssy5 peptidase (Saccharomyces cerevisiae) No
S65 picornain-like cysteine peptidase (Breda-1 torovirus) (Breda virus) No
S75 White bream virus serine peptidase (White bream virus) No

See also

External resources

References

  1. ^ Rawlings, ND (2012 Jan). "MEROPS: the database of proteolytic enzymes, their substrates and inhibitors". Nucleic acids research. 40 (Database issue): D343-50. PMID 22086950. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ Bazan, JF (1988 Nov). "Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications". Proceedings of the National Academy of Sciences of the United States of America. 85 (21): 7872–6. PMID 3186696. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ a b c Laskar, A (2012 May 24). "Modeling and structural analysis of PA clan serine proteases". BMC research notes. 5: 256. PMID 22624962. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ Barbosa, JA (1996 Jul). "Novel features of serine protease active sites and specificity pockets: sequence analysis and modelling studies of glutamate-specific endopeptidases and epidermolytic toxins". Protein engineering. 9 (7): 591–601. PMID 8844831. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ "MEROPS - Archeal S01 proteases". Retrieved 2013. {{cite web}}: Check date values in: |accessdate= (help)
  6. ^ Ruiz-Perez, F (2013 May 21). "Bacterial serine proteases secreted by the autotransporter pathway: classification, specificity, and role in virulence". Cellular and molecular life sciences : CMLS. PMID 23689588. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Bazan, JF (1988 Nov). "Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications". Proceedings of the National Academy of Sciences of the United States of America. 85 (21): 7872–6. PMID 3186696. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Dougherty, WG (1989 Sep). "Characterization of the catalytic residues of the tobacco etch virus 49-kDa proteinase". Virology. 172 (1): 302–10. PMID 2475971. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ Phan, J (2002 Dec 27). "Structural basis for the substrate specificity of tobacco etch virus protease". The Journal of biological chemistry. 277 (52): 50564–72. PMID 12377789. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

PA domain Provide feedback

The PA (Protease associated) domain is found as an insert domain in diverse proteases. The PA domain is also found in a plant vacuolar sorting receptor O22925 and members of the RZF family O43567. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors [1].

Literature references

  1. Luo X, Hofmann K; , Trends Biochem Sci 2001;26:147-148.: The protease-associated domain: a homology domain associated with multiple classes of proteases. PUBMED:11246007 EPMC:11246007


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003137

The PA (Protease associated) domain is found as an insert domain in diverse proteases, which include the MEROPS peptidase families A22B, M28, and S8A [ PUBMED:7674922 ]. The PA domain is also found in a plant vacuolar sorting receptor SWISSPROT and members of the RZF family, e.g. SWISSPROT . It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors [ PUBMED:11246007 ].

Domain organisation

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

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Pfam Clan

This family is a member of clan Leu-IlvD (CL0364), which has the following description:

Superfamily includes LeuD-like, IlvD/EDD C-terminal domain-like, and AF0055-like families.

The clan contains the following 10 members:

AcnX_swivel_put Aconitase_2_N Aconitase_C CPSase_sm_chain Cyclase DUF2172 PA PEP-utilizers Peptidase_S66C RraA-like

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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB 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
(339)
Full
(25301)
Representative proteomes UniProt
(59359)
RP15
(3382)
RP35
(10910)
RP55
(21438)
RP75
(31559)
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PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

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  Seed
(339)
Full
(25301)
Representative proteomes UniProt
(59359)
RP15
(3382)
RP35
(10910)
RP55
(21438)
RP75
(31559)
Alignment:
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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
(339)
Full
(25301)
Representative proteomes UniProt
(59359)
RP15
(3382)
RP35
(10910)
RP55
(21438)
RP75
(31559)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
Gzipped 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.

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: Pfam-B_259 (release 5.2)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Bateman A , Mahon P
Number in seed: 339
Number in full: 25301
Average length of the domain: 96.6 aa
Average identity of full alignment: 18 %
Average coverage of the sequence by the domain: 14.22 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.9 23.9
Trusted cut-off 23.9 23.9
Noise cut-off 23.8 23.8
Model length: 92
Family (HMM) version: 25
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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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. More...

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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 PA domain has been found. There are 167 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 sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A044SDU9 View 3D Structure Click here
A0A044SSX9 View 3D Structure Click here
A0A077ZG12 View 3D Structure Click here
A0A0D2E222 View 3D Structure Click here
A0A0D2E3J0 View 3D Structure Click here
A0A0D2GAQ3 View 3D Structure Click here
A0A0D2H7R2 View 3D Structure Click here
A0A0G2KE94 View 3D Structure Click here
A0A0K0E107 View 3D Structure Click here
A0A0K0EN07 View 3D Structure Click here
A0A0K0EQD9 View 3D Structure Click here
A0A0N4UDF3 View 3D Structure Click here
A0A0N4ULJ0 View 3D Structure Click here
A0A0P0V749 View 3D Structure Click here
A0A0P0V830 View 3D Structure Click here
A0A0P0VQA5 View 3D Structure Click here
A0A0P0WDQ9 View 3D Structure Click here
A0A0P0WYV3 View 3D Structure Click here
A0A0P0XEJ6 View 3D Structure Click here
A0A0P0XGM3 View 3D Structure Click here
A0A0P0XUA3 View 3D Structure Click here
A0A0R0F403 View 3D Structure Click here
A0A0R0F591 View 3D Structure Click here
A0A0R0FG78 View 3D Structure Click here
A0A0R0FI48 View 3D Structure Click here
A0A0R0FJI5 View 3D Structure Click here
A0A0R0FN77 View 3D Structure Click here
A0A0R0GDI6 View 3D Structure Click here
A0A0R0GGN1 View 3D Structure Click here
A0A0R0H350 View 3D Structure Click here
A0A0R0HBM9 View 3D Structure Click here
A0A0R0I8R4 View 3D Structure Click here
A0A0R0IAN9 View 3D Structure Click here
A0A0R0K1X6 View 3D Structure Click here
A0A0R0K2M4 View 3D Structure Click here
A0A0R4IGH0 View 3D Structure Click here
A0A0R4J339 View 3D Structure Click here
A0A0R4J5Q8 View 3D Structure Click here
A0A0R4J678 View 3D Structure Click here
A0A158Q4C5 View 3D Structure Click here