Summary: PA domain
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PA clan of proteases Edit Wikipedia article
|PA clan of proteases|
|SCOPe||50494 / SUPFAM|
The PA clan (Proteases of mixed nucleophile, superfamily A) is the largest group of proteases with common ancestry as identified by structural homology. Members have a chymotrypsin-like fold and similar proteolysis mechanisms but can have identity of <10%. The clan contains both cysteine and serine proteases (different nucleophiles). PA clan proteases can be found in plants, animals, fungi, eubacteria, archaea and viruses.
The common use of the catalytic triad for hydrolysis by multiple clans of proteases, including the PA clan, represents an example of convergent evolution. The differences in the catalytic triad within the PA clan is also an example of divergent evolution of active sites in enzymes.
In the 1960s, the sequence similarity of several proteases indicated that they were evolutionarily related. These were grouped into the chymotrypsin-like serine proteases (now called the S1 family). As the structures of these, and other proteases were solved by X-ray crystallography in the 1970s and 80s, it was noticed that several viral proteases such as Tobacco Etch Virus protease showed structural homology despite no discernible sequence similarity and even a different nucleophile. Based on structural homology, a superfamily was defined and later named the PA clan (by the MEROPS classification system). As more structures are solved, more protease families have been added to the PA clan superfamily.
The P refers to Proteases of mixed nucleophile. The A indicates that it was the first such clan to be identified (there also exist the PB, PC, PD and PE clans).
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).
PA clan proteases all share a core motif of two Î²-barrels with covalent catalysis performed by an acid-histidine-nucleophile catalytic triad motif. The barrels are arranged perpendicularly beside each other with hydrophobic residues holding them together as the core scaffold for the enzyme. The triad residues are split between the two barrels so that catalysis takes place at their interface.
Viral protease loop
In addition to the double Î²-barrel core, some viral proteases (such as TEV protease) have a long, flexible C-terminal loop that forms a lid that 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 P1â€™) is bound in a complementary site (S6 to S1â€™) 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
Structural homology indicates that the PA clan members are descended from a common ancestor of the same fold. Although PA clan proteases use a catalytic triad perform 2-step nucleophilic catalysis, some families use serine as the nucleophile whereas others use cysteine. The superfamily is therefore an extreme example of divergent enzyme evolution since during evolutionary history, the core catalytic residue of the enzyme has switched in different families. In addition to their structural similarity, directed evolution has been shown to be able to convert a cysteine protease into an active serine protease. All cellular PA clan proteases are serine proteases, however there are both serine and cysteine protease families of viral proteases. The majority are endopeptidases, with the exception being the S46 family of exopeptidases.
Biological role and substrate specificity
In addition to divergence in their core catalytic machinery, the PA clan proteases also show wide divergent evolution in function. Members of the PA clan can be found in eukaryotes, prokaryotes and viruses and encompass a wide range of functions. In mammals, some are involved in blood clotting (e.g. thrombin) and so have high substrate specificity as well as digestion (e.g. trypsin) with broad substrate specificity. Several snake venoms are also PA clan proteases, such as pit viper haemotoxin and interfere with the victim's blood clotting cascade. Additionally, bacteria such as Staphylococcus aureus secrete exfoliative toxin which digest and damage the host's tissues. Many viruses express their genome as a single, massive polyprotein and use a PA clan protease to cleave this into functional units (e.g. polio, norovirus, and TEV proteases).
There are also several pseudoenzymes in the superfamily, where the catalytic triad residues have been mutated and so function as binding proteins. For example, the heparin-binding protein Azurocidin has a glycine in place of the nucleophile and a serine in place of the histidine.
Within the PA clan (P=proteases of mixed nucleophiles), families are designated by their catalytic nucleophile (C=cysteine proteases, S=serine proteases). Despite the lack of sequence homology for the PA clan as a whole, individual families within it can be identified by sequence similarity.
- Rawlings ND, Barrett AJ, Bateman A (January 2012). "MEROPS: the database of proteolytic enzymes, their substrates and inhibitors". Nucleic Acids Research. 40 (Database issue): D343â€“50. doi:10.1093/nar/gkr987. PMC 3245014. PMID 22086950.
- Bazan JF, Fletterick RJ (November 1988). "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): 7872â€“6. Bibcode:1988PNAS...85.7872B. doi:10.1073/pnas.85.21.7872. PMC 282299. PMID 3186696.
- Laskar A, Rodger EJ, Chatterjee A, Mandal C (May 2012). "Modeling and structural analysis of PA clan serine proteases". BMC Research Notes. 5: 256. doi:10.1186/1756-0500-5-256. PMC 3434108. PMID 22624962.
- Barbosa JA, Saldanha JW, Garratt RC (July 1996). "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): 591â€“601. doi:10.1093/protein/9.7.591. PMID 8844831.
- "MEROPS - Archaeal S01 proteases".
- Ruiz-Perez F, Nataro JP (March 2014). "Bacterial serine proteases secreted by the autotransporter pathway: classification, specificity, and role in virulence". Cellular and Molecular Life Sciences. 71 (5): 745â€“70. doi:10.1007/s00018-013-1355-8. PMC 3871983. PMID 23689588.
- Buller AR, Townsend CA (February 2013). "Intrinsic evolutionary constraints on protease structure, enzyme acylation, and the identity of the catalytic triad". Proceedings of the National Academy of Sciences of the United States of America. 110 (8): E653â€“61. Bibcode:2013PNAS..110E.653B. doi:10.1073/pnas.1221050110. PMC 3581919. PMID 23382230.
- de HaÃ«n C, Neurath H, Teller DC (February 1975). "The phylogeny of trypsin-related serine proteases and their zymogens. New methods for the investigation of distant evolutionary relationships". Journal of Molecular Biology. 92 (2): 225â€“59. doi:10.1016/0022-2836(75)90225-9. PMID 1142424.
- Lesk AM, Fordham WD (May 1996). "Conservation and variability in the structures of serine proteinases of the chymotrypsin family". Journal of Molecular Biology. 258 (3): 501â€“37. doi:10.1006/jmbi.1996.0264. PMID 8642605.
- Gorbalenya AE, Blinov VM, Donchenko AP (January 1986). "Poliovirus-encoded proteinase 3C: a possible evolutionary link between cellular serine and cysteine proteinase families". FEBS Letters. 194 (2): 253â€“7. doi:10.1016/0014-5793(86)80095-3. PMID 3000829.
- Phan J, Zdanov A, Evdokimov AG, Tropea JE, Peters HK, Kapust RB, Li M, Wlodawer A, Waugh DS (December 2002). "Structural basis for the substrate specificity of tobacco etch virus protease". The Journal of Biological Chemistry. 277 (52): 50564â€“72. doi:10.1074/jbc.M207224200. PMID 12377789.
- Allaire M, Chernaia MM, Malcolm BA, James MN (May 1994). "Picornaviral 3C cysteine proteinases have a fold similar to chymotrypsin-like serine proteinases". Nature. 369 (6475): 72â€“6. Bibcode:1994Natur.369...72A. doi:10.1038/369072a0. PMID 8164744.
- Snijder EJ, Wassenaar AL, van Dinten LC, Spaan WJ, Gorbalenya AE (March 1996). "The arterivirus nsp4 protease is the prototype of a novel group of chymotrypsin-like enzymes, the 3C-like serine proteases". The Journal of Biological Chemistry. 271 (9): 4864â€“71. doi:10.1074/jbc.271.9.4864. PMID 8617757.
- Dougherty WG, Parks TD, Cary SM, Bazan JF, Fletterick RJ (September 1989). "Characterization of the catalytic residues of the tobacco etch virus 49-kDa proteinase". Virology. 172 (1): 302â€“10. doi:10.1016/0042-6822(89)90132-3. PMID 2475971.
- Laskar A, Rodger EJ, Chatterjee A, Mandal C (May 2012). "Modeling and structural analysis of PA clan serine proteases". BMC Research Notes. 5 (1): 256. doi:10.1186/1756-0500-5-256. PMC 3434108. PMID 22624962.
- Shafee T, Gatti-Lafranconi P, Minter R, Hollfelder F (September 2015). "Handicap-Recover Evolution Leads to a Chemically Versatile, Nucleophile-Permissive Protease". ChemBioChem. 16 (13): 1866â€“1869. doi:10.1002/cbic.201500295. PMC 4576821. PMID 26097079.
- Suzuki Y, Sakamoto Y, Tanaka N, Okada H, Morikawa Y, Ogasawara W (March 2014). "Identification of the catalytic triad of family S46 exopeptidases, closely related to clan PA endopeptidases". Scientific Reports. 4: 4292. doi:10.1038/srep04292. PMC 3944710. PMID 24598890.
- Sakamoto Y, Suzuki Y, Iizuka I, Tateoka C, Roppongi S, Fujimoto M, Inaka K, Tanaka H, Masaki M, Ohta K, Okada H, Nonaka T, Morikawa Y, Nakamura KT, Ogasawara W, Tanaka N (May 2014). "S46 peptidases are the first exopeptidases to be members of clan PA". Scientific Reports. 4: 4977. doi:10.1038/srep04977. PMC 4021333. PMID 24827749.
- Salvesen G (2013). Rawlings N (ed.). Handbook of proteolytic enzymes. Boston: Academic Press. ISBN 9780123822192.
- PolgÃ¡r L (October 2005). "The catalytic triad of serine peptidases". Cellular and Molecular Life Sciences. 62 (19â€“20): 2161â€“72. doi:10.1007/s00018-005-5160-x. PMID 16003488.
- Todd AE, Orengo CA, Thornton JM (October 2002). "Sequence and structural differences between enzyme and nonenzyme homologs". Structure. 10 (10): 1435â€“51. doi:10.1016/s0969-2126(02)00861-4. PMID 12377129.
- Iversen LF, Kastrup JS, BjÃ¸rn SE, Rasmussen PB, Wiberg FC, Flodgaard HJ, Larsen IK (April 1997). "Structure of HBP, a multifunctional protein with a serine proteinase fold". Nature Structural Biology. 4 (4): 265â€“8. doi:10.1038/nsb0497-265. PMID 9095193.
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 .
Internal database links
External database links
|MEROPS:||S8 M28 A22|
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 ].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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Superfamily includes LeuD-like, IlvD/EDD C-terminal domain-like, and AF0055-like families.
The clan contains the following 10 members:Aconitase_2_N Aconitase_C CPSase_sm_chain Cyclase DUF126 DUF2172 PA PEP-utilizers Peptidase_S66C RraA-like
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...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
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You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
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.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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...
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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.
|Seed source:||Pfam-B_259 (release 5.2)|
|Author:||Bateman A , Mahon P|
|Number in seed:||341|
|Number in full:||22947|
|Average length of the domain:||96.70 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||14.14 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||24|
|Download:||download the raw HMM for this family|
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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 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, its 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:
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".
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.
The tree shows the occurrence of this domain across different species. More...
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.
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
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.
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 157 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.