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1008  structures 573  species 12  interactions 7835  sequences 132  architectures

Family: Asp (PF00026)

Summary: Eukaryotic aspartyl protease

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Eukaryotic aspartyl protease Provide feedback

Aspartyl (acid) proteases include pepsins, cathepsins, and renins. Two-domain structure, probably arising from ancestral duplication. This family does not include the retroviral nor retrotransposon proteases (PF00077), which are much smaller and appear to be homologous to a single domain of the eukaryotic asp proteases.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001461

Peptidase family A1, also known as the pepsin family, contains peptidases with bilobed structures [PUBMED:2115088],[PUBMED:2115087]. The two domains most probably evolved from the duplication of an ancestral gene encoding a primordial domain [PUBMED:24179]. The active site is formed from an aspartic acid residue from each domain. Each aspartic acid occurs within a motif with the sequence D(T/S)G(T/S). Exceptionally, in the histoaspactic peptidase from Plasmodium falciparum, one of the Asp residues is replaced by His [PUBMED:11782538]. A third essential residue, Tyr or Phe, is found on the N-terminal domain only in a beta-hairpin loop known as the "flap"; this residue is important for substrate binding, and most members of the family have a preference for a hydrophobic residue in the S1 substrate binding pocket. Most members of the family are active at acidic pH, but renin is unusually active at neutral pH. Family A1 peptidases are found predominantly in eukaryotes (but examples are known from bacteria ([PUBMED:19758436],[PUBMED:21749650]). Currently known eukaryotic aspartyl peptidases and homologues include the following:

  • Vertebrate gastric pepsins A (EC), gastricsin (EC, also known pepsin C), chymosin (EC; formerly known as rennin), and cathepsin E (EC). Pepsin A is widely used in protein sequencing because of its limited and predictable specificity. Chymosin is used to clot milk for cheese making.
  • Lysosomal cathepsin D (EC).
  • Renin (EC) which functions in control of blood pressure by generating angiotensin I from angiotensinogen in the plasma.
  • Memapsins 1 (EC; also known as BACE 2) and 2 (EC; also known as BACE) are membrane-bound and are able to perform one of the two cleavages (the beta-cleavage, hence they are also known as beta-secretases) in the beta-amyloid precursor to release the the amyloid-beta peptide, which accumulates in the plaques of Alzheimer's disease patients.
  • Fungal peptidases such as aspergillopepsin A (EC), candidapepsin (EC), mucorpepsin (EC; also known as Mucor rennin), endothiapepsin (EC), polyporopepsin (EC), and rhizopuspepsin (EC) are secreted for sapprophytic protein digestion.
  • Fungal saccharopepsin (EC) (proteinase A) (gene PEP4) is implicated in post-translational regulation of vacuolar hydrolases.
  • Yeast barrierpepsin (EC) (gene BAR1); a protease that cleaves alpha-factor and thus acts as an antagonist of the mating pheromone.
  • Fission yeast Sxa1 may be involved in degrading or processing the mating pheromones [PUBMED:1549128].
  • In plants, phytepsin (EC) degrades seed storage proteins and nepenthesin (EC 3.4.23.12) from a pitcher plant digests insect proteins.
  • Plasmepsins (EC and EC) from Plasmodium species are important for the degradation of host haemoglobin.
  • Non-peptidase homologues where one or more active site residues have been replaced, include mammalian pregnancy-associated glycoproteins, an allergen from a cockroach, and a xylanase inhibitor [PUBMED:15166216].

Aspartic peptidases, also known as aspartyl proteases (EC), are widely distributed proteolytic enzymes [PUBMED:6795036, PUBMED:2194475, PUBMED:1851433] known to exist in vertebrates, fungi, plants, protozoa, bacteria, archaea, retroviruses and some plant viruses. All known aspartic peptidases are endopeptidases. A water molecule, activated by two aspartic acid residues, acts as the nucleophile in catalysis. Aspartic peptidases can be grouped into five clans, each of which shows a unique structural fold [PUBMED:8439290].

  • Peptidases in clan AA are either bilobed (family A1 or the pepsin family) or are a homodimer (all other families in the clan, including retropepsin from HIV-1/AIDS) [PUBMED:2682266]. Each lobe consists of a single domain with a closed beta-barrel and each lobe contributes one Asp to form the active site. Most peptidases in the clan are inhibited by the naturally occurring small-molecule inhibitor pepstatin [PUBMED:4912600].
  • Clan AC contains the single family A8: the signal peptidase 2 family. Members of the family are found in all bacteria. Signal peptidase 2 processes the premurein precursor, removing the signal peptide. The peptidase has four transmembrane domains and the active site is on the periplasmic side of the cell membrane. Cleavage occurs on the amino side of a cysteine where the thiol group has been substituted by a diacylglyceryl group. Site-directed mutagenesis has identified two essential aspartic acid residues which occur in the motifs GNXXDRX and FNXAD (where X is a hydrophobic residue) [PUBMED:10497172]. No tertiary structures have been solved for any member of the family, but because of the intramembrane location, the structure is assumed not to be pepsin-like.
  • Clan AD contains two families of transmembrane endopeptidases: A22 and A24. These are also known as "GXGD peptidases" because of a common GXGD motif which includes one of the pair of catalytic aspartic acid residues. Structures are known for members of both families and show a unique, common fold with up to nine transmembrane regions [PUBMED:21765428]. The active site aspartic acids are located within a large cavity in the membrane amnd into which water can gain access [PUBMED:23254940].
  • Clan AE contains two families, A25 and A31. Tertiary structures have been solved for members of both families and show a common fold consisting of an alpha-beta-alpha sandwich, in which the beta sheet is five stranded [PUBMED:10331925, PUBMED:10864493].
  • Clan AF contains the single family A26. Members of the clan are membrane-proteins with a unique fold. Homologues are known only from bacteria. The structure of omptin (also known as OmpT) shows a cylindrical barrel containing ten beta strands inserted in the membrane with the active site residues on the outer surface [PUBMED:11566868].
  • There are two families of aspartic peptidases for which neither structure nor active site residues are known and these are not assigned to clans. Family A5 includes thermopsin, an endopeptidase found only in thermophilic archaea. Family A36 contains sporulation factor SpoIIGA, which is known to process and activate sigma factor E, one of the transcription factors that controls sporulation in bacteria [PUBMED:21751400].

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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Pfam Clan

This family is a member of clan Peptidase_AA (CL0129), which has the following description:

This clan contains aspartic peptidases, including the pepsins and retropepsins. These enzymes contains a catalytic dyad composed of two aspartates. In the retropepsins one is provided by each copy of a homodimeric protein, whereas in the pepsin-like peptidases these aspartates come from a single protein composed of two duplicated domains.

The clan contains the following 14 members:

Asp Asp_protease Asp_protease_2 DUF1758 gag-asp_proteas Peptidase_A2B Peptidase_A2E Peptidase_A3 RVP RVP_2 Spuma_A9PTase TAXi_C TAXi_N Zn_protease

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, the UniProtKB sequence database, 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
(24)
Full
(7835)
Representative proteomes UniProt
(15161)
NCBI
(23184)
Meta
(72)
RP15
(2129)
RP35
(4451)
RP55
(6162)
RP75
(7686)
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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.

Format an alignment

  Seed
(24)
Full
(7835)
Representative proteomes UniProt
(15161)
NCBI
(23184)
Meta
(72)
RP15
(2129)
RP35
(4451)
RP55
(6162)
RP75
(7686)
Alignment:
Format:
Order:
Sequence:
Gaps:
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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
(24)
Full
(7835)
Representative proteomes UniProt
(15161)
NCBI
(23184)
Meta
(72)
RP15
(2129)
RP35
(4451)
RP55
(6162)
RP75
(7686)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   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.

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 enriched
Previous IDs: asp;
Type: Family
Author: Eddy SR, Griffiths-Jones SR, Finn RD
Number in seed: 24
Number in full: 7835
Average length of the domain: 286.80 aa
Average identity of full alignment: 22 %
Average coverage of the sequence by the domain: 68.73 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 19.9 19.9
Trusted cut-off 19.9 19.9
Noise cut-off 19.8 19.8
Model length: 315
Family (HMM) version: 21
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

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Interactions

There are 12 interactions for this family. More...

Inhibitor_I34 SH3_1 Serpin Serpin A1_Propeptide V-set SapB_1 A1_Propeptide Asp Pepsin-I3 SapB_2 SapB_2

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 Asp domain has been found. There are 1008 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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