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656  structures 583  species 4  interactions 4762  sequences 56  architectures

Family: Asp (PF00026)

Summary: Eukaryotic aspartyl protease

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Aspartate protease Edit Wikipedia article

Eukaryotic aspartyl protease
PDB 1lyb EBI.jpg
Structures of native and inhibited forms of human cathepsin D.[1]
Identifiers
Symbol Asp
Pfam PF00026
InterPro IPR001461
PROSITE PDOC00128
SCOP 1mpp
SUPERFAMILY 1mpp
OPM superfamily 108
OPM protein 1lyb

Aspartic proteases are a family of protease enzymes that use an aspartate residue for catalysis of their peptide substrates. In general, they have two highly conserved aspartates in the active site and are optimally active at acidic pH. Nearly all known aspartyl proteases are inhibited by pepstatin.

Aspartic endopeptidases EC 3.4.23. of vertebrate, fungal and retroviral origin have been characterised.[2] More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin[3] and archaean preflagellin have been described.[4][5]

Eukaryotic aspartic proteases include pepsins, cathepsins, and renins. They have a two-domain structure, arising from ancestral duplication. Retroviral and retrotransposon proteases (Pfam PF00077) are much smaller and appear to be homologous to a single domain of the eukaryotic aspartyl proteases. Each domain contributes a catalytic Asp residue, with an extended active site cleft localized between the two lobes of the molecule. One lobe has probably evolved from the other through a gene duplication event in the distant past. In modern-day enzymes, although the three-dimensional structures are very similar, the amino acid sequences are more divergent, except for the catalytic site motif, which is very conserved. The presence and position of disulfide bridges are other conserved features of aspartic peptidases.

Catalytic Mechanism

Aspartyl proteases are a highly specific family of proteases - they tend to cleave dipeptide bonds that have hydrophobic residues as well as a beta-methylene group. Unlike the closely related serine proteases these proteases do not form a covalent intermediate during cleavage.

While a number of different mechanisms for aspartyl proteases have been proposed, the most widely accepted is a general acid-base mechanism involving coordination of a water molecule between the two highly conserved aspartate residues.[6][7] One aspartate activates the water by abstracting a proton, enabling the water to attack the carbonyl carbon of the substrate scissile bond, generating a tetrahedral oxyanion intermediate. Rearrangement of this intermediate leads to protonation of the scissile amide.

Proposed mechanism of peptide cleavage by aspartyl proteases.[6]

Inhibition

Pepstatin is an inhibitor of aspartate proteases.

Evolution

All aspartate proteases have a highly conserved sequence of Asp-Thr-Gly. In general, with the exception of HIV - a dimer of two identical subunits - these enzymes are monomeric enzymes consisting of two domains. Because of this organisation, it is thought that these domains may have arisen through ancestral gene duplication.

Classification

There are six catalytic types of protease: aspartic acid, cysteine, glutamic acid, metallo, serine and threonine.

The aspartase proteases are divided into four families.

  • Family A01 (Pepsin family)
  • Family A02
  • Family A22
  • Family Ax1

A fifth family has also been described. This family is derived from the prolactin-induced protein/gross cystic disease fluid protein-15 (PIP/GCDFP15).

Propeptide

A1_Propeptide
PDB 1htr EBI.jpg
crystal and molecular structures of human progastricsin at 1.62 angstroms resolution
Identifiers
Symbol A1_Propeptide
Pfam PF07966
InterPro IPR012848

Many eukaryotic aspartic endopeptidases (MEROPS peptidase family A1) are synthesised with signal and propeptides. The animal pepsin-like endopeptidase propeptides form a distinct family of propeptides, which contain a conserved motif approximately 30 residues long. In pepsinogen A, the first 11 residues of the mature pepsin sequence are displaced by residues of the propeptide. The propeptide contains two helices that block the active site cleft, in particular the conserved Asp11 residue, in pepsin, hydrogen bonds to a conserved Arg residue in the propeptide. This hydrogen bond stabilises the propeptide conformation and is probably responsible for triggering the conversion of pepsinogen to pepsin under acidic conditions.[8][9]

Examples

Human

Human proteins containing this domain

BACE1; BACE2; CTSD; CTSE; NAPSA; PGA5; PGC; REN;

Other organisms

External links

See also

References

  1. ^ Baldwin ET, Bhat TN, Gulnik S, et al. (July 1993). "Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design". Proc. Natl. Acad. Sci. U.S.A. 90 (14): 6796–800. doi:10.1073/pnas.90.14.6796. PMC 47019. PMID 8393577. 
  2. ^ Szecsi PB (1992). "The aspartic proteases". Scand. J. Clin. Lab. In vest. Suppl. 210: 5–22. doi:10.3109/00365519209104650. PMID 1455179. 
  3. ^ Taylor R K, LaPointe CF (2000). "The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases". J. Biol. Chem. 275 (2): 1502–10. doi:10.1074/jbc.275.2.1502. PMID 10625704. 
  4. ^ Jarrell KF, Ng SY, Chaban B (2006). "Archaeal flagella, bacterial flagella and type IV pili: a comparison of genes and posttranslational modifications". J. Mol. Microbiol. Bio technol. 11 (3): 167–91. doi:10.1159/000094053. PMID 16983194. 
  5. ^ Jarrell KF, Bardy SL (2003). "Cleavage of preflagellins by an aspartic acid signal peptidase is essential for flagellation in the archaeon Methanococcus voltae". Mol. Microbiol. 50 (4): 1339–1347. doi:10.1046/j.1365-2958.2003.03758.x. PMID 14622420. 
  6. ^ a b Suguna K, Padlan EA, Smith CW, Carlson WD, Davies DR (1987). "Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action". Proc. Natl. Acad. Sci. U.S.A. 84 (20): 7009–13. doi:10.1073/pnas.84.20.7009. PMC 299218. PMID 3313384. 
  7. ^ Brik A, Wong CH (2003). "HIV-1 protease: mechanism and drug discovery". Org. Biomol. Chem. 1 (1): 5–14. doi:10.1039/b208248a. PMID 12929379. 
  8. ^ Hartsuck JA, Koelsch G, Remington SJ (May 1992). "The high-resolution crystal structure of porcine pepsinogen". Proteins 13 (1): 1–25. doi:10.1002/prot.340130102. PMID 1594574. 
  9. ^ Sielecki AR, Fujinaga M, Read RJ, James MN (June 1991). "Refined structure of porcine pepsinogen at 1.8 A resolution". J. Mol. Biol. 219 (4): 671–92. doi:10.1016/0022-2836(91)90664-R. PMID 2056534. 

This article incorporates text from the public domain Pfam and InterPro IPR012848

This article incorporates text from the public domain Pfam and InterPro IPR000036

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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

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.

Aspartic endopeptidases EC of vertebrate, fungal and retroviral origin have been characterised [PUBMED:1455179]. More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin [PUBMED:10625704] and archaean preflagellin have been described [PUBMED:16983194, PUBMED:14622420].

Structurally, aspartic endopeptidases are bilobal enzymes, each lobe contributing a catalytic Asp residue, with an extended active site cleft localised between the two lobes of the molecule. One lobe has probably evolved from the other through a gene duplication event in the distant past. In modern-day enzymes, although the three-dimensional structures are very similar, the amino acid sequences are more divergent, except for the catalytic site motif, which is very conserved. The presence and position of disulphide bridges are other conserved features of aspartic peptidases. All or most aspartate peptidases are endopeptidases. These enzymes have been assigned into clans (proteins which are evolutionary related), and further sub-divided into families, largely on the basis of their tertiary structure.

This group of aspartic peptidases belong to MEROPS peptidase family A1 (pepsin family, clan AA). The type example is pepsin A from Homo sapiens (Human) .

More than 70 aspartic peptidases, from all from eukaryotic organisms, have been identified. These include pepsins, cathepsins, and renins. The enzymes are synthesised with signal peptides, and the proenzymes are secreted or passed into the lysosomal/endosomal system, where acidification leads to autocatalytic activation.

Most members of the pepsin family specifically cleave bonds in peptides that are at least six residues in length, with hydrophobic residues in both the P1 and P1' positions [PUBMED:7674916]. Crystallography has shown the active site to form a groove across the junction of the two lobes, with an extended loop projecting over the cleft to form an 11-residue flap, which encloses substrates and inhibitors within the active site [PUBMED:7674916]. Specificity is determined by several hydrophobic residues surrounding the catalytic aspartates, and by three residues in the flap. Cysteine residues are well conserved within the pepsin family, pepsin itself containing three disulphide loops. The first loop is found in all but the fungal enzymes, and is usually around five residues in length, but is longer in barrierpepsin and candidapepsin; the second loop is also small and found only in the animal enzymes; and the third loop is the largest, found in all members of the family, except for the cysteine-free polyporopepsin. The loops are spread unequally throughout the two lobes, suggesting that they formed after the initial gene duplication and fusion event [PUBMED:7674916].

This family does not include the retroviral nor retrotransposon aspartic proteases which are much smaller and appear to be homologous to the single domain aspartic proteases.

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 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
(23)
Full
(4762)
Representative proteomes NCBI
(6175)
Meta
(72)
RP15
(1115)
RP35
(1670)
RP55
(2449)
RP75
(3018)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

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

Format an alignment

  Seed
(23)
Full
(4762)
Representative proteomes NCBI
(6175)
Meta
(72)
RP15
(1115)
RP35
(1670)
RP55
(2449)
RP75
(3018)
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
(23)
Full
(4762)
Representative proteomes NCBI
(6175)
Meta
(72)
RP15
(1115)
RP35
(1670)
RP55
(2449)
RP75
(3018)
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 enriched
Previous IDs: asp;
Type: Family
Author: Eddy SR, Griffiths-Jones SR, Finn RD
Number in seed: 23
Number in full: 4762
Average length of the domain: 282.30 aa
Average identity of full alignment: 24 %
Average coverage of the sequence by the domain: 71.72 %

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 19.9 19.9
Trusted cut-off 19.9 19.9
Noise cut-off 19.8 19.8
Model length: 317
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 4 interactions for this family. More...

Asp Pepsin-I3 Inhibitor_I34 A1_Propeptide

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 656 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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