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0  structures 409  species 0  interactions 1458  sequences 107  architectures

Family: Asp_protease_2 (PF13650)

Summary: 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]
Symbol Asp
Pfam PF00026
InterPro IPR001461
SCOP 1mpp
OPM superfamily 108
OPM protein 1lyb

Aspartic proteases are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues 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

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

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 serine or cysteine proteases these proteases do not form a covalent intermediate during cleavage. Proteolysis therefore occurs in a single step.

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 perform a nucleophilic attack on the carbonyl carbon of the substrate scissile bond, generating a tetrahedral oxyanion intermediate. Rearrangement of this intermediate leads to protonation of the scissile amide which results in the splitting of the substrate peptide into two product peptides.


Pepstatin is an inhibitor of aspartate proteases.


Five superfamilies (clans) of aspartic proteases are known, each representing an independent evolution of the same active site and mechanisms. Each superfamily contains several families with similar sequences. The MEROPS classification system names these clans alphabetically.


PDB 1htr EBI.jpg
crystal and molecular structures of human progastricsin at 1.62 angstroms resolution
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]



Human proteins containing this domain


Other organisms

External links

See also


  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 IPR000036 This article incorporates text from the public domain Pfam and InterPro IPR012848

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

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Aspartyl protease Provide feedback

This family consists of predicted aspartic proteases, typically from 180 to 230 amino acids in length, in MEROPS clan AA. This model describes the well-conserved 121-residue C-terminal region. The poorly conserved, variable length N-terminal region usually contains a predicted transmembrane helix.

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This tab holds annotation information from the InterPro database.

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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


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Seed source: Jackhmmer:C6QGC6
Previous IDs: none
Type: Domain
Author: Coggill P
Number in seed: 159
Number in full: 1458
Average length of the domain: 90.90 aa
Average identity of full alignment: 17 %
Average coverage of the sequence by the domain: 14.66 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 24.0 24.0
Trusted cut-off 24.0 24.0
Noise cut-off 23.9 23.9
Model length: 90
Family (HMM) version: 3
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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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