| Eukaryotic aspartyl protease |
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Structures of native and inhibited forms of human cathepsin D.[1]
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| Identifiers |
| Symbol |
Asp |
| Pfam |
PF00026 |
| InterPro |
IPR001461 |
| PROSITE |
PDOC00128 |
| SCOP |
1mpp |
| SUPERFAMILY |
1mpp |
| OPM superfamily |
108 |
| OPM protein |
1lyb |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe; PDBj |
| PDBsum |
structure summary |
|
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.
Contents
- 1 Catalytic Mechanism
- 2 Inhibition
- 3 Evolution
- 4 Classification
- 5 Propeptide
- 6 Examples
- 6.1 Human
- 6.2 Human proteins containing this domain
- 6.3 Other organisms
- 7 External links
- 8 See also
- 9 References
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.
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, nearly-symmetrical 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 |
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crystal and molecular structures of human progastricsin at 1.62 angstroms resolution
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| Identifiers |
| Symbol |
A1_Propeptide |
| Pfam |
PF07966 |
| InterPro |
IPR012848 |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe; PDBj |
| PDBsum |
structure summary |
|
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
- BACE1, BACE2
- Cathepsin D
- Cathepsin E
- Chymosin (or "rennin")
- Napsin-A
- Nepenthesin
- Pepsin
- Plasmepsin
- Presenilin
- Renin
Human proteins containing this domain
BACE1; BACE2; CTSD; CTSE; NAPSA; PGA5; PGC; REN;
Other organisms
- HIV-1 protease - a major drug-target for treatment of HIV
External links
- The MEROPS online database for peptidases and their inhibitors: Aspartic Peptidases
- Aspartic Endopeptidases at the US National Library of Medicine Medical Subject Headings (MeSH)
- MEROPS family A1
See also
References
- ^ 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.
- ^ Szecsi PB (1992). "The aspartic proteases". Scand. J. Clin. Lab. In vest. Suppl. 210: 5–22. doi:10.3109/00365519209104650. PMID 1455179.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
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Hydrolase: proteases (EC 3.4)
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| 3.4.11-19: Exopeptidase |
| 3.4.11 |
- Aminopeptidase
- Alanine
- Arginyl
- Aspartyl
- Cystinyl
- Leucyl
- Glutamyl
- Methionyl
- O
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| 3.4.13 |
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| 3.4.14 |
- Dipeptidyl peptidase
- Cathepsin C
- Dipeptidyl peptidase-4
- Tripeptidyl peptidase
- Tripeptidyl peptidase I
- Tripeptidyl peptidase II
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| 3.4.15 |
- Angiotensin-converting enzyme
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| 3.4.16 |
- Serine type carboxypeptidases: Cathepsin A
- DD-transpeptidase
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| 3.4.17 |
- Metallocarboxypeptidases: Carboxypeptidase
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| Other/ungrouped |
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| 3.4.21-24: Endopeptidase |
- Serine proteases
- Cysteine protease
- Aspartic acid protease
- Metalloendopeptidases
- Other/ungrouped: Amyloid precursor protein secretase
- Alpha secretase
- Beta-secretase 1
- Beta-secretase 2
- Gamma secretase
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| 3.4.99: Unknown |
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- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Proteases: aspartic acid proteases (EC 3.4.23)
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| Vertebrate |
- Pepsin
- Chymosin
- Renin
- Signal peptide peptidase
- Beta secretase
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| Pathogenic |
- Plasmepsin
- HIV-1 protease
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| Plant |
|
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| Cathepsin |
|
|
- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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This article incorporates text from the public domain Pfam and InterPro IPR000036
