| Clan type peptidase | A01.001 - pepsin A (Homo sapiens), MEROPS Accession MER0000885 (peptidase unit: 63-388); PDB accession 1PSO |
| History | Biochem.J. 290:205-218 (1993) |
| Description | Water nucleophile; water bound by two Asp from monomer or dimer; all endopeptidases, from eukaryote organisms, some bacteria and viruses or virus-like organisms |
| Contents of clan | Peptidase clan AA contains endopeptidases. |
| Evidence | Pepsin A (A01.001) is the type peptidase of clan AA, and the structure of retropepsin (A02.001) resembles that of one of the structural domains of pepsin. A sequence motif that contains the active site Asp residues can be recognised in all the families of the clan. This is Xaa-Xaa-Asp-Xbb-Gly-Xcc, where a Xaa is hydrophobic, Xbb is Thr or Ser, and Xcc is Ser, Thr or Ala (see the Alignment). Histoaspartic peptidase (A01.043) in family A1 has one Asp replaced by His. |
| Catalytic mechanism | Activity is dependent upon two aspartic residues, which support a water molecule that is the nucleophile in catalysis. Accordingly, the peptidases of clan AA are termed 'water nucleophile' peptidases in MEROPS. The catalytic mechanism has been reviewed by James (2004). |
| Peptidase activity | All the peptidases in clan AA are endopeptidases, and the great majority have pH optima at acidic pH. Hydrophobic residues are commonly preferred near the scissile bond. |
| Protein fold | Tertiary structures have been determined for members of families A1 (for example pepsin A, Fujinaga et al., 1995) and A2 (Jaskolski et al., 1991). Peptidases in family A1 are all-beta proteins consisting of two similar beta barrel domains, each of which contributes one active site Asp. Each domain contains two psi-loops, which are parallel beta strands that resemble the Greek letter psi. One of the psi-loops contains the active site Asp and a second conserved "hydrophobic-hydrophobic-Gly" motif (Castillo et al., 1999). The barrel domains are believed to be derived from a very ancient duplication event. The N-terminal barrel is partially open and carries a beta hairpin loop known as the 'flap' which carries residues important for specificity, especially Tyr137, that interact with the substrate and are part of the S1 subsite. The C-terminal barrel is closed. In family A2, the protein consists of a single beta barrel domain and to form an active peptidase dimerization must occur, producing a structure very similar to that of pepsin, except that the flap is not present. |
| Evolution | Clan AA is unusual in being unknown from all but a few prokaryotic organisms, and may have arisen in an early eukaryote. The prokaryote homologues may have arisen by lateral transfer of a eukaryote gene. |
| Homologous non-peptidase families | The beta barrel domain, also known as a double-psi beta barrel (because the domain contains two psi-loops), has been in several families of proteins that are not peptidases, including the enzymes dimethylsulfoxide reductase, formate dehydrogenase H, endoglucanase V and the plant defense protein barwin. A circular permutation of the secondary structure elements has occurred in the aspartic proteinases (Castillo et al., 1999). |
| Activation mechanism | Most of the peptidases in family A1 have proenzymes that are activated by cleavage of the propeptide, like pepsin (A01.001: Sielecki et al., 1991). The peptidases in the other families are encoded in the polyproteins of viruses and transposons, and they become active only when two monomers assemble to form the catalytically active dimer (Ingr et al., 2003). |
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Other databases
| PFAM | CL0129 |
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| SCOP | 50630 |