| Interpro abstract (IPR005080): |
Aspartic peptidases, also known as aspartyl proteases ([intenz:3.4.23.-]), 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 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) ].
This group of peptidases belong to MEROPS peptidase family A25 (GPR peptidase family, clan AE). During the germination of bacterial spores, the GPR peptidase initiates the degradation of the small acid-soluble proteins that make up 10-20% of the spore content [ (PUBMED:3059997) ]. The peptidase prefers an acidic residue in P1' and P4' and a hydrophobic residue in P1' and P2'. There has been controversy concerning the catalytic type of this peptidase, but the consensus is now that it is aspartic-type: two aspartic acid residues have been shown to be essential because mutation of either of these residues prevents autocatalytic activation [ (PUBMED:16199582) ]. The peptidase is active as a homotetramer [ (PUBMED:6801023) ]. The structure of a truncated form of the peptidase precursor has been solved, and shows each monomer consists on a core domain and a cap domain. The core domain contains an eight-stranded beta sheet and two alpha helices, and the cap domain contains three helices [ (PUBMED:10864493) ]. The structure of the hydrogenase-processing peptidase from peptidase family A31 is similar [ (PUBMED:11847292) ], and both families are included in clan AE.
|
|---|
