InterPro domain: IPR007369

Aspartic peptidases, also known as aspartyl proteases ([intenz:3.4.23.-]), are widely distributed proteolytic enzymes [ 1 , 2 , 3 ] 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 [ 4 ].

• 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) [ 5 ]. 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 [ 6 ].
• 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) [ 7 ]. 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 [ 8 ]. The active site aspartic acids are located within a large cavity in the membrane into which water can gain access [ 9 ].
• 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 [ 10 , 11 ].
• 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 [ 12 ].
• 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 [ 13 ].

This group of sequences contain aspartic endopeptidases that belong to MEROPS peptidase family A22 (presenilin family), subfamily A22B. These are intramembrane cleaving proteases (I-CLiPs). They are also known as signal peptide peptidases (SPPs) [ 14 ]. SPP cleaves remnant signal peptides left behind in the membrane by the action of signal peptidase and also plays key roles in immune surveillance and the maturation of certain viral proteins [ 15 ].

The tertiary structure of a homologue from the archaean Methanoculleus marisnigri has been solved and shows a unique fold which includes nine transmembrane segments that form a horseshoe shape [ 16 ]. SPPs do not require cofactors as demonstrated by expression in bacteria and purification of a proteolytically active form. The C-terminal region defines the functional domain, which is in itself sufficient for proteolytic activity [ 16 ].

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