| Clan type peptidase | A24.016 - FlaK peptidase (Methanococcus maripaludis), MEROPS Accession MER0078598 (peptidase unit: 1-230); PDB accession 3S0X |
| History | MEROPS 5.00 (20 Apr 2000) |
| Description | Water nucleophile; water bound by two Asp; all membrane-bound endopeptidases known only from eubacteria with active site on cytoplasmic side of cell membrane. |
| Contents of clan | Peptidase clan AD contains endopeptidases that hydrolyse peptide bonds within biological membranes. |
| Evidence | There is no direct information on protein folds for families A22 and A24, so the evidence of their relationship is indirect. The peptidases in both families are molecules with nine transmembrane domains, and active sites either within the membrane or very close to it. Putative aspartic catalytic residues are in conserved sequence motifs like GLGDF or GYGDF, and the central Gly in each of these is strictly conserved (Steiner et al., 2000). It has recently been found that comparison of hidden Markov models for families A22 and A24 by use of the PRC program (http://supfam.mrc-lmb.cam.ac.uk/PRC/) reveals significant similarities (MEROPS: unpublished results). |
| Catalytic mechanism | Two Asp residues in presenilin 1 have been shown to react with inhibitors of the Alzheimer"s disease gamma-secretase activity (Esler et al., 2000; Li et al., 2000). Similarly, in family A24, two Asp residues are strongly implicated in the activity (LaPointe & Taylor, 2000; Akahane et al., 2005), but little more is known of the catalytic mechanism. |
| Peptidase activity | The catalytic activities of peptidases in clan AD can be illustrated with examples from the four subfamilies in the clan. gamma-Secretase is a protein complex with peptidase activity in which presenilin (A22.001) contains the catalytic unit. gamma-Secretase catalyses limited proteolysis of Alzheimer"s precursor protein (Micchelli et al., 2002) and also the Notch signaling protein (Song et al., 1999), both in transmembrane sequences. Impas 1 endopeptidase (A22.003) is a signal peptide peptidase that degrades signal peptides after release by the signal peptidase complex (XS26-001) (Friedmann et al., 2004). Type 4 prepilin peptidase 1 (A24.001) catalyses the maturation of type IV prepilin by cleaving off a short, basic, N-terminal signal peptide (Dupuy et al., 2004). Finally, preflagellin peptidase (A24.016) removes a leader peptide from archaeal preflagellins (Bardy & Jarrell, 2003). |
| Protein fold | Topologies of presenilins and type 4 prepilin peptidases have been deduced (Steiner et al., 2000), but no protein folds have been described. All members of the clan have transmembrane domains that are presumed to be helical, so the protein fold must be different to the all-beta folds found in members of clan AA. Unlike members of clan AC, which also contains membrane-bound proteins, the active site is on cytoplasmic side of the cell membrane. |
| Activation mechanism | Presenilin 1 and presenilin 2 are post-translationally-cleaved, and the C-terminal fragments form the catalytically active core of the gamma-secretase complex (Knappenberger et al., 2004). Other components of the gamma-secretase complex are nicastrin, anterior pharynx defective-1 protein (APH-1) and presenilin enhancer-2 protein (PEN-2) (Capell et al., 2004). Protein CD147 may be an additional component (Zhou et al., 2005). |
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Other databases
| PFAM | CL0130 |
