Family A22
Summary for family A22
Name | Peptidase family A22 (presenilin family) |
Family type peptidase | A22.001 - presenilin 1 (Homo sapiens), MEROPS Accession MER0005221 (peptidase unit: 1-467) |
Content of family | Peptidase family A22 contains membrane-inserted endopeptidases. |
History |
Identifier created: MEROPS 5.00 (20 April 2000) Much of the research on the peptidases of subfamily A22A has been driven by the evidence that the presenilins may be functional in Alzheimer"s disease. A crucial aspect of Alzheimer"s disease is the formation of extracellular deposits of amyloid, composed of aggregates of the amyloid-beta peptides. The beta peptides are derived from an internal segment (about 42 amino acids) of the large Alzheimer"s precursor protein that is excised by peptidase activities known as 'beta-secretase' (cleaving at the N-terminus of the beta-peptide) and 'gamma-secretase' (cleaving at the C-terminus). The gamma-secretase cleavage occurs in a transmembrane segment of the APP, and is mediated by presenilin in complex with nicastrin, APH-1 and PEN-2. A third activity termed 'alpha-secretase' degrades the beta-peptide, making it harmless. More than one individual peptidase may be responsible for each of the secretase activities. Memapsin-2 (A01.004) has beta-secretase activity, and alpha-secretase activity may be due to ADAM endopeptidases (Asai et al., 2003) and/or neprilysin (M13.001). A cleavage a few residues C-terminal to the gamma-secretase site has been attributed to an 'epsilon-secretase' (Chen et al., 2002). |
Catalytic type | Aspartic |
Active site | Both the active site residues of the peptidases of family A22 are aspartates. That nearest to the N-terminus is found within a transmembrane domain in a Tyr-Asp motif, and that nearer to the C-terminus is found within a Gly-Leu-Gly-Asp-Phe motif (see the Alignment). It has not yet been possible to demonstrate peptidase activity of isolated presenilin. |
Activities and specificities | Gamma-Secretase produces the amyloid beta-peptide deposited in the brains of Alzheimer"s disease patients (Martoglio & Golde, 2003). Presenilin-1 from Drosophila has been shown to cleave a protein called Notch at a site similar to that of the epsilon-secretase site in the amyloid beta protein, implying that presenilin-1 may also be epsilon-secretase (Chen et al., 2002). The signal peptide peptidases of subfamily A22B cleave signal peptides following their release from the prepeptide. Signal peptide peptidase is not part of a multiprotein complex. |
Inhibitors | Pepstatin derivatives inhibit presenilins 1 and 2 (Evin et al., 2001). Potent inhibitors of the gamma-secretase complex include (hydroxyethyl)urea peptidomimetics (Esler et al., 2004) and hydroxytriamides (Prasad et al., 2004). Signal peptide peptidase is inhibited by (Z-LL)(2)-ketone (Heimann et al., 2006). Several inhibitors of gamma-secretase also inhibit signal peptide peptidase (Dev et al., 2006), but an inhibitor that is selective for gamma-secretase is DAPT, which does not bind to the active site but to an exosite at the C-terminus of presenilin-1 (Morohashi et al., 2006). |
Molecular structure | The tertiary structure for a homologue from the archaean Methanoculleus marisnigri has been determined and shows a unique fold which includes nine transmembrane segments (Li et al., 2012). Other peptidases of family A22 contain at least eight transmembrane domains (see the Alignment). Presenilin-1 naturally forms homodimers (Herl et al., 2006). The gamma-secretase complex is visible under electron microscopy and contains an aqueous chamber with two pores (Lazarov et al., 2006). A low-resolution structure has been solved showing two opposing domains forming a heart shape (Ogura et al., 2006). The presenilins of subfamily A22A are synthesized as 50 kDa proteins that are rapidly cleaved into an N-terminal fragment of about 30 kDa and a C-terminal fragment of about 20 kDa, possibly by intramolecular autolysis (Brunkan et al., 2005). |
Clan | AD |
Basis of clan assignment | Protein fold of the peptidase unit for members of this family resembles that of preflagellin peptidase, the type example of clan AD. |
Biological functions | Following the processing of the beta-amyloid precursor protein by beta-secretase (A01.004), the presenilins as part of gamma-secretase cleave the membrane bound C-terminal of the precursor protein within its transmembrane region to generate the 4 kDa amyloid beta-peptide and a C-terminal cleavage product (Martoglio & Golde, 2003). Signal peptide peptidase activity is required for further processing of the MHC class I signal peptide following its release from the preprotein. Cleavage releases an HLA-E epitope-containing fragment, enabling its transport form the lipid bilayer to the endoplasmic reticulum (Lemberg et al., 2001). Some viruses exploit signal peptide peptidase activity in the production of viral components; such viruses include hepatitis C virus (Lemberg et al., 2002) and pestiviruses (Heimann et al., 2006). |
Pharmaceutical and biotech relevance | The presenilins are a drug target for Alzheimer"s disease as they are a component of gamma-secretase (Beher et al., 2003). The signal peptide peptidases are of interest to the pharmaceutical industry because of their requirement in hepatitis C virus maturation and also because their activity is liable to be affected by inhibitors of gamma-secretase (Weihofen et al., 2003). Notch, a protein involved in short range communication between cells, requires cleavage by presenelin-1 for signal transduction (Struhl & Greenwald, 2001). Therefore, the decision to inhibit gamma-secretase for the treatment of Alzheimer"s disease is not one that should be taken lightly. |
Reviews | Bunkan & Goate, 2005 |
Statistics for family A22 | Sequences: | 3642 |
| Identifiers: | 31 |
| Identifiers with PDB entries: | 3 |
Downloadable files |
Sequence library (FastA format) |
| Sequence alignment (FastA format) |
| Phylogenetic tree (Newick format) |
Peptidases and Homologues |
MEROPS ID |
Structure |
presenilin 1 | A22.001 | Yes |
presenilin 2 | A22.002 | - |
SEL-12 peptidase (Caenorhabditis-type) | A22.009 | - |
hop-1 peptidase | A22.010 | - |
SPE-4 peptidase | A22.012 | - |
Psn peptidase (Drosophila-type) | A22.014 | - |
AtPS1 protein (Arabidopsis thaliana) | A22.A01 | - |
AtPS2 protein (Arabidopsis thaliana) | A22.A02 | - |
psenA (Dictyostelium discoideum) | A22.A09 | - |
psenB (Dictyostelium discoideum) | A22.A10 | - |
possible family A22 pseudogene (Homo sapiens chromosome 11) | A22.P02 | - |
Subfamily A22A non-peptidase homologues | non-peptidase homologue | - |
Subfamily A22A unassigned peptidases | unassigned | - |
Peptidases and Homologues |
MEROPS ID |
Structure |
impas 1 peptidase | A22.003 | - |
signal peptide peptidase-like protein 2B | A22.004 | - |
impas 2 peptidase | A22.005 | - |
signal peptide peptidase-like protein 2C | A22.006 | - |
signal peptide peptidase-like protein 2A | A22.007 | Yes |
yeast presenilin fold 1 | A22.008 | - |
mSPP peptidase (Plasmodium-type) | A22.013 | - |
intramembrane aspartyl peptidase (Methanoculleus marisnigri JR1) | A22.015 | Yes |
At1g01650 (Arabidopsis thaliana) | A22.A03 | - |
At1g05820 (Arabidopsis thaliana) | A22.A04 | - |
At1g63690 (Arabidopsis thaliana) | A22.A05 | - |
At2g43105 (Arabidopsis thaliana)-type peptidase | A22.A06 | - |
imp-3 g.p. (Caenorhabditis elegans) | A22.A07 | - |
imp-1 g.p. (Caenorhabditis elegans) | A22.A08 | - |
SPAC25B8.17 (Schizosaccharomyces pombe) | A22.A11 | - |
DDB_G0292836 (Dictyostelium discoideum) | A22.A12 | - |
DDB_G0287521 (Dictyostelium discoideum) | A22.A13 | - |
At4g33410 g.p. (Arabidopsis thaliana) | A22.A14 | - |
At2g03120 g.p. (Arabidopsis thaliana) | A22.A15 | - |
possible family A22 pseudogene (Homo sapiens chromosome 18) | A22.P01 | - |
Subfamily A22B non-peptidase homologues | non-peptidase homologue | - |
Subfamily A22B unassigned peptidases | unassigned | - |
Peptidases not assigned to subfamily
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