Family A22

Family

Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

A22A

Summary Holotypes Alignment Tree Genomes Literature

A22B

Summary Holotypes Alignment Tree Genomes Literature

Summary for family A22

NamePeptidase family A22 (presenilin family)
Family type peptidaseA22.001 - presenilin 1 (Homo sapiens), MEROPS Accession MER0005221 (peptidase unit: 1-467)
Content of familyPeptidase 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 typeAspartic
Active siteBoth 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 specificitiesGamma-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, and only the C-terminal half is required for proteolytic activity (Narayanan et al., 2007).
InhibitorsPepstatin 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 structureThe 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). The tertiary structure of the gamma-secretase complex has been solved, and shows that nicastrin is extracellular, but presenilin, PEN-2 and APH-1 are transmembrane protein, with the transmembrane regions forming a horseshoe shape (Bai et al., 2015). 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).
ClanAD
Basis of clan assignmentProtein fold of the peptidase unit for members of this family resembles that of preflagellin peptidase, the type example of clan AD.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsFollowing 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 relevanceThe 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.
ReviewsBunkan & Goate, 2005
Statistics for family A22Sequences:3673
Identifiers:31
Identifiers with PDB entries:3
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily A22A
Name Peptidase subfamily A22A
Subfamily type peptidase A22.001 - presenilin 1 (Homo sapiens), MEROPS Accession MER0005221 (peptidase unit: 1-467)
Active site residues D257 D385 
Statistics Sequences: 1044
Identifiers: 11
Identifiers with PDB entries: 1
Other databases INTERPRO IPR001108
PANTHER PTHR10202
PFAM PF01080
PFAM PF06550
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
presenilin 1A22.001Yes
presenilin 2A22.002-
SEL-12 peptidase (Caenorhabditis-type)A22.009-
hop-1 peptidaseA22.010-
SPE-4 peptidaseA22.012-
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 homologuesnon-peptidase homologue-
subfamily A22A unassigned peptidasesunassigned-
Subfamily A22B
Name Peptidase subfamily A22B
Subfamily type peptidase A22.003 - impas 1 peptidase (Homo sapiens), MEROPS Accession MER0019701 (peptidase unit: 1-377)
Active site residues D219 D265 
Statistics Sequences: 2626
Identifiers: 20
Identifiers with PDB entries: 2
Other databases INTERPRO IPR007369
PANTHER PTHR12174
PFAM PF04258
PFAM PF06550
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
impas 1 peptidaseA22.003-
signal peptide peptidase-like protein 2BA22.004-
impas 2 peptidaseA22.005-
signal peptide peptidase-like protein 2CA22.006-
signal peptide peptidase-like protein 2AA22.007Yes
yeast presenilin fold 1A22.008-
mSPP peptidase (Plasmodium-type)A22.013-
intramembrane aspartyl peptidase (Methanoculleus marisnigri JR1)A22.015Yes
At1g01650 (Arabidopsis thaliana)A22.A03-
At1g05820 (Arabidopsis thaliana)A22.A04-
At1g63690 (Arabidopsis thaliana)A22.A05-
At2g43105 (Arabidopsis thaliana)-type peptidaseA22.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 homologuesnon-peptidase homologue-
subfamily A22B unassigned peptidasesunassigned-
Peptidases not assigned to subfamily
Peptidases and Homologues MEROPS ID Structure
family A22 non-peptidase homologuesnon-peptidase homologue-
family A22 unassigned peptidasesunassigned-