Peptidase A22A, presenilin 1 (IPR002031)
Short name: Pept_A22A_PS1
Overlapping homologous superfamilies
This group of aspartic peptidases belong to MEROPS peptidase family A22 (presenilin family, clan AD): subfamily A22A, the type example being presenilin 1 from Homo sapiens (Human).
Presenilins are polytopic transmembrane (TM) proteins, mutations in which are associated with the occurrence of early-onset familial Alzheimer's disease, a rare form of the disease that results from a single-gene mutation [PMID: 9791530, PMID: 9521418]. The physiological functions of presenilins are unknown, but they may be related to developmental signalling, apoptotic signal transduction, or processing of selected proteins, such as the beta-amyloid precursor protein(beta-APP). There are a number of subtypes which belong to this presenilin family. That presenilin homologues have been identified in species that do not have an Alzhemier's disease correlate suggests that they may have functions unrelated to the disease, homologues having been identified in Mus musculus (Mouse), Drosophila melanogaster, Caenorhabditis elegans [PMID: 7566091] and other members of the eukarya including plants.
In humans, there are two presenilin genes (PS1 and PS2) that share 67% amino acid identity, the greatest divergence between the two falling in the N terminus and in the large hydrophilic loop towards the C terminus of each molecule. Six to nine TM domains are predicted for each, and biochemical analysis has demonstrated that their C-termini are cytoplasmic; but the orientation of their N-termini and large hydrophilic loops remains to be resolved. They are expressed in almost all tissues, including the brain and, at a cellular level, they have been localised to the nuclear envelope, endoplasmic reticulum and Golgi apparatus.
Presenilin 1 has been shown to be phosphorylated by protein kinase C, and is endogenously cleaved into 28 kDa N-terminal and 19 kDa C-terminal fragments. Consequently, little of the uncleaved peptide is detectable in vivo. PS1 gene mutations are thought to account for the majority of early-onset familial Alzheimer's disease cases. To date, 45 different mutations have been identified in PS1, all but one of which result in a single amino change in the presenilin 1 molecule. Affected residues always occur in regions of the sequence that are conserved between presenilins 1 and 2, and the C. elegans homologue, sel-12 [PMID: 9791532]. The mutations are thought to be responsible for ~50% of cases of early-onset familial Alzheimer's disease, in contrast, less than 1% resulting from mutations in PS2. How the mutations trigger disease is unknown, but one biochemical effect consistently associated with them is an alteration in the proteolytic cleavage of beta-APP such that there is overproduction of long-tailed beta-amyloid peptide derivatives.
Presenilin-1 (MEROPS identifer A22.001) has been identified as the gamma-secretase that performs one of the cleavages that leads to the release of the amyloid-beta peptide from its precursor protein. Processing of the amyloid beta precursor requires an initial cleavage by beta-secretase (now identified as BACE-1), which releases the extracellular domain, followed by cleavages by presenilin-1 to release the amyloid-beta peptide and an intracellular domain [PMID: 11851430]. Released amyloid-beta peptide can form the plaques that are depoited in the brains of patients suffering Alzheimer's disease [PMID: 17082447]. Presenilin-1 is a transmembrane peptidase in which the active site is buried in the membrane [PMID: 10864326, PMID: 10801983]. Native presenilin-1 is processed in the large loop between the sixth and seventh transmembrane regions to form a two-chain protein, with a larger N-terminal domain [PMID: 16046406, PMID: 16135086]. The heterodimer forms a complex with three other membrane proteins, nicastrin, Aph-1 and Pen-2 [PMID: 15734686]. In addition to the amyloid beta protein, presenilin-1 also cleaves Notch, various cadherins, Notch ligands Delta and Jagged, and other proteins [PMID: 15173829, PMID: 18239854]
- PR01073 (PRESENILIN1)