Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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PSN Presenilin, signal peptide peptidase, family

SMART accession number:	SM00730
Description:	Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. Distant homologues, present in eukaryotes and archaea, also contain conserved aspartic acid residues which are predicted to contribute to catalysis. At least one member of this family has been shown to possess signal peptide peptidase activity.
Interpro abstract (IPR006639):	In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold: Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins. Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases. In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding. Aspartic endopeptidases EC 3.4.23. of vertebrate, fungal and retroviral origin have been characterised [(PUBMED:1455179)]. More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin [(PUBMED:10625704)] and archaean preflagellin have been described [(PUBMED:16983194), (PUBMED:14622420)]. Structurally, aspartic endopeptidases are bilobal enzymes, each lobe contributing a catalytic Asp residue, with an extended active site cleft localised between the two lobes of the molecule. One lobe has probably evolved from the other through a gene duplication event in the distant past. In modern-day enzymes, although the three-dimensional structures are very similar, the amino acid sequences are more divergent, except for the catalytic site motif, which is very conserved. The presence and position of disulphide bridges are other conserved features of aspartic peptidases. All or most aspartate peptidases are endopeptidases. These enzymes have been assigned into clans (proteins which are evolutionary related), and further sub-divided into families, largely on the basis of their tertiary structure. This group of aspartic peptidases belong to MEROPS peptidase family A22 (presenilin family, clan AD). SPP and potential eukaryotic homologues represent a family of aspartic proteases that promote intramembrane proteolysis to release biologically important peptides. Signal peptide peptidase (SPP) catalyses intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. In humans, SPP activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognised by the immune system, and are required in the processing of the hepatitis C virus core protein.
GO component:	integral to membrane (GO:0016021)
GO function:	aspartic-type endopeptidase activity (GO:0004190)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 633 PSN domains in 633 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a PSN domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with PSN domain is also avaliable.

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  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Cellular role: signalling
  Binding / catalysis: Likely aspartyl protease

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • McLauchlan J, Lemberg MK, Hope G, Martoglio B
  • Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets.
  • EMBO J. 2002; 21: 3980-8
  • Display abstract

  • Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The virus has a positive-sense RNA genome encoding a single polyprotein with the virion components located in the N-terminal portion. During biosynthesis of the polyprotein, an internal signal sequence between the core protein and the envelope protein E1 targets the nascent polypeptide to the endoplasmic reticulum (ER) membrane for translocation of E1 into the ER. Following membrane insertion, the signal sequence is cleaved from E1 by signal peptidase. Here we provide evidence that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane-cleaving protease SPP that promotes the release of core protein from the ER membrane. Core protein is then free for subsequent trafficking to lipid droplets. This study represents an example of a potential role for intramembrane proteolysis in the maturation of a viral protein.

  • Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE
  • Identification of a novel family of presenilin homologues.
  • Hum Mol Genet. 2002; 11: 1037-44
  • Display abstract

  • Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. Presenilins have been shown to influence limited proteolysis of amyloid beta protein precursor (APP), Notch and ErbB4, and have been proposed to be gamma-secretases that perform the terminal cleavage of APP. In this model, two conserved and apparently intramembranous aspartic acids participate in catalysis. Highly sequence-similar presenilin homologues are known in plants, invertebrates and vertebrates. In this work, we have used a combination of different sequence database search methods to identify a new family of proteins homologous to presenilins. Members of this family, which we term presenilin homologues (PSH), have significant sequence similarities to presenilins and also possess two conserved aspartic acid residues within adjacent predicted transmembrane segments. The PSH family is found throughout the eukaryotes, in fungi as well as plants and animals, and in archaea. Five PSHs are detectable in the human genome, of which three possess 'protease-associated' domains that are consistent with the proposed protease function of PSs. Based on these findings, we propose that PSs and PSHs represent different sub-branches of a larger family of polytopic membrane-associated aspartyl proteases.

  • Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B
  • Identification of signal peptide peptidase, a presenilin-type aspartic protease.
  • Science. 2002; 296: 2215-8
  • Display abstract

  • Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. In humans, SPP activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein. We have identified human SPP as a polytopic membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. SPP and potential eukaryotic homologs may represent another family of aspartic proteases that promote intramembrane proteolysis to release biologically important peptides.

  • Wolfe MS
  • Presenilin and gamma-secretase: structure meets function.
  • J Neurochem. 2001; 76: 1615-20
• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 47.17 map04330 Notch signaling pathway 33.96 map05010 Alzheimer's disease 18.87 map04310 Wnt signaling pathway This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with PSN domain which could be assigned to a KEGG orthologous group, and not all proteins containing PSN domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Links (links to other resources describing this domain)

• INTERPRO	IPR006639

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