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1  structure 156  species 0  interactions 478  sequences 7  architectures

Family: Presenilin (PF01080)

Summary: Presenilin

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Presenilin Edit Wikipedia article

Solution structure of the human presenilin-1 CTF subunit.[1]
Symbol Presenilin
Pfam PF01080
Pfam clan CL0130
InterPro IPR001108
TCDB 1.A.54
OPM superfamily 277
OPM protein 4hyg
presenilin 1
(Alzheimer's disease 3)
Symbol PSEN1
Alt. symbols AD3
Entrez 5663
HUGO 9508
OMIM 104311
RefSeq NM_000021
UniProt P49768
Other data
Locus Chr. 14 q24.3
presenilin 2
(Alzheimer's disease 4)
Symbol PSEN2
Alt. symbols AD4
Entrez 5664
HUGO 9509
OMIM 600759
RefSeq NM_000447
UniProt P49810
Other data
Locus Chr. 1 q31-q42

Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase intramembrane protease complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's Disease by Peter St George-Hyslop at the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and now also at the University of Cambridge.[2] Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that encodes presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.[3]

Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a larger N-terminal and a smaller C-terminal fragment that together form part of the functional protein. Cleavage of presenilin 1 can be prevented by a mutation that causes the loss of exon 9, and results in loss of function. Presenilins play a key role in the modulation of intracellular Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction.[4]

Dominant mutations in the genes that encode presenilin proteins are the most common cause of familial early-onset Alzheimer's disease.[5]


The structure of presenilin-1 is still controversial, although recent research has produced a more widely accepted model. When first discovered, the PSEN1 gene was subjected to hydrophobicity analysis that predicted that the protein would contain ten trans-membrane domains. All previous models agreed that the first six putative membrane-spanning regions cross the membrane. These regions correspond to the N-terminal fragment of PS-1 but the structure of the C-terminal fragment was disputed. A recent paper by Spasic et al.[6] provides strong evidence of a nine transmembrane structure with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane. However, because this is a protein with large numbers of hydrophobic regions, it is unlikely that x-ray crystallography will provide definitive proof of the structure.

The structure of the presenilin-1 C-terminal catalytic fragment was determined using solution NMR. It is made up of alpha helices and is 176 amino acids in length. It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2). This information was found at the protein data bank


Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and have a strong genetic element. In patients suffering from Alzheimer's disease (autosomal dominant hereditary), mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important part of the disease process in Alzheimer's disease is the accumulation of Amyloid beta (Aβ) protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP.

Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The lengths associated with Alzheimer's disease are 40 and 42 amino acids long. Aβ 42 is more likely to aggregate to form plaques in the brain than Aβ 40. Presenilin mutations lead to an increase in the ratio of Aβ 42 produced compared to Aβ 40, although the total quantity of Aβ produced remains constant.[7] This can come about by various effects of the mutations upon gamma secretase.[8] Presenilins are also implicated in the processing of notch, an important developmental protein. Mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted.[9]

The genes for the presenilins were found through linkage studies using mutations present in familial Alzheimer's cases in 1995.[2]

The genetic inactivation of presenilins in hippocampal synapses has shown this selectively affects the long-term potentiation caused by theta with the inactivation in presynapse but not the postsynapse impairing short-term plasticity and synaptic facilitation.[4] The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca2+ release.[4] This has been suggested to "represent a general convergent mechanism leading to neurodegeneration".[4]


  1. ^ PDB 2KR6; Doetsch V (2010). "Solution structure of presenilin-1 CTF subunit". To be published. doi:10.2210/pdb2kr6/pdb. 
  2. ^ a b Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K (June 1995). "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease". Nature 375 (6534): 754–60. doi:10.1038/375754a0. PMID 7596406. 
  3. ^ Smialowska A, Baumeister R (2006). "Presenilin function in Caenorhabditis elegans". Neurodegener Dis 3 (4–5): 227–32. doi:10.1159/000095260. PMID 17047361. 
  4. ^ a b c d Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J (July 2009). "Presenilins are Essential for Regulating Neurotransmitter Release". Nature 460 (7255): 632–6. doi:10.1038/nature08177. PMC 2744588. PMID 19641596. 
  5. ^ Brouwers N, Sleegers K, Van Broeckhoven C (2008). "Molecular genetics of Alzheimer's disease: an update". Ann Med 40 (8): 562–83. doi:10.1080/07853890802186905. PMID 18608129. 
  6. ^ Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W (September 2006). "Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway". J. Biol. Chem. 281 (36): 26569–77. doi:10.1074/jbc.M600592200. PMID 16846981. 
  7. ^ Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (January 1997). "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice". Nat. Med. 3 (1): 67–72. doi:10.1038/nm0197-67. PMID 8986743. 
  8. ^ Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, Esselmann H, De Strooper B (February 2006). "Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms". J. Neurochem. 96 (3): 732–42. doi:10.1111/j.1471-4159.2005.03578.x. PMID 16405513. 
  9. ^ Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (May 1997). "Skeletal and CNS defects in Presenilin-1-deficient mice". Cell 89 (4): 629–39. doi:10.1016/S0092-8674(00)80244-5. PMID 9160754. 

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Presenilin Provide feedback

Mutations in presenilin-1 are a major cause of early onset Alzheimer's disease [2]. It has been found that presenilin-1 (P49768) binds to beta-catenin in-vivo [4]. This family also contains SPE proteins from C.elegans.

Literature references

  1. Kim TW, Tanzi RE; , Curr Opin Neurobiol 1997;7:683-688.: Presenilins and Alzheimer's disease. PUBMED:9384549 EPMC:9384549

  2. Kim TW, Tanzi RE; , Curr Opin Neurobiol 1997;7:683-688.: Presenilins and Alzheimer's disease. PUBMED:9384549 EPMC:9384549

  3. Zhang W, Han SW, McKeel DW, Goate A, Wu JY; , J Neurosci 1998;18:914-922.: Interaction of presenilins with the filamin family of actin-binding proteins. PUBMED:9437013 EPMC:9437013

  4. Zhang Z, Hartmann H, Do VM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Sommer B, van de Wetering M, Clevers H, Saftig P, De Strooper B, He X, Yankner BA; , Nature 1998;395:698-702.: Destabilisation of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. PUBMED:9790190 EPMC:9790190

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001108

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 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): 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 [PUBMED:9791530, PUBMED: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 mouse, Drosophila melanogaster, Caenorhabditis elegans [PUBMED:7566091] and other members of the eukarya including plants.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Peptidase_AD (CL0130), which has the following description:

Members of this clan are peptidases that are integral membrane proteins. The catalytic aspartate is in the conserved GXGD motif.

The clan contains the following 4 members:

DUF1119 Peptidase_A22B Peptidase_A24 Presenilin


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_789 (release 3.0)
Previous IDs: none
Type: Family
Author: Finn RD, Bateman A
Number in seed: 6
Number in full: 478
Average length of the domain: 264.60 aa
Average identity of full alignment: 37 %
Average coverage of the sequence by the domain: 83.85 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 24.5 24.5
Trusted cut-off 24.5 24.7
Noise cut-off 24.0 24.4
Model length: 403
Family (HMM) version: 12
Download: download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Presenilin domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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