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7  structures 264  species 0  interactions 730  sequences 14  architectures

Family: Presenilin (PF01080)

Summary: Presenilin

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Presenilin Edit Wikipedia article

Solution structure of the human presenilin-1 CTF subunit.[1][2]
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
EC number 3.4.23.-
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
EC number 3.4.23.-
Locus Chr. 1 q31-q42

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits 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.[3] 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.[4]

Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein.[1] 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.[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.[1] It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2).[7]


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.[8] This can come about by various effects of the mutations upon gamma secretase.[9] 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.[10]

The genes for the presenilins were found through linkage studies using mutations present in familial Alzheimer's cases in 1995.[3]

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.[5] The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca2+ release.[5] This has been suggested to "represent a general convergent mechanism leading to neurodegeneration".[5]


  1. ^ a b c Sobhanifar, S; Schneider, B; Löhr, F; Gottstein, D; Ikeya, T; Mlynarczyk, K; Pulawski, W; Ghoshdastider, U; Kolinski, M; Filipek, S; Güntert, P; Bernhard, F; Dötsch, V (2010). "Structural investigation of the C-terminal catalytic fragment of presenilin 1". Proceedings of the National Academy of Sciences. 107 (21): 9644–9. doi:10.1073/pnas.1000778107. PMC 2906861free to read. PMID 20445084. 
  2. ^ PDB: 2KR6​; Doetsch V (2010). "Solution structure of presenilin-1 CTF subunit". To be published. doi:10.2210/pdb2kr6/pdb. 
  3. ^ 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. 
  4. ^ Smialowska A, Baumeister R (2006). "Presenilin function in Caenorhabditis elegans". Neurodegener Dis. 3 (4–5): 227–32. doi:10.1159/000095260. PMID 17047361. 
  5. ^ 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 2744588free to read. PMID 19641596. 
  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. ^ Doetsch, V. "2KR6: Solution structure of presenilin-1 CTF subunit". RCSB Protein Data Bank. Retrieved 16 August 2016. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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

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

This group of aspartic peptidases belong to MEROPS peptidase family A22 (presenilin family), 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]. Alzheimer's disease is associated with the formation of extracellular deposits of amyloid, which contain aggrgates of the amyloid-beta peptide. The beta-peptides are released from the Alzheimer's protein APP by the action of two peptidase activities: "beta-secretase" cleaves at the N terminus of the peptide, and "gamma-secretase" cleaves at the C terminus. The gamma-secretase cleavage occurs in a transmembrane segment of APP. Presenilin, which exists in a complex with nicastrin, APH-1 and PEN-2, has been identified as gamma-secretase, from its deficiency [PUBMED:9450754] and mutation of its active site residues [PUBMED:10206644], but proteolytic activity has only been directly demonstrated on a peptide derived from APP [PUBMED:9450754].

Presenilin-1 is also known to process notch proteins [PUBMED:11518718] and syndecan-3 [PUBMED:14504279].

Presenilin has nine transmembrane regions with the active site aspartic acid residues located on TM6, within a Tyr-Asp motif, and TM7, within a Gly-Xaa-Gly-Asp motif [PUBMED:10206644]. The protein autoprocesses to form an amino-terminal fragment (TMs 1-6) and a C-terminal fragment (TMs 7-9) [PUBMED:8755489]. The tertiary structure of the human gamma-sectretase complex has been solved [PUBMED:26280335]. Nicastrin is extracellular, whereas presenilin-1, APH-1 and PEN-2 are all transmembrane proteins. The transmembrane regions of all three proteins form a horseshoe shape.

Aspartic peptidases, also known as aspartyl proteases (EC), are widely distributed proteolytic enzymes [PUBMED:6795036, PUBMED:2194475, PUBMED:1851433] known to exist in vertebrates, fungi, plants, protozoa, bacteria, archaea, retroviruses and some plant viruses. All known aspartic peptidases are endopeptidases. A water molecule, activated by two aspartic acid residues, acts as the nucleophile in catalysis. Aspartic peptidases can be grouped into five clans, each of which shows a unique structural fold [PUBMED:8439290].

  • Peptidases in clan AA are either bilobed (family A1 or the pepsin family) or are a homodimer (all other families in the clan, including retropepsin from HIV-1/AIDS) [PUBMED:2682266]. Each lobe consists of a single domain with a closed beta-barrel and each lobe contributes one Asp to form the active site. Most peptidases in the clan are inhibited by the naturally occurring small-molecule inhibitor pepstatin [PUBMED:4912600].
  • Clan AC contains the single family A8: the signal peptidase 2 family. Members of the family are found in all bacteria. Signal peptidase 2 processes the premurein precursor, removing the signal peptide. The peptidase has four transmembrane domains and the active site is on the periplasmic side of the cell membrane. Cleavage occurs on the amino side of a cysteine where the thiol group has been substituted by a diacylglyceryl group. Site-directed mutagenesis has identified two essential aspartic acid residues which occur in the motifs GNXXDRX and FNXAD (where X is a hydrophobic residue) [PUBMED:10497172]. No tertiary structures have been solved for any member of the family, but because of the intramembrane location, the structure is assumed not to be pepsin-like.
  • Clan AD contains two families of transmembrane endopeptidases: A22 and A24. These are also known as "GXGD peptidases" because of a common GXGD motif which includes one of the pair of catalytic aspartic acid residues. Structures are known for members of both families and show a unique, common fold with up to nine transmembrane regions [PUBMED:21765428]. The active site aspartic acids are located within a large cavity in the membrane amnd into which water can gain access [PUBMED:23254940].
  • Clan AE contains two families, A25 and A31. Tertiary structures have been solved for members of both families and show a common fold consisting of an alpha-beta-alpha sandwich, in which the beta sheet is five stranded [PUBMED:10331925, PUBMED:10864493].
  • Clan AF contains the single family A26. Members of the clan are membrane-proteins with a unique fold. Homologues are known only from bacteria. The structure of omptin (also known as OmpT) shows a cylindrical barrel containing ten beta strands inserted in the membrane with the active site residues on the outer surface [PUBMED:11566868].
  • There are two families of aspartic peptidases for which neither structure nor active site residues are known and these are not assigned to clans. Family A5 includes thermopsin, an endopeptidase found only in thermophilic archaea. Family A36 contains sporulation factor SpoIIGA, which is known to process and activate sigma factor E, one of the transcription factors that controls sporulation in bacteria [PUBMED:21751400].

Gene Ontology

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

Domain organisation

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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:

Peptidase_A22B Peptidase_A24 Presenilin SPP


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Curation and family details

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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: 66
Number in full: 730
Average length of the domain: 270.50 aa
Average identity of full alignment: 31 %
Average coverage of the sequence by the domain: 83.19 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 34.2 34.2
Trusted cut-off 34.4 34.4
Noise cut-off 34.1 34.1
Model length: 399
Family (HMM) version: 15
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Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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 7 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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