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P49768

- PSN1_HUMAN

UniProt

P49768 - PSN1_HUMAN

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Protein

Presenilin-1

Gene

PSEN1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis.8 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei257 – 25711 Publication
Sitei291 – 2922Cleavage; alternate
Sitei292 – 2932Cleavage; alternate
Sitei298 – 2992Cleavage
Sitei345 – 3462Cleavage; by caspase
Active sitei385 – 38511 Publication

GO - Molecular functioni

  1. aspartic-type endopeptidase activity Source: InterPro
  2. beta-catenin binding Source: UniProtKB
  3. cadherin binding Source: RefGenome
  4. calcium channel activity Source: UniProtKB
  5. endopeptidase activity Source: MGI
  6. PDZ domain binding Source: UniProtKB

GO - Biological processi

  1. activation of MAPKK activity Source: Ensembl
  2. amyloid precursor protein catabolic process Source: HGNC
  3. anagen Source: Ensembl
  4. autophagic vacuole assembly Source: Ensembl
  5. beta-amyloid formation Source: Ensembl
  6. beta-amyloid metabolic process Source: RefGenome
  7. blood vessel development Source: Ensembl
  8. brain morphogenesis Source: Ensembl
  9. Cajal-Retzius cell differentiation Source: Ensembl
  10. calcium ion transmembrane transport Source: GOC
  11. canonical Wnt signaling pathway Source: RefGenome
  12. cell fate specification Source: Ensembl
  13. cellular response to DNA damage stimulus Source: Ensembl
  14. cerebral cortex cell migration Source: Ensembl
  15. choline transport Source: Ensembl
  16. dorsal/ventral neural tube patterning Source: Ensembl
  17. embryonic limb morphogenesis Source: Ensembl
  18. endoplasmic reticulum calcium ion homeostasis Source: UniProtKB
  19. epithelial cell proliferation Source: Ensembl
  20. extracellular matrix disassembly Source: Reactome
  21. extracellular matrix organization Source: Reactome
  22. heart looping Source: Ensembl
  23. hematopoietic progenitor cell differentiation Source: Ensembl
  24. intracellular signal transduction Source: InterPro
  25. L-glutamate transport Source: Ensembl
  26. membrane protein ectodomain proteolysis Source: HGNC
  27. memory Source: Ensembl
  28. mitochondrial transport Source: Ensembl
  29. myeloid leukocyte differentiation Source: Ensembl
  30. negative regulation of apoptotic process Source: UniProtKB
  31. negative regulation of apoptotic signaling pathway Source: Ensembl
  32. negative regulation of axonogenesis Source: Ensembl
  33. negative regulation of epidermal growth factor-activated receptor activity Source: Ensembl
  34. negative regulation of neuron apoptotic process Source: Ensembl
  35. negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: Ensembl
  36. negative regulation of transcription from RNA polymerase II promoter Source: Ensembl
  37. negative regulation of ubiquitin-protein transferase activity Source: Ensembl
  38. neuron apoptotic process Source: Ensembl
  39. neuron development Source: Ensembl
  40. neuron migration Source: Ensembl
  41. Notch receptor processing Source: HGNC
  42. Notch signaling pathway Source: UniProtKB-KW
  43. positive regulation of apoptotic process Source: Ensembl
  44. positive regulation of catalytic activity Source: HGNC
  45. positive regulation of coagulation Source: Ensembl
  46. positive regulation of MAP kinase activity Source: Ensembl
  47. positive regulation of proteasomal ubiquitin-dependent protein catabolic process Source: Ensembl
  48. positive regulation of receptor recycling Source: Ensembl
  49. post-embryonic development Source: Ensembl
  50. protein glycosylation Source: Ensembl
  51. protein processing Source: HGNC
  52. protein transport Source: Ensembl
  53. regulation of phosphorylation Source: UniProtKB
  54. regulation of protein binding Source: Ensembl
  55. regulation of resting membrane potential Source: Ensembl
  56. regulation of synaptic plasticity Source: Ensembl
  57. regulation of synaptic transmission, glutamatergic Source: Ensembl
  58. response to oxidative stress Source: Ensembl
  59. single organismal cell-cell adhesion Source: MGI
  60. skeletal system morphogenesis Source: Ensembl
  61. skin morphogenesis Source: Ensembl
  62. smooth endoplasmic reticulum calcium ion homeostasis Source: RefGenome
  63. somitogenesis Source: Ensembl
  64. synaptic vesicle targeting Source: Ensembl
  65. T cell activation involved in immune response Source: Ensembl
  66. T cell receptor signaling pathway Source: Ensembl
  67. thymus development Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease

Keywords - Biological processi

Apoptosis, Cell adhesion, Notch signaling pathway

Enzyme and pathway databases

ReactomeiREACT_118572. Degradation of the extracellular matrix.
SignaLinkiP49768.

Protein family/group databases

MEROPSiA22.001.
TCDBi1.A.54.1.1. the presenilin er ca(2+) leak channel (presenilin) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Presenilin-1 (EC:3.4.23.-)
Short name:
PS-1
Alternative name(s):
Protein S182
Cleaved into the following 3 chains:
Gene namesi
Name:PSEN1
Synonyms:AD3, PS1, PSNL1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 14

Organism-specific databases

HGNCiHGNC:9508. PSEN1.

Subcellular locationi

Endoplasmic reticulum membrane; Multi-pass membrane protein. Golgi apparatus membrane; Multi-pass membrane protein. Cell surface
Note: Bound to NOTCH1 also at the cell surface. Colocalizes with CDH1/2 at sites of cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the proximity of the plasma membrane. Also present in azurophil granules of neutrophils.

GO - Cellular componenti

  1. apical plasma membrane Source: RefGenome
  2. axon Source: RefGenome
  3. cell cortex Source: RefGenome
  4. cell surface Source: RefGenome
  5. centrosome Source: UniProtKB
  6. ciliary rootlet Source: RefGenome
  7. cytoplasmic vesicle Source: Ensembl
  8. dendritic shaft Source: RefGenome
  9. endoplasmic reticulum Source: HGNC
  10. gamma-secretase complex Source: UniProtKB
  11. Golgi apparatus Source: UniProtKB
  12. growth cone Source: RefGenome
  13. integral component of membrane Source: UniProtKB
  14. integral component of plasma membrane Source: HGNC
  15. kinetochore Source: UniProtKB
  16. lysosomal membrane Source: RefGenome
  17. membrane Source: MGI
  18. membrane raft Source: UniProt
  19. mitochondrial inner membrane Source: RefGenome
  20. mitochondrion Source: UniProtKB
  21. neuromuscular junction Source: RefGenome
  22. neuronal cell body Source: RefGenome
  23. nuclear membrane Source: UniProtKB
  24. nuclear outer membrane Source: MGI
  25. perinuclear region of cytoplasm Source: RefGenome
  26. rough endoplasmic reticulum Source: UniProtKB
  27. smooth endoplasmic reticulum Source: UniProtKB
  28. Z disc Source: RefGenome
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Golgi apparatus, Membrane

Pathology & Biotechi

Involvement in diseasei

Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.33 Publications
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti79 – 791A → V in AD3; no effect on interaction with GFAP. 2 Publications
VAR_006413
Natural varianti82 – 821V → L in AD3; no effect on interaction with GFAP. 2 Publications
VAR_006414
Natural varianti92 – 921C → S in AD3. 1 Publication
VAR_016214
Natural varianti96 – 961V → F in AD3. 1 Publication
VAR_006415
Natural varianti105 – 1051F → L in AD3. 1 Publication
VAR_009208
Natural varianti115 – 1151Y → C in AD3. 1 Publication
VAR_006416
Natural varianti115 – 1151Y → H in AD3. 2 Publications
VAR_006417
Natural varianti116 – 1161T → N in AD3. 1 Publication
VAR_010120
Natural varianti117 – 1171P → L in AD3. 1 Publication
VAR_009209
Natural varianti120 – 1201E → D in AD3. 2 Publications
VAR_006418
Natural varianti120 – 1201E → K in AD3.
VAR_006419
Natural varianti134 – 1341L → R in AD3; uncertain pathological significance. 1 Publication
VAR_070023
Natural varianti135 – 1351N → D in AD3. 1 Publication
VAR_010121
Natural varianti139 – 1391M → I in AD3.
VAR_006420
Natural varianti139 – 1391M → K in AD3. 1 Publication
VAR_010122
Natural varianti139 – 1391M → T in AD3. 2 Publications
VAR_006421
Natural varianti139 – 1391M → V in AD3. 2 Publications
VAR_006422
Natural varianti143 – 1431I → F in AD3. 1 Publication
VAR_006423
Natural varianti143 – 1431I → T in AD3. 1 Publication
VAR_006424
Natural varianti146 – 1461M → I in AD3.
VAR_006425
Natural varianti146 – 1461M → L in AD3. 2 Publications
VAR_006426
Natural varianti146 – 1461M → V in AD3. 1 Publication
VAR_006427
Natural varianti147 – 1471T → I in AD3. 1 Publication
VAR_010123
Natural varianti163 – 1631H → R in AD3. 6 Publications
VAR_006428
Natural varianti163 – 1631H → Y in AD3. 1 Publication
VAR_006429
Natural varianti165 – 1651W → C in AD3. 1 Publication
VAR_010124
Natural varianti166 – 1661L → P in AD3; onset in adolescence. 1 Publication
VAR_016216
Natural varianti169 – 1691S → L in AD3. 1 Publication
VAR_006430
Natural varianti169 – 1691S → P in AD3. 1 Publication
VAR_006431
Natural varianti171 – 1711L → P in AD3. 1 Publication
VAR_006432
Natural varianti173 – 1731L → W in AD3. 1 Publication
VAR_010125
Natural varianti174 – 1741L → M in AD3. 1 Publication
VAR_016217
Natural varianti206 – 2061G → A in AD3. 1 Publication
VAR_016218
Natural varianti209 – 2091G → R in AD3. 1 Publication
VAR_009210
Natural varianti209 – 2091G → V in AD3. 1 Publication
VAR_006433
Natural varianti213 – 2131I → T in AD3. 1 Publication
VAR_006434
Natural varianti219 – 2191L → P in AD3. 1 Publication
VAR_010126
Natural varianti231 – 2311A → T in AD3. 2 Publications
VAR_006435
Natural varianti231 – 2311A → V in AD3. 1 Publication
VAR_006436
Natural varianti233 – 2331M → L in AD3. 1 Publication
VAR_009211
Natural varianti233 – 2331M → T in AD3. 2 Publications
VAR_006437
Natural varianti246 – 2461A → E in AD3. 1 Publication
VAR_006439
Natural varianti250 – 2501L → S in AD3.
VAR_006440
Natural varianti260 – 2601A → V in AD3. 2 Publications
VAR_006441
Natural varianti262 – 2621L → F in AD3.
VAR_006442
Natural varianti262 – 2621L → V in AD3. 1 Publication
VAR_070025
Natural varianti263 – 2631C → R in AD3.
VAR_006443
Natural varianti264 – 2641P → L in AD3. 3 Publications
VAR_006444
Natural varianti266 – 2661G → S in AD3. 1 Publication
VAR_016219
Natural varianti267 – 2671P → S in AD3.
VAR_006445
Natural varianti267 – 2671P → T in AD3. 1 Publication
VAR_006446
Natural varianti269 – 2691R → G in AD3.
VAR_006447
Natural varianti269 – 2691R → H in AD3.
VAR_006448
Natural varianti271 – 2711L → V in AD3. 1 Publication
VAR_016220
Natural varianti278 – 2781R → T in AD3. 1 Publication
VAR_006449
Natural varianti280 – 2801E → A in AD3. 2 Publications
VAR_006450
Natural varianti280 – 2801E → G in AD3. 1 Publication
VAR_006451
Natural varianti282 – 2821L → R in AD3. 1 Publication
VAR_009212
Natural varianti285 – 2851A → V in AD3. 1 Publication
VAR_006452
Natural varianti286 – 2861L → V in AD3. 1 Publication
VAR_006453
Natural varianti289 – 2891S → C in AD3.
VAR_010127
Natural varianti378 – 3781G → E in AD3. 1 Publication
VAR_006455
Natural varianti384 – 3841G → A in AD3. 1 Publication
VAR_006456
Natural varianti390 – 3901S → I in AD3. 1 Publication
VAR_010128
Natural varianti392 – 3921L → V in AD3. 3 Publications
VAR_006457
Natural varianti396 – 3961A → T in AD3; uncertain pathological significance.
VAR_070026
Natural varianti405 – 4051N → S in AD3. 1 Publication
VAR_010129
Natural varianti409 – 4091A → T in AD3. 1 Publication
VAR_009213
Natural varianti410 – 4101C → Y in AD3. 3 Publications
Corresponds to variant rs661 [ dbSNP | Ensembl ].
VAR_006458
Natural varianti426 – 4261A → P in AD3. 1 Publication
VAR_006459
Natural varianti431 – 4311A → E in AD3. 1 Publication
VAR_025605
Natural varianti436 – 4361P → Q in AD3. 1 Publication
Corresponds to variant rs28930977 [ dbSNP | Ensembl ].
VAR_006460
Natural varianti436 – 4361P → S in AD3. 1 Publication
VAR_008141
Frontotemporal dementia (FTD) [MIM:600274]: A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Cardiomyopathy, dilated 1U (CMD1U) [MIM:613694]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti333 – 3331D → G in CMD1U. 1 Publication
VAR_064902
Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi66 – 727Missing: No effect on interaction with GFAP. 1 Publication
Mutagenesisi76 – 772KY → AA: No effect on interaction with GFAP. 1 Publication
Mutagenesisi82 – 832VI → EE: Loss of interaction with GFAP. 1 Publication
Mutagenesisi82 – 821V → K or E: Loss of interaction with GFAP. 1 Publication
Mutagenesisi84 – 852ML → EE: Loss of interaction with GFAP. 1 Publication
Mutagenesisi256 – 2561Y → F: Alters gamma-secretase cleavage specificity. Increased production of amyloid beta(42). No effect on enzymatic activity. 1 Publication
Mutagenesisi257 – 2571D → A: Loss of endoproteolytic cleavage; reduces production of amyloid beta in APP processing and of NICD in NOTCH1 processing. 3 Publications
Mutagenesisi257 – 2571D → E: Abolishes gamma-secretase activity. Reduces production of amyloid beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor. 3 Publications
Mutagenesisi286 – 2861L → A, E, P, Q, R or W: Increases production of amyloid beta in APP processing. 1 Publication
Mutagenesisi286 – 2861L → E or R: Reduces production of NICD in NOTCH1 processing. 1 Publication
Mutagenesisi292 – 2921M → D: Loss of endoproteolytic cleavage. 1 Publication
Mutagenesisi310 – 3101S → A: Abolishes PKA-mediated phosphorylation; no effect on caspase-mediated cleavage. 1 Publication
Mutagenesisi345 – 3451D → N: Abolishes caspase cleavage. 1 Publication
Mutagenesisi346 – 3461S → A: Abolishes PKC-mediated phosphorylation; no effect on PKA-mediated phosphorylation. 1 Publication
Mutagenesisi346 – 3461S → E: Inhibits caspase-mediated cleavage. Modulates progression of apoptosis. 1 Publication
Mutagenesisi373 – 3731D → N: No effect on caspase cleavage. 1 Publication
Mutagenesisi385 – 3851D → A: Loss of endoproteolytic cleavage. Reduces production of amyloid beta in APP processing. Disassembly of the N-cadherin/PS1 complex at the cell surface. Impairs CDH2 processing. 5 Publications
Mutagenesisi385 – 3851D → E: Abolishes gamma-secretase activity. Reduces production of amyloid beta in APP processing. Accumulation of full-length PS1. Loss of binding of transition state analog gamma-secretase inhibitor. 5 Publications
Mutagenesisi385 – 3851D → N: No effect on caspase cleavage. 5 Publications
Mutagenesisi389 – 3891Y → F: Alters gamma-secretase cleavage specificity. Increased production of amyloid beta(42). No effect on enzymatic activity. 1 Publication
Mutagenesisi433 – 4331P → A: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Slightly increased Abeta42/Abeta40 ratio. 1 Publication
Mutagenesisi433 – 4331P → D, F, L, N or V: No endoproteolytic cleavage; no APP nor NOTCH1 processing. No detectable Abetano detectable Abeta. 1 Publication
Mutagenesisi433 – 4331P → G: Very little endoproteolysis. Little APP processing. No NOTCH1 processing. Very low levels Abeta40 and no detectable Abeta42. 1 Publication
Mutagenesisi434 – 4341A → C: Some loss of endoproteolytic cleavage. Some loss of APP and NOTCH1 processing. Six-fold increase in Abeta42/Abeta40 ratio. 1 Publication
Mutagenesisi434 – 4341A → D, I, L or V: No endoproteolytic cleavage. No APP nor NOTCH1 processing. No detectable Abeta. 1 Publication
Mutagenesisi434 – 4341A → G: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Reduced Abeta42/Abeta40 ratio. 1 Publication
Mutagenesisi435 – 4351L → A: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Greatly reduced Abeta42/Abeta40 ratio. 1 Publication
Mutagenesisi435 – 4351L → F: No endoproteolytic cleavage. No APP nor NOTCH1 processing. No detectable Abeta. 1 Publication
Mutagenesisi435 – 4351L → G: Greatly reduced endoproteolytic cleavage. Very little APP and NOTCH1 processing. Very low levels of Abeta40 and no detectable Abeta42. 1 Publication
Mutagenesisi435 – 4351L → I: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. 1 Publication
Mutagenesisi435 – 4351L → V: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Some increase in Abeta42/Abeta40 ratio. 1 Publication

Keywords - Diseasei

Alzheimer disease, Amyloidosis, Cardiomyopathy, Disease mutation, Neurodegeneration

Organism-specific databases

MIMi600274. phenotype.
607822. phenotype.
613694. phenotype.
613737. phenotype.
Orphaneti275864. Behavioral variant of frontotemporal dementia.
1020. Early-onset autosomal dominant Alzheimer disease.
154. Familial isolated dilated cardiomyopathy.
387. Hidradenitis suppurativa.
100070. Progressive non-fluent aphasia.
100069. Semantic dementia.
PharmGKBiPA33855.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 298298Presenilin-1 NTF subunitPRO_0000025591Add
BLAST
Chaini299 – 467169Presenilin-1 CTF subunitPRO_0000025592Add
BLAST
Chaini346 – 467122Presenilin-1 CTF12PRO_0000236055Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei43 – 431Phosphoserine2 Publications
Modified residuei310 – 3101Phosphoserine; by PKA1 Publication
Modified residuei346 – 3461Phosphoserine; by PKC1 Publication
Modified residuei367 – 3671Phosphoserine1 Publication

Post-translational modificationi

Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12.1 Publication
After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.4 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP49768.
PaxDbiP49768.
PRIDEiP49768.

PTM databases

PhosphoSiteiP49768.

Miscellaneous databases

PMAP-CutDBP49768.

Expressioni

Tissue specificityi

Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes.2 Publications

Gene expression databases

BgeeiP49768.
CleanExiHS_PSEN1.
ExpressionAtlasiP49768. baseline and differential.
GenevestigatoriP49768.

Organism-specific databases

HPAiCAB006844.
HPA030760.

Interactioni

Subunit structurei

Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity. Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment. Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP). Associates with NOTCH1. Associates with cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2. Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation. Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane. Interacts with CTNND2, CTNNB1, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with isoform 3 of GFAP. Interacts with DOCK3 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
APBA1Q024104EBI-297277,EBI-368690
Apba2P980842EBI-297277,EBI-81669From a different organism.
APPP050676EBI-297277,EBI-77613
APPP05067-43EBI-297277,EBI-302641
ArcQ630533EBI-2606326,EBI-5275794From a different organism.
CDC37Q165433EBI-297277,EBI-295634
CTNNB1P352222EBI-297277,EBI-491549
ECSITQ9BQ954EBI-297277,EBI-712452
JUPP149234EBI-297277,EBI-702484
NCSTNQ925423EBI-297277,EBI-998440
ST13P505023EBI-297277,EBI-357285
TMED10P497553EBI-297277,EBI-998422

Protein-protein interaction databases

BioGridi111642. 78 interactions.
DIPiDIP-1134N.
IntActiP49768. 41 interactions.
MINTiMINT-88325.
STRINGi9606.ENSP00000326366.

Structurei

Secondary structure

1
467
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi293 – 2997Combined sources
Beta strandi341 – 3455Combined sources
Helixi356 – 36813Combined sources
Turni383 – 3853Combined sources
Helixi386 – 39914Combined sources
Turni403 – 4064Combined sources
Helixi407 – 42822Combined sources
Beta strandi433 – 4375Combined sources
Helixi442 – 4498Combined sources
Turni450 – 4534Combined sources
Helixi456 – 4583Combined sources

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2KR6NMR-A292-467[»]
ProteinModelPortaliP49768.
SMRiP49768. Positions 292-467.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP49768.

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 8282CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini104 – 13229LumenalSequence AnalysisAdd
BLAST
Topological domaini154 – 1607CytoplasmicSequence Analysis
Topological domaini182 – 1909LumenalSequence Analysis
Topological domaini212 – 2209CytoplasmicSequence Analysis
Topological domaini242 – 2432LumenalSequence Analysis
Topological domaini265 – 380116CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini402 – 4076LumenalSequence Analysis
Topological domaini429 – 4324CytoplasmicSequence Analysis
Topological domaini454 – 46714CytoplasmicSequence AnalysisAdd
BLAST

Intramembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Intramembranei433 – 45321HelicalSequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei83 – 10321HelicalSequence AnalysisAdd
BLAST
Transmembranei133 – 15321HelicalSequence AnalysisAdd
BLAST
Transmembranei161 – 18121HelicalSequence AnalysisAdd
BLAST
Transmembranei191 – 21121HelicalSequence AnalysisAdd
BLAST
Transmembranei221 – 24121HelicalSequence AnalysisAdd
BLAST
Transmembranei244 – 26421HelicalSequence AnalysisAdd
BLAST
Transmembranei381 – 40121HelicalSequence AnalysisAdd
BLAST
Transmembranei408 – 42821HelicalSequence AnalysisAdd
BLAST

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni322 – 450129Required for interaction with CTNNB1Add
BLAST
Regioni372 – 39928Required for interaction with CTNND2Add
BLAST
Regioni464 – 4674Interaction with MTCH1

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi433 – 4353PAL

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi94 – 974Poly-Val
Compositional biasi171 – 1744Poly-Leu
Compositional biasi418 – 4258Poly-Leu

Domaini

The PAL motif is required for normal active site conformation.

Sequence similaritiesi

Belongs to the peptidase A22A family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG237920.
GeneTreeiENSGT00390000016593.
HOVERGENiHBG011375.
InParanoidiP49768.
KOiK04505.
OMAiEARDHEI.
PhylomeDBiP49768.
TreeFamiTF315040.

Family and domain databases

InterProiIPR002031. Pept_A22A_PS1.
IPR001108. Peptidase_A22A.
IPR006639. Preselin/SPP.
[Graphical view]
PANTHERiPTHR10202. PTHR10202. 1 hit.
PTHR10202:SF7. PTHR10202:SF7. 1 hit.
PfamiPF01080. Presenilin. 1 hit.
[Graphical view]
PRINTSiPR01072. PRESENILIN.
PR01073. PRESENILIN1.
SMARTiSM00730. PSN. 1 hit.
[Graphical view]

Sequences (7)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 7 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: P49768-1) [UniParc]FASTAAdd to Basket

Also known as: I-467

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL
60 70 80 90 100
SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI
110 120 130 140 150
KSVSFYTRKD GQLIYTPFTE DTETVGQRAL HSILNAAIMI SVIVVMTILL
160 170 180 190 200
VVLYKYRCYK VIHAWLIISS LLLLFFFSFI YLGEVFKTYN VAVDYITVAL
210 220 230 240 250
LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY LPEWTAWLIL
260 270 280 290 300
AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE
310 320 330 340 350
GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP
360 370 380 390 400
HRSTPESRAA VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA
410 420 430 440 450
SGDWNTTIAC FVAILIGLCL TLLLLAIFKK ALPALPISIT FGLVFYFATD
460
YLVQPFMDQL AFHQFYI
Length:467
Mass (Da):52,668
Last modified:October 1, 1996 - v1
Checksum:i5E0F451EF82BCF20
GO
Isoform 2 (identifier: P49768-2) [UniParc]FASTAAdd to Basket

Also known as: I-463

The sequence of this isoform differs from the canonical sequence as follows:
     26-29: Missing.

Show »
Length:463
Mass (Da):52,197
Checksum:i955325791A81470F
GO
Isoform 3 (identifier: P49768-3) [UniParc]FASTAAdd to Basket

Also known as: I-374

The sequence of this isoform differs from the canonical sequence as follows:
     26-29: Missing.
     319-467: STERESQDTV...DQLAFHQFYI → RACLPPAAIN...RNGKPRGTVI

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Show »
Length:374
Mass (Da):42,287
Checksum:i5172C076410745BF
GO
Isoform 4 (identifier: P49768-4) [UniParc]FASTAAdd to Basket

Also known as: Minilin

The sequence of this isoform differs from the canonical sequence as follows:
     162-184: IHAWLIISSLLLLFFFSFIYLGE → SMRHRSLLSTLFFLWLGILVTVT
     185-467: Missing.

Show »
Length:184
Mass (Da):21,073
Checksum:i95C68A7EA0020874
GO
Isoform 5 (identifier: P49768-5) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     319-467: STERESQDTV...DQLAFHQFYI → RACLPPAAIN...RNGKPRGTVI

Show »
Length:378
Mass (Da):42,757
Checksum:iA09D682EC6F568FD
GO
Isoform 6 (identifier: P49768-6) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     319-376: Missing.

Show »
Length:409
Mass (Da):46,328
Checksum:i4855BDDCCD1D7D71
GO
Isoform 7 (identifier: P49768-7) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     257-289: Missing.

Show »
Length:434
Mass (Da):48,997
Checksum:iC3930DB665C32929
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti128 – 1281R → G in AAL16811. (PubMed:12508121)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti79 – 791A → V in AD3; no effect on interaction with GFAP. 2 Publications
VAR_006413
Natural varianti82 – 821V → L in AD3; no effect on interaction with GFAP. 2 Publications
VAR_006414
Natural varianti92 – 921C → S in AD3. 1 Publication
VAR_016214
Natural varianti96 – 961V → F in AD3. 1 Publication
VAR_006415
Natural varianti105 – 1051F → L in AD3. 1 Publication
VAR_009208
Natural varianti113 – 1131L → P in frontotemporal dementia. 1 Publication
VAR_016215
Natural varianti115 – 1151Y → C in AD3. 1 Publication
VAR_006416
Natural varianti115 – 1151Y → H in AD3. 2 Publications
VAR_006417
Natural varianti116 – 1161T → N in AD3. 1 Publication
VAR_010120
Natural varianti117 – 1171P → L in AD3. 1 Publication
VAR_009209
Natural varianti120 – 1201E → D in AD3. 2 Publications
VAR_006418
Natural varianti120 – 1201E → K in AD3.
VAR_006419
Natural varianti134 – 1341L → R in AD3; uncertain pathological significance. 1 Publication
VAR_070023
Natural varianti135 – 1351N → D in AD3. 1 Publication
VAR_010121
Natural varianti139 – 1391M → I in AD3.
VAR_006420
Natural varianti139 – 1391M → K in AD3. 1 Publication
VAR_010122
Natural varianti139 – 1391M → T in AD3. 2 Publications
VAR_006421
Natural varianti139 – 1391M → V in AD3. 2 Publications
VAR_006422
Natural varianti143 – 1431I → F in AD3. 1 Publication
VAR_006423
Natural varianti143 – 1431I → T in AD3. 1 Publication
VAR_006424
Natural varianti146 – 1461M → I in AD3.
VAR_006425
Natural varianti146 – 1461M → L in AD3. 2 Publications
VAR_006426
Natural varianti146 – 1461M → V in AD3. 1 Publication
VAR_006427
Natural varianti147 – 1471T → I in AD3. 1 Publication
VAR_010123
Natural varianti163 – 1631H → R in AD3. 6 Publications
VAR_006428
Natural varianti163 – 1631H → Y in AD3. 1 Publication
VAR_006429
Natural varianti165 – 1651W → C in AD3. 1 Publication
VAR_010124
Natural varianti166 – 1661L → P in AD3; onset in adolescence. 1 Publication
VAR_016216
Natural varianti169 – 1691S → L in AD3. 1 Publication
VAR_006430
Natural varianti169 – 1691S → P in AD3. 1 Publication
VAR_006431
Natural varianti171 – 1711L → P in AD3. 1 Publication
VAR_006432
Natural varianti173 – 1731L → W in AD3. 1 Publication
VAR_010125
Natural varianti174 – 1741L → M in AD3. 1 Publication
VAR_016217
Natural varianti205 – 2051F → L.
Corresponds to variant rs1042864 [ dbSNP | Ensembl ].
VAR_011876
Natural varianti206 – 2061G → A in AD3. 1 Publication
VAR_016218
Natural varianti209 – 2091G → R in AD3. 1 Publication
VAR_009210
Natural varianti209 – 2091G → V in AD3. 1 Publication
VAR_006433
Natural varianti213 – 2131I → T in AD3. 1 Publication
VAR_006434
Natural varianti214 – 2141H → Y Probable disease-associated mutation found in a patient with dementia. 1 Publication
VAR_070024
Natural varianti219 – 2191L → P in AD3. 1 Publication
VAR_010126
Natural varianti231 – 2311A → T in AD3. 2 Publications
VAR_006435
Natural varianti231 – 2311A → V in AD3. 1 Publication
VAR_006436
Natural varianti233 – 2331M → L in AD3. 1 Publication
VAR_009211
Natural varianti233 – 2331M → T in AD3. 2 Publications
VAR_006437
Natural varianti235 – 2351L → P in A3D. 1 Publication
VAR_006438
Natural varianti246 – 2461A → E in AD3. 1 Publication
VAR_006439
Natural varianti250 – 2501L → S in AD3.
VAR_006440
Natural varianti260 – 2601A → V in AD3. 2 Publications
VAR_006441
Natural varianti262 – 2621L → F in AD3.
VAR_006442
Natural varianti262 – 2621L → V in AD3. 1 Publication
VAR_070025
Natural varianti263 – 2631C → R in AD3.
VAR_006443
Natural varianti264 – 2641P → L in AD3. 3 Publications
VAR_006444
Natural varianti266 – 2661G → S in AD3. 1 Publication
VAR_016219
Natural varianti267 – 2671P → S in AD3.
VAR_006445
Natural varianti267 – 2671P → T in AD3. 1 Publication
VAR_006446
Natural varianti269 – 2691R → G in AD3.
VAR_006447
Natural varianti269 – 2691R → H in AD3.
VAR_006448
Natural varianti271 – 2711L → V in AD3. 1 Publication
VAR_016220
Natural varianti278 – 2781R → T in AD3. 1 Publication