Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Basket 0
(max 400 entries)x

Your basket is currently empty.

Select item(s) and click on "Add to basket" to create your own collection here
(400 entries max)

P49768

- PSN1_HUMAN

UniProt

P49768 - PSN1_HUMAN

Protein

Presenilin-1

Gene

PSEN1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
    • BLAST
    • Align
    • Format
    • Add to basket
    • History
      Entry version 177 (01 Oct 2014)
      Sequence version 1 (01 Oct 1996)
      Previous versions | rss
    • Help video
    • Feedback
    • Comment

    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
    7. protein binding Source: IntAct

    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

    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. endoplasmic reticulum membrane Source: UniProtKB-SubCell
    11. gamma-secretase complex Source: UniProtKB
    12. Golgi apparatus Source: UniProtKB
    13. Golgi membrane Source: UniProtKB-SubCell
    14. growth cone Source: RefGenome
    15. integral component of membrane Source: UniProtKB
    16. integral component of plasma membrane Source: HGNC
    17. kinetochore Source: UniProtKB
    18. lysosomal membrane Source: RefGenome
    19. membrane Source: MGI
    20. membrane raft Source: UniProt
    21. mitochondrial inner membrane Source: RefGenome
    22. mitochondrion Source: UniProtKB
    23. neuromuscular junction Source: RefGenome
    24. neuronal cell body Source: RefGenome
    25. nuclear membrane Source: UniProtKB
    26. nuclear outer membrane Source: MGI
    27. perinuclear region of cytoplasm Source: RefGenome
    28. rough endoplasmic reticulum Source: UniProtKB
    29. smooth endoplasmic reticulum Source: UniProtKB
    30. Z disc Source: RefGenome

    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.
    Mutagenesisi76 – 772KY → AA: No effect on interaction with GFAP.
    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.
    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 – 431Phosphoserine3 Publications
    Modified residuei310 – 3101Phosphoserine; by PKA2 Publications
    Modified residuei346 – 3461Phosphoserine; by PKC2 Publications
    Modified residuei367 – 3671Phosphoserine2 Publications

    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

    ArrayExpressiP49768.
    BgeeiP49768.
    CleanExiHS_PSEN1.
    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. 77 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 – 2997
    Beta strandi341 – 3455
    Helixi356 – 36813
    Turni383 – 3853
    Helixi386 – 39914
    Turni403 – 4064
    Helixi407 – 42822
    Beta strandi433 – 4375
    Helixi442 – 4498
    Turni450 – 4534
    Helixi456 – 4583

    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.
    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

    MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL    50
    SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI 100
    KSVSFYTRKD GQLIYTPFTE DTETVGQRAL HSILNAAIMI SVIVVMTILL 150
    VVLYKYRCYK VIHAWLIISS LLLLFFFSFI YLGEVFKTYN VAVDYITVAL 200
    LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY LPEWTAWLIL 250
    AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE 300
    GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP 350
    HRSTPESRAA VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA 400
    SGDWNTTIAC FVAILIGLCL TLLLLAIFKK ALPALPISIT FGLVFYFATD 450
    YLVQPFMDQL AFHQFYI 467
    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
    VAR_006449
    Natural varianti280 – 2801E → A in AD3. 2 Publications