Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Presenilin-1

Gene

PSEN1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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)DescriptionActionsGraphical viewLength
Active sitei2571 Publication1
Active sitei3851 Publication1

GO - Molecular functioni

  • aspartic-type endopeptidase activity Source: InterPro
  • beta-catenin binding Source: UniProtKB
  • cadherin binding Source: GO_Central
  • calcium channel activity Source: UniProtKB
  • endopeptidase activity Source: MGI
  • PDZ domain binding Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease

Keywords - Biological processi

Apoptosis, Cell adhesion, Notch signaling pathway

Enzyme and pathway databases

BioCyciZFISH:ENSG00000080815-MONOMER.
ReactomeiR-HSA-1474228. Degradation of the extracellular matrix.
R-HSA-6798695. Neutrophil degranulation.
SignaLinkiP49768.
SIGNORiP49768.

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
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:9508. PSEN1.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 82CytoplasmicSequence analysisAdd BLAST82
Transmembranei83 – 103HelicalSequence analysisAdd BLAST21
Topological domaini104 – 132LumenalSequence analysisAdd BLAST29
Transmembranei133 – 153HelicalSequence analysisAdd BLAST21
Topological domaini154 – 160CytoplasmicSequence analysis7
Transmembranei161 – 181HelicalSequence analysisAdd BLAST21
Topological domaini182 – 190LumenalSequence analysis9
Transmembranei191 – 211HelicalSequence analysisAdd BLAST21
Topological domaini212 – 220CytoplasmicSequence analysis9
Transmembranei221 – 241HelicalSequence analysisAdd BLAST21
Topological domaini242 – 243LumenalSequence analysis2
Transmembranei244 – 264HelicalSequence analysisAdd BLAST21
Topological domaini265 – 380CytoplasmicSequence analysisAdd BLAST116
Transmembranei381 – 401HelicalSequence analysisAdd BLAST21
Topological domaini402 – 407LumenalSequence analysis6
Transmembranei408 – 428HelicalSequence analysisAdd BLAST21
Topological domaini429 – 432CytoplasmicSequence analysis4
Intramembranei433 – 453HelicalSequence analysisAdd BLAST21
Topological domaini454 – 467CytoplasmicSequence analysisAdd BLAST14

GO - Cellular componenti

  • aggresome Source: UniProtKB
  • axon Source: Ensembl
  • cell junction Source: HPA
  • cell surface Source: UniProtKB-SubCell
  • centrosome Source: UniProtKB
  • ciliary rootlet Source: Ensembl
  • cytoplasmic vesicle Source: Ensembl
  • dendritic shaft Source: Ensembl
  • endoplasmic reticulum Source: HGNC
  • endoplasmic reticulum membrane Source: UniProtKB-SubCell
  • gamma-secretase complex Source: UniProtKB
  • Golgi apparatus Source: UniProtKB
  • Golgi membrane Source: UniProtKB-SubCell
  • growth cone Source: Ensembl
  • integral component of membrane Source: UniProtKB
  • integral component of plasma membrane Source: HGNC
  • kinetochore Source: UniProtKB
  • lysosomal membrane Source: Ensembl
  • membrane Source: MGI
  • membrane raft Source: UniProtKB
  • mitochondrial inner membrane Source: Ensembl
  • mitochondrion Source: UniProtKB
  • neuromuscular junction Source: Ensembl
  • neuronal cell body Source: Ensembl
  • nuclear membrane Source: UniProtKB
  • nuclear outer membrane Source: MGI
  • nucleus Source: HPA
  • plasma membrane Source: UniProtKB
  • presynapse Source: GOC
  • rough endoplasmic reticulum Source: UniProtKB
  • smooth endoplasmic reticulum Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Golgi apparatus, Membrane

Pathology & Biotechi

Involvement in diseasei

Alzheimer disease 3 (AD3)37 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:607822
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07526035R → Q in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750592dbSNPEnsembl.1
Natural variantiVAR_00641379A → V in AD3; unknown pathological significance; no effect on interaction with GFAP. 4 PublicationsCorresponds to variant rs63749824dbSNPEnsembl.1
Natural variantiVAR_00641482V → L in AD3; no effect on interaction with GFAP. 3 PublicationsCorresponds to variant rs63749967dbSNPEnsembl.1
Natural variantiVAR_07526183I → T in AD3. 1 Publication1
Natural variantiVAR_01621492C → S in AD3. 1 PublicationCorresponds to variant rs63751141dbSNPEnsembl.1
Natural variantiVAR_00641596V → F in AD3. 1 PublicationCorresponds to variant rs63750601dbSNPEnsembl.1
Natural variantiVAR_009208105F → L in AD3. 1 PublicationCorresponds to variant rs63750321dbSNPEnsembl.1
Natural variantiVAR_006416115Y → C in AD3. 2 PublicationsCorresponds to variant rs63750450dbSNPEnsembl.1
Natural variantiVAR_006417115Y → H in AD3. 2 Publications1
Natural variantiVAR_010120116T → N in AD3. 2 Publications1
Natural variantiVAR_009209117P → L in AD3. 1 PublicationCorresponds to variant rs63749805dbSNPEnsembl.1
Natural variantiVAR_006418120E → D in AD3. 2 PublicationsCorresponds to variant rs63751272dbSNPEnsembl.1
Natural variantiVAR_006419120E → K in AD3. Corresponds to variant rs63750800dbSNPEnsembl.1
Natural variantiVAR_070023134L → R in AD3; uncertain pathological significance. 1 Publication1
Natural variantiVAR_010121135N → D in AD3. 1 PublicationCorresponds to variant rs63750353dbSNPEnsembl.1
Natural variantiVAR_006420139M → I in AD3. Corresponds to variant rs63750522dbSNPEnsembl.1
Natural variantiVAR_010122139M → K in AD3. 1 Publication1
Natural variantiVAR_006421139M → T in AD3. 2 PublicationsCorresponds to variant rs63751106dbSNPEnsembl.1
Natural variantiVAR_006422139M → V in AD3. 2 PublicationsCorresponds to variant rs63751037dbSNPEnsembl.1
Natural variantiVAR_006423143I → F in AD3. 1 PublicationCorresponds to variant rs63750322dbSNPEnsembl.1
Natural variantiVAR_006424143I → T in AD3. 2 PublicationsCorresponds to variant rs63750004dbSNPEnsembl.1
Natural variantiVAR_006425146M → I in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750391dbSNPEnsembl.1
Natural variantiVAR_006426146M → L in AD3. 3 PublicationsCorresponds to variant rs63750306dbSNPEnsembl.1
Natural variantiVAR_006427146M → V in AD3. 2 PublicationsCorresponds to variant rs63750306dbSNPEnsembl.1
Natural variantiVAR_010123147T → I in AD3. 1 PublicationCorresponds to variant rs63750907dbSNPEnsembl.1
Natural variantiVAR_075262156Y → FTY in AD3; unknown pathological significance. 1 Publication1
Natural variantiVAR_006428163H → R in AD3. 7 PublicationsCorresponds to variant rs63750590dbSNPEnsembl.1
Natural variantiVAR_006429163H → Y in AD3. 1 PublicationCorresponds to variant rs63749885dbSNPEnsembl.1
Natural variantiVAR_010124165W → C in AD3. 1 PublicationCorresponds to variant rs63751484dbSNPEnsembl.1
Natural variantiVAR_016216166L → P in AD3; onset in adolescence. 1 PublicationCorresponds to variant rs63750265dbSNPEnsembl.1
Natural variantiVAR_006430169S → L in AD3. 1 PublicationCorresponds to variant rs63751210dbSNPEnsembl.1
Natural variantiVAR_006431169S → P in AD3. 1 PublicationCorresponds to variant rs63750418dbSNPEnsembl.1
Natural variantiVAR_006432171L → P in AD3. 1 PublicationCorresponds to variant rs63750963dbSNPEnsembl.1
Natural variantiVAR_010125173L → W in AD3. 1 PublicationCorresponds to variant rs63750299dbSNPEnsembl.1
Natural variantiVAR_016217174L → M in AD3. 1 PublicationCorresponds to variant rs63751144dbSNPEnsembl.1
Natural variantiVAR_075263177F → L in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63749911dbSNPEnsembl.1
Natural variantiVAR_075264177F → S in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63749806dbSNPEnsembl.1
Natural variantiVAR_075265178S → P in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750155dbSNPEnsembl.1
Natural variantiVAR_016218206G → A in AD3. 2 PublicationsCorresponds to variant rs63750082dbSNPEnsembl.1
Natural variantiVAR_075266206G → S in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750569dbSNPEnsembl.1
Natural variantiVAR_075267209G → E in AD3; unknown pathological significance. 1 Publication1
Natural variantiVAR_009210209G → R in AD3. 1 PublicationCorresponds to variant rs63749880dbSNPEnsembl.1
Natural variantiVAR_006433209G → V in AD3. 1 PublicationCorresponds to variant rs63750053dbSNPEnsembl.1
Natural variantiVAR_075268213I → L in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750861dbSNPEnsembl.1
Natural variantiVAR_006434213I → T in AD3. 1 PublicationCorresponds to variant rs63751309dbSNPEnsembl.1
Natural variantiVAR_010126219L → P in AD3. 1 PublicationCorresponds to variant rs63750761dbSNPEnsembl.1
Natural variantiVAR_075269222Q → R in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750009dbSNPEnsembl.1
Natural variantiVAR_006435231A → T in AD3. 3 PublicationsCorresponds to variant rs63749836dbSNPEnsembl.1
Natural variantiVAR_006436231A → V in AD3. 1 PublicationCorresponds to variant rs63750799dbSNPEnsembl.1
Natural variantiVAR_009211233M → L in AD3. 2 PublicationsCorresponds to variant rs63751287dbSNPEnsembl.1
Natural variantiVAR_006437233M → T in AD3. 2 PublicationsCorresponds to variant rs63751024dbSNPEnsembl.1
Natural variantiVAR_006438235L → P in AD3. 2 PublicationsCorresponds to variant rs63749835dbSNPEnsembl.1
Natural variantiVAR_006439246A → E in AD3. 1 PublicationCorresponds to variant rs63750526dbSNPEnsembl.1
Natural variantiVAR_006440250L → S in AD3. Corresponds to variant rs63751163dbSNPEnsembl.1
Natural variantiVAR_006441260A → V in AD3. 2 PublicationsCorresponds to variant rs63751420dbSNPEnsembl.1
Natural variantiVAR_075270261V → F in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750964dbSNPEnsembl.1
Natural variantiVAR_006442262L → F in AD3. Corresponds to variant rs63750248dbSNPEnsembl.1
Natural variantiVAR_070025262L → V in AD3. 1 Publication1
Natural variantiVAR_006443263C → R in AD3. Corresponds to variant rs63750543dbSNPEnsembl.1
Natural variantiVAR_006444264P → L in AD3. 3 PublicationsCorresponds to variant rs63750301dbSNPEnsembl.1
Natural variantiVAR_016219266G → S in AD3. 1 PublicationCorresponds to variant rs121917807dbSNPEnsembl.1
Natural variantiVAR_006445267P → S in AD3. Corresponds to variant rs63751229dbSNPEnsembl.1
Natural variantiVAR_006446267P → T in AD3. 1 Publication1
Natural variantiVAR_006447269R → G in AD3. Corresponds to variant rs63751019dbSNPEnsembl.1
Natural variantiVAR_006448269R → H in AD3. Corresponds to variant rs63750900dbSNPEnsembl.1
Natural variantiVAR_016220271L → V in AD3. 1 PublicationCorresponds to variant rs63750886dbSNPEnsembl.1
Natural variantiVAR_075271274T → R in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750284dbSNPEnsembl.1
Natural variantiVAR_006449278R → T in AD3. 1 PublicationCorresponds to variant rs63749891dbSNPEnsembl.1
Natural variantiVAR_006450280E → A in AD3. 2 PublicationsCorresponds to variant rs63750231dbSNPEnsembl.1
Natural variantiVAR_006451280E → G in AD3. 1 PublicationCorresponds to variant rs63750231dbSNPEnsembl.1
Natural variantiVAR_009212282L → R in AD3. 1 PublicationCorresponds to variant rs63750050dbSNPEnsembl.1
Natural variantiVAR_006452285A → V in AD3. 1 PublicationCorresponds to variant rs63751139dbSNPEnsembl.1
Natural variantiVAR_006453286L → V in AD3. 1 PublicationCorresponds to variant rs63751235dbSNPEnsembl.1
Natural variantiVAR_010127289S → C in AD3. 1
Natural variantiVAR_075272352R → RR in AD3; unknown pathological significance. 1 Publication1
Natural variantiVAR_075273354T → I in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63751164dbSNPEnsembl.1
Natural variantiVAR_075274358R → Q in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63751174dbSNPEnsembl.1
Natural variantiVAR_075275365S → Y in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750941dbSNPEnsembl.1
Natural variantiVAR_006455378G → E in AD3. 1 Publication1
Natural variantiVAR_006456384G → A in AD3. 1 PublicationCorresponds to variant rs63750646dbSNPEnsembl.1
Natural variantiVAR_010128390S → I in AD3. 1 PublicationCorresponds to variant rs63750883dbSNPEnsembl.1
Natural variantiVAR_006457392L → V in AD3. 3 PublicationsCorresponds to variant rs63751416dbSNPEnsembl.1
Natural variantiVAR_075276394G → V in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750929dbSNPEnsembl.1
Natural variantiVAR_070026396A → T in AD3; uncertain pathological significance. 1
Natural variantiVAR_010129405N → S in AD3. 1 PublicationCorresponds to variant rs63751254dbSNPEnsembl.1
Natural variantiVAR_075277408I → T in AD3. 1 Publication1
Natural variantiVAR_009213409A → T in AD3. 1 PublicationCorresponds to variant rs63750227dbSNPEnsembl.1
Natural variantiVAR_006458410C → Y in AD3. 3 PublicationsCorresponds to variant rs661dbSNPEnsembl.1
Natural variantiVAR_075278418L → F in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63751316dbSNPEnsembl.1
Natural variantiVAR_006459426A → P in AD3. 1 PublicationCorresponds to variant rs63751223dbSNPEnsembl.1
Natural variantiVAR_025605431A → E in AD3. 2 PublicationsCorresponds to variant rs63750083dbSNPEnsembl.1
Natural variantiVAR_075280435L → F in AD3; no endoproteolytic cleavage; no APP nor NOTCH1 processing; no detectable Abeta; almost abolishes gamma-secretase activity. 3 PublicationsCorresponds to variant rs63750001dbSNPEnsembl.1
Natural variantiVAR_006460436P → Q in AD3; partially abolishes gamma-secretase activity. 2 PublicationsCorresponds to variant rs28930977dbSNPEnsembl.1
Natural variantiVAR_008141436P → S in AD3; partially abolishes gamma-secretase activity. 2 PublicationsCorresponds to variant rs63749925dbSNPEnsembl.1
Natural variantiVAR_075282439I → V in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750249dbSNPEnsembl.1
Frontotemporal dementia (FTD)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:600274
Cardiomyopathy, dilated 1U (CMD1U)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
See also OMIM:613694
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_064902333D → G in CMD1U. 1 PublicationCorresponds to variant rs121917809dbSNPEnsembl.1
Acne inversa, familial, 3 (ACNINV3)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.
See also OMIM:613737

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi66 – 72Missing : No effect on interaction with GFAP. 1 Publication7
Mutagenesisi76 – 77KY → AA: No effect on interaction with GFAP. 1 Publication2
Mutagenesisi82 – 83VI → EE: Loss of interaction with GFAP. 1 Publication2
Mutagenesisi82V → K or E: Loss of interaction with GFAP. 1 Publication1
Mutagenesisi84 – 85ML → EE: Loss of interaction with GFAP. 1 Publication2
Mutagenesisi256Y → F: Alters gamma-secretase cleavage specificity. Increased production of amyloid beta(42). No effect on enzymatic activity. 1 Publication1
Mutagenesisi257D → A: Loss of endoproteolytic cleavage; reduces production of amyloid beta in APP processing and of NICD in NOTCH1 processing. 3 Publications1
Mutagenesisi257D → 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 Publications1
Mutagenesisi286L → A, E, P, Q, R or W: Increases production of amyloid beta in APP processing. 1 Publication1
Mutagenesisi286L → E or R: Reduces production of NICD in NOTCH1 processing. 1 Publication1
Mutagenesisi292M → D: Loss of endoproteolytic cleavage. 1 Publication1
Mutagenesisi310S → A: Abolishes PKA-mediated phosphorylation; no effect on caspase-mediated cleavage. 1 Publication1
Mutagenesisi345D → N: Abolishes caspase cleavage. 1 Publication1
Mutagenesisi346S → A: Abolishes PKC-mediated phosphorylation; no effect on PKA-mediated phosphorylation. 1 Publication1
Mutagenesisi346S → E: Inhibits caspase-mediated cleavage. Modulates progression of apoptosis. 1 Publication1
Mutagenesisi373D → N: No effect on caspase cleavage. 1 Publication1
Mutagenesisi385D → 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 Publications1
Mutagenesisi385D → 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 Publications1
Mutagenesisi385D → N: No effect on caspase cleavage. 5 Publications1
Mutagenesisi389Y → F: Alters gamma-secretase cleavage specificity. Increased production of amyloid beta(42). No effect on enzymatic activity. 1 Publication1
Mutagenesisi433P → A: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Slightly increased Abeta42/Abeta40 ratio. 1 Publication1
Mutagenesisi433P → D, F, L, N or V: No endoproteolytic cleavage; no APP nor NOTCH1 processing. No detectable Abetano detectable Abeta. 1 Publication1
Mutagenesisi433P → G: Very little endoproteolysis. Little APP processing. No NOTCH1 processing. Very low levels Abeta40 and no detectable Abeta42. 1 Publication1
Mutagenesisi434A → C: Some loss of endoproteolytic cleavage. Some loss of APP and NOTCH1 processing. Six-fold increase in Abeta42/Abeta40 ratio. 1 Publication1
Mutagenesisi434A → D, I, L or V: No endoproteolytic cleavage. No APP nor NOTCH1 processing. No detectable Abeta. 1 Publication1
Mutagenesisi434A → G: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. Reduced Abeta42/Abeta40 ratio. 1 Publication1
Mutagenesisi435L → A: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Greatly reduced Abeta42/Abeta40 ratio. 1 Publication1
Mutagenesisi435L → G: Greatly reduced endoproteolytic cleavage. Very little APP and NOTCH1 processing. Very low levels of Abeta40 and no detectable Abeta42. 1 Publication1
Mutagenesisi435L → I: No effect on endoproteolytic cleavage. No effect on APP nor NOTCH1 processing. 1 Publication1
Mutagenesisi435L → V: No effect on endoproteolytic cleavage. No effect on APP processing. Impaired NOTCH1 processing. Some increase in Abeta42/Abeta40 ratio. 1 Publication1

Keywords - Diseasei

Alzheimer disease, Amyloidosis, Cardiomyopathy, Disease mutation, Neurodegeneration

Organism-specific databases

DisGeNETi5663.
MalaCardsiPSEN1.
MIMi600274. phenotype.
607822. phenotype.
613694. phenotype.
613737. phenotype.
OpenTargetsiENSG00000080815.
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.

Chemistry databases

ChEMBLiCHEMBL2473.
GuidetoPHARMACOLOGYi2402.

Polymorphism and mutation databases

BioMutaiPSEN1.
DMDMi1709856.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000255911 – 298Presenilin-1 NTF subunitAdd BLAST298
ChainiPRO_0000025592299 – 467Presenilin-1 CTF subunitAdd BLAST169
ChainiPRO_0000236055346 – 467Presenilin-1 CTF12Add BLAST122

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei43PhosphoserineCombined sources1
Modified residuei51PhosphoserineBy similarity1
Modified residuei310Phosphoserine; by PKA1 Publication1
Modified residuei346Phosphoserine; by PKC1 Publication1
Modified residuei367PhosphoserineCombined sources1

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.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei291 – 292Cleavage; alternate2
Sitei292 – 293Cleavage; alternate2
Sitei298 – 299Cleavage2
Sitei345 – 346Cleavage; by caspase2

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP49768.
MaxQBiP49768.
PaxDbiP49768.
PeptideAtlasiP49768.
PRIDEiP49768.

PTM databases

iPTMnetiP49768.
PhosphoSitePlusiP49768.
SwissPalmiP49768.

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

BgeeiENSG00000080815.
CleanExiHS_PSEN1.
ExpressionAtlasiP49768. baseline and differential.
GenevisibleiP49768. HS.

Organism-specific databases

HPAiCAB006844.
HPA030760.
HPA067496.

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). Interacts with isoform 1 and isoform 3 of UBQLN1.By similarity12 Publications

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
Ctnnb1Q022483EBI-297277,EBI-397872From a different organism.
ECSITQ9BQ954EBI-297277,EBI-712452
JUPP149234EBI-297277,EBI-702484
NCSTNQ925423EBI-297277,EBI-998440
ST13P505023EBI-297277,EBI-357285
TMED10P497553EBI-297277,EBI-998422

GO - Molecular functioni

  • beta-catenin binding Source: UniProtKB
  • cadherin binding Source: GO_Central
  • PDZ domain binding Source: UniProtKB

Protein-protein interaction databases

BioGridi111642. 85 interactors.
DIPiDIP-1134N.
IntActiP49768. 127 interactors.
MINTiMINT-88325.
STRINGi9606.ENSP00000326366.

Chemistry databases

BindingDBiP49768.

Structurei

Secondary structure

1467
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi293 – 299Combined sources7
Beta strandi341 – 345Combined sources5
Helixi356 – 368Combined sources13
Turni383 – 385Combined sources3
Helixi386 – 399Combined sources14
Turni403 – 406Combined sources4
Helixi407 – 428Combined sources22
Beta strandi433 – 437Combined sources5
Helixi442 – 449Combined sources8
Turni450 – 453Combined sources4
Helixi456 – 458Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2KR6NMR-A292-467[»]
4UISelectron microscopy4.40B81-463[»]
5A63electron microscopy3.40B1-467[»]
5FN2electron microscopy4.20B1-467[»]
5FN3electron microscopy4.10B1-467[»]
5FN4electron microscopy4.00B1-467[»]
5FN5electron microscopy4.30B1-467[»]
ProteinModelPortaliP49768.
SMRiP49768.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP49768.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni322 – 450Required for interaction with CTNNB1Add BLAST129
Regioni372 – 399Required for interaction with CTNND21 PublicationAdd BLAST28
Regioni464 – 467Interaction with MTCH11 Publication4

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi433 – 435PAL3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi94 – 97Poly-Val4
Compositional biasi171 – 174Poly-Leu4
Compositional biasi418 – 425Poly-Leu8

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

eggNOGiKOG2736. Eukaryota.
ENOG410XPZD. LUCA.
GeneTreeiENSGT00390000016593.
HOVERGENiHBG011375.
InParanoidiP49768.
KOiK04505.
OMAiNTNDNRE.
OrthoDBiEOG091G0C72.
PhylomeDBiP49768.
TreeFamiTF315040.

Family and domain databases

InterProiIPR002031. Pept_A22A_PS1.
IPR001108. Peptidase_A22A.
IPR006639. Preselin/SPP.
[Graphical view]
PANTHERiPTHR10202. PTHR10202. 1 hit.
PTHR10202:SF18. PTHR10202:SF18. 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. AlignAdd to basket

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)DescriptionActionsGraphical viewLength
Sequence conflicti128R → G in AAL16811 (PubMed:12508121).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07526035R → Q in AD3; unknown pathological significance. 1 PublicationCorresponds to variant rs63750592dbSNPEnsembl.1
Natural variantiVAR_00641379A → V in AD3; unknown pathological significance; no effect on interaction with GFAP. 4 PublicationsCorresponds to variant rs63749824dbSNPEnsembl.1
Natural variantiVAR_00641482V → L in AD3; no effect on interaction with GFAP. 3 PublicationsCorresponds to variant rs63749967dbSNPEnsembl.1
Natural variantiVAR_07526183I → T in AD3. 1 Publication