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Protein

Presenilin-2

Gene

PSEN2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 (amyloid-beta 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. May function in the cytoplasmic partitioning of proteins.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei2631 Publication1
Active sitei3662 Publications1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease
Biological processNotch signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-193692 Regulated proteolysis of p75NTR
R-HSA-205043 NRIF signals cell death from the nucleus
R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-3928665 EPH-ephrin mediated repulsion of cells
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700 NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802 Noncanonical activation of NOTCH3
SignaLinkiP49810
SIGNORiP49810

Protein family/group databases

MEROPSiA22.002
TCDBi1.A.54.1.2 the presenilin er ca(2+) leak channel (presenilin) family

Names & Taxonomyi

Protein namesi
Recommended name:
Presenilin-2 (EC:3.4.23.-)
Short name:
PS-2
Alternative name(s):
AD3LP
AD5
E5-1
STM-2
Cleaved into the following 2 chains:
Gene namesi
Name:PSEN2
Synonyms:AD4, PS2, PSNL2, STM2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000143801.16
HGNCiHGNC:9509 PSEN2
MIMi600759 gene
neXtProtiNX_P49810

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 87CytoplasmicSequence analysisAdd BLAST87
Transmembranei88 – 108HelicalSequence analysisAdd BLAST21
Topological domaini109 – 138LumenalSequence analysisAdd BLAST30
Transmembranei139 – 159HelicalSequence analysisAdd BLAST21
Topological domaini160 – 166CytoplasmicSequence analysis7
Transmembranei167 – 187HelicalSequence analysisAdd BLAST21
Topological domaini188 – 200LumenalSequence analysisAdd BLAST13
Transmembranei201 – 221HelicalSequence analysisAdd BLAST21
Topological domaini222 – 223CytoplasmicSequence analysis2
Transmembranei224 – 244HelicalSequence analysisAdd BLAST21
Topological domaini245 – 249LumenalSequence analysis5
Transmembranei250 – 270HelicalSequence analysisAdd BLAST21
Topological domaini271 – 361CytoplasmicSequence analysisAdd BLAST91
Transmembranei362 – 382HelicalSequence analysisAdd BLAST21
Topological domaini383 – 388LumenalSequence analysis6
Transmembranei389 – 409HelicalSequence analysisAdd BLAST21
Topological domaini410 – 413CytoplasmicSequence analysis4
Intramembranei414 – 434HelicalSequence analysisAdd BLAST21
Topological domaini435 – 448CytoplasmicSequence analysisAdd BLAST14

Keywords - Cellular componenti

Endoplasmic reticulum, Golgi apparatus, Membrane

Pathology & Biotechi

Involvement in diseasei

Alzheimer disease 4 (AD4)6 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 constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
See also OMIM:606889
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00646162R → H in AD4; uncertain pathological significance. 2 PublicationsCorresponds to variant dbSNP:rs58973334EnsemblClinVar.1
Natural variantiVAR_07002771R → W in AD4; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs140501902EnsemblClinVar.1
Natural variantiVAR_009214122T → P in AD4. 1 PublicationCorresponds to variant dbSNP:rs63749851EnsemblClinVar.1
Natural variantiVAR_006462141N → I in AD4. 2 PublicationsCorresponds to variant dbSNP:rs63750215EnsemblClinVar.1
Natural variantiVAR_007958148V → I in AD4; late-onset Alzheimer disease. 1 PublicationCorresponds to variant dbSNP:rs63750812EnsemblClinVar.1
Natural variantiVAR_009215239M → I in AD4. 1 PublicationCorresponds to variant dbSNP:rs63749884EnsemblClinVar.1
Natural variantiVAR_006463239M → V in AD4; Italian patients. 1 PublicationCorresponds to variant dbSNP:rs28936379EnsemblClinVar.1
Cardiomyopathy, dilated 1V (CMD1V)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:613697

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi263D → A: Reduces production of amyloid-beta in APP processing. 1 Publication1
Mutagenesisi366D → A: Reduces production of amyloid-beta in APP processing and of NICD in NOTCH1 processing. 2 Publications1

Keywords - Diseasei

Alzheimer disease, Amyloidosis, Cardiomyopathy, Disease mutation, Neurodegeneration

Organism-specific databases

DisGeNETi5664
GeneReviewsiPSEN2
MalaCardsiPSEN2
MIMi606889 phenotype
613697 phenotype
OpenTargetsiENSG00000143801
Orphaneti1020 Early-onset autosomal dominant Alzheimer disease
154 Familial isolated dilated cardiomyopathy
PharmGKBiPA33856

Chemistry databases

ChEMBLiCHEMBL3708

Polymorphism and mutation databases

BioMutaiPSEN2
DMDMi1709858

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000256031 – 297Presenilin-2 NTF subunitBy similarityAdd BLAST297
ChainiPRO_0000025604298 – 448Presenilin-2 CTF subunitBy similarityAdd BLAST151

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei22PhosphoserineCombined sources1
Modified residuei25PhosphoserineCombined sources1
Modified residuei30PhosphoserineBy similarity1

Post-translational modificationi

Heterogeneous proteolytic processing generates N-terminal and C-terminal fragments.
Phosphorylated on serine residues.

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP49810
MaxQBiP49810
PaxDbiP49810
PeptideAtlasiP49810
PRIDEiP49810
ProteomicsDBi56139
56140 [P49810-2]
56141 [P49810-3]

PTM databases

iPTMnetiP49810
PhosphoSitePlusiP49810
SwissPalmiP49810

Expressioni

Tissue specificityi

Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney.1 Publication

Gene expression databases

BgeeiENSG00000143801 Expressed in 156 organ(s), highest expression level in body of pancreas
CleanExiHS_PSEN2
ExpressionAtlasiP49810 baseline and differential
GenevisibleiP49810 HS

Organism-specific databases

HPAiCAB013634

Interactioni

Subunit structurei

Interacts with DOCK3 (By similarity). 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, although other components may exist. Interacts with HERPUD1, FLNA, FLNB and PARL.By similarity2 Publications

Binary interactionsi

Protein-protein interaction databases

BioGridi111643, 58 interactors
CORUMiP49810
IntActiP49810, 24 interactors
MINTiP49810
STRINGi9606.ENSP00000355747

Chemistry databases

BindingDBiP49810

Structurei

3D structure databases

ProteinModelPortaliP49810
SMRiP49810
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi414 – 416PAL3

Domaini

The PAL motif is required for normal active site conformation.By similarity

Sequence similaritiesi

Belongs to the peptidase A22A family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2736 Eukaryota
ENOG410XPZD LUCA
GeneTreeiENSGT00390000016593
HOGENOMiHOG000240228
HOVERGENiHBG011375
InParanoidiP49810
KOiK04522
PhylomeDBiP49810
TreeFamiTF315040

Family and domain databases

InterProiView protein in InterPro
IPR001493 Pept_A22A_PS2
IPR001108 Peptidase_A22A
IPR006639 Preselin/SPP
PANTHERiPTHR10202 PTHR10202, 2 hits
PfamiView protein in Pfam
PF01080 Presenilin, 2 hits
PRINTSiPR01072 PRESENILIN
PR01074 PRESENILIN2
SMARTiView protein in SMART
SM00730 PSN, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

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

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 3 described isoforms and 5 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: P49810-1) [UniParc]FASTAAdd to basket

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
MLTFMASDSE EEVCDERTSL MSAESPTPRS CQEGRQGPED GENTAQWRSQ
60 70 80 90 100
ENEEDGEEDP DRYVCSGVPG RPPGLEEELT LKYGAKHVIM LFVPVTLCMI
110 120 130 140 150
VVVATIKSVR FYTEKNGQLI YTPFTEDTPS VGQRLLNSVL NTLIMISVIV
160 170 180 190 200
VMTIFLVVLY KYRCYKFIHG WLIMSSLMLL FLFTYIYLGE VLKTYNVAMD
210 220 230 240 250
YPTLLLTVWN FGAVGMVCIH WKGPLVLQQA YLIMISALMA LVFIKYLPEW
260 270 280 290 300
SAWVILGAIS VYDLVAVLCP KGPLRMLVET AQERNEPIFP ALIYSSAMVW
310 320 330 340 350
TVGMAKLDPS SQGALQLPYD PEMEEDSYDS FGEPSYPEVF EPPLTGYPGE
360 370 380 390 400
ELEEEEERGV KLGLGDFIFY SVLVGKAAAT GSGDWNTTLA CFVAILIGLC
410 420 430 440
LTLLLLAVFK KALPALPISI TFGLIFYFST DNLVRPFMDT LASHQLYI
Length:448
Mass (Da):50,140
Last modified:October 1, 1996 - v1
Checksum:iA927EEC623468116
GO
Isoform 2 (identifier: P49810-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     263-296: Missing.

Show »
Length:414
Mass (Da):46,387
Checksum:i75A03F21290BAFF8
GO
Isoform 3 (identifier: P49810-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     324-324: Missing.

Note: No experimental confirmation available.
Show »
Length:447
Mass (Da):50,011
Checksum:iAA9D4FD8CB46E669
GO

Computationally mapped potential isoform sequencesi

There are 5 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
B1AP22B1AP22_HUMAN
Presenilin
PSEN2 hCG_15757
481Annotation score:
E5RG63E5RG63_HUMAN
Presenilin
PSEN2
304Annotation score:
E5RFW4E5RFW4_HUMAN
Presenilin
PSEN2
144Annotation score:
E5RHT1E5RHT1_HUMAN
Presenilin-2
PSEN2
129Annotation score:
E5RJM5E5RJM5_HUMAN
Presenilin-2
PSEN2
21Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti123P → T (PubMed:7638622).Curated1
Sequence conflicti123P → T (Ref. 10) Curated1
Sequence conflicti295S → L in AAL16812 (Ref. 10) Curated1
Sequence conflicti325Missing in AAC50290 (PubMed:8618867).Curated1
Sequence conflicti358R → SQG in AAC50290 (PubMed:8618867).Curated1
Sequence conflicti432 – 448NLVRP…HQLYI → RKHSRFIQMN (PubMed:8618867).CuratedAdd BLAST17

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00646162R → H in AD4; uncertain pathological significance. 2 PublicationsCorresponds to variant dbSNP:rs58973334EnsemblClinVar.1
Natural variantiVAR_07002771R → W in AD4; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs140501902EnsemblClinVar.1
Natural variantiVAR_009214122T → P in AD4. 1 PublicationCorresponds to variant dbSNP:rs63749851EnsemblClinVar.1
Natural variantiVAR_064903130S → L in CMD1V and AD4; unknown pathological significance. 2 PublicationsCorresponds to variant dbSNP:rs63750197EnsemblClinVar.1
Natural variantiVAR_006462141N → I in AD4. 2 PublicationsCorresponds to variant dbSNP:rs63750215EnsemblClinVar.1
Natural variantiVAR_007958148V → I in AD4; late-onset Alzheimer disease. 1 PublicationCorresponds to variant dbSNP:rs63750812EnsemblClinVar.1
Natural variantiVAR_009215239M → I in AD4. 1 PublicationCorresponds to variant dbSNP:rs63749884EnsemblClinVar.1
Natural variantiVAR_006463239M → V in AD4; Italian patients. 1 PublicationCorresponds to variant dbSNP:rs28936379EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_005194263 – 296Missing in isoform 2. CuratedAdd BLAST34
Alternative sequenceiVSP_043648324Missing in isoform 3. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L43964 mRNA Translation: AAB59557.1
L44577 mRNA Translation: AAC42012.1
U34349 mRNA Translation: AAC50290.1
U50871 Genomic DNA Translation: AAB50054.1
BT006984 mRNA Translation: AAP35630.1
AK292299 mRNA Translation: BAF84988.1
AL391628 Genomic DNA No translation available.
CH471098 Genomic DNA Translation: EAW69798.1
CH471098 Genomic DNA Translation: EAW69800.1
BC006365 mRNA Translation: AAH06365.1
AF416718 mRNA Translation: AAL16812.1
CCDSiCCDS1556.1 [P49810-1]
CCDS44324.1 [P49810-3]
PIRiA56993
I39174
RefSeqiNP_000438.2, NM_000447.2 [P49810-1]
NP_036618.2, NM_012486.2 [P49810-3]
XP_005273256.1, XM_005273199.3 [P49810-1]
XP_016857324.1, XM_017001835.1 [P49810-1]
XP_016857325.1, XM_017001836.1 [P49810-3]
UniGeneiHs.25363

Genome annotation databases

EnsembliENST00000366783; ENSP00000355747; ENSG00000143801 [P49810-1]
ENST00000422240; ENSP00000403737; ENSG00000143801 [P49810-3]
GeneIDi5664
KEGGihsa:5664
UCSCiuc009xeo.2 human [P49810-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Web resourcesi

Alzheimer Research Forum

Presenilins mutations

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L43964 mRNA Translation: AAB59557.1
L44577 mRNA Translation: AAC42012.1
U34349 mRNA Translation: AAC50290.1
U50871 Genomic DNA Translation: AAB50054.1
BT006984 mRNA Translation: AAP35630.1
AK292299 mRNA Translation: BAF84988.1
AL391628 Genomic DNA No translation available.
CH471098 Genomic DNA Translation: EAW69798.1
CH471098 Genomic DNA Translation: EAW69800.1
BC006365 mRNA Translation: AAH06365.1
AF416718 mRNA Translation: AAL16812.1
CCDSiCCDS1556.1 [P49810-1]
CCDS44324.1 [P49810-3]
PIRiA56993
I39174
RefSeqiNP_000438.2, NM_000447.2 [P49810-1]
NP_036618.2, NM_012486.2 [P49810-3]
XP_005273256.1, XM_005273199.3 [P49810-1]
XP_016857324.1, XM_017001835.1 [P49810-1]
XP_016857325.1, XM_017001836.1 [P49810-3]
UniGeneiHs.25363

3D structure databases

ProteinModelPortaliP49810
SMRiP49810
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111643, 58 interactors
CORUMiP49810
IntActiP49810, 24 interactors
MINTiP49810
STRINGi9606.ENSP00000355747

Chemistry databases

BindingDBiP49810
ChEMBLiCHEMBL3708

Protein family/group databases

MEROPSiA22.002
TCDBi1.A.54.1.2 the presenilin er ca(2+) leak channel (presenilin) family

PTM databases

iPTMnetiP49810
PhosphoSitePlusiP49810
SwissPalmiP49810

Polymorphism and mutation databases

BioMutaiPSEN2
DMDMi1709858

Proteomic databases

EPDiP49810
MaxQBiP49810
PaxDbiP49810
PeptideAtlasiP49810
PRIDEiP49810
ProteomicsDBi56139
56140 [P49810-2]
56141 [P49810-3]

Protocols and materials databases

DNASUi5664
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000366783; ENSP00000355747; ENSG00000143801 [P49810-1]
ENST00000422240; ENSP00000403737; ENSG00000143801 [P49810-3]
GeneIDi5664
KEGGihsa:5664
UCSCiuc009xeo.2 human [P49810-1]

Organism-specific databases

CTDi5664
DisGeNETi5664
EuPathDBiHostDB:ENSG00000143801.16
GeneCardsiPSEN2
GeneReviewsiPSEN2
HGNCiHGNC:9509 PSEN2
HPAiCAB013634
MalaCardsiPSEN2
MIMi600759 gene
606889 phenotype
613697 phenotype
neXtProtiNX_P49810
OpenTargetsiENSG00000143801
Orphaneti1020 Early-onset autosomal dominant Alzheimer disease
154 Familial isolated dilated cardiomyopathy
PharmGKBiPA33856
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2736 Eukaryota
ENOG410XPZD LUCA
GeneTreeiENSGT00390000016593
HOGENOMiHOG000240228
HOVERGENiHBG011375
InParanoidiP49810
KOiK04522
PhylomeDBiP49810
TreeFamiTF315040

Enzyme and pathway databases

ReactomeiR-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-193692 Regulated proteolysis of p75NTR
R-HSA-205043 NRIF signals cell death from the nucleus
R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-3928665 EPH-ephrin mediated repulsion of cells
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700 NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802 Noncanonical activation of NOTCH3
SignaLinkiP49810
SIGNORiP49810

Miscellaneous databases

ChiTaRSiPSEN2 human
GeneWikiiPSEN2
GenomeRNAii5664
PROiPR:P49810
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000143801 Expressed in 156 organ(s), highest expression level in body of pancreas
CleanExiHS_PSEN2
ExpressionAtlasiP49810 baseline and differential
GenevisibleiP49810 HS

Family and domain databases

InterProiView protein in InterPro
IPR001493 Pept_A22A_PS2
IPR001108 Peptidase_A22A
IPR006639 Preselin/SPP
PANTHERiPTHR10202 PTHR10202, 2 hits
PfamiView protein in Pfam
PF01080 Presenilin, 2 hits
PRINTSiPR01072 PRESENILIN
PR01074 PRESENILIN2
SMARTiView protein in SMART
SM00730 PSN, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiPSN2_HUMAN
AccessioniPrimary (citable) accession number: P49810
Secondary accession number(s): A8K8D4, B1AP21, Q96P32
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: September 12, 2018
This is version 200 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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