Tchem PSEN1 Presenilin-1

Protein Classes

PANTHER Classes

Protein / Signaling Molecule / Membrane-bound Signaling Molecule / Presenilin-1

Protein / Hydrolase / Protease / Aspartic Protease / Presenilin-1

Protein / Calcium-binding Protein / Presenilin-1

DTO Classes

Protein / Enzyme / Protease / Aspartic Protease / Presenilin-1

Protein Summary

Description

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) (PubMed:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795). Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]

Uniprot Accession IDs

• P49768
• B2R6D3
• O95465
• Q14762
• Q15719
• Q15720
• Q96P33
• Q9UIF0
• PS-1

Gene Name

• PSEN1

Ensembl ID

• ENST00000324501
• ENSP00000326366
• ENSG00000080815
• ENST00000357710
• ENSP00000350342
• ENST00000394157
• ENSP00000377712
• ENST00000394164
• ENSP00000377719
• ENST00000553855
• ENSP00000452242
• ENST00000555386
• ENSP00000450845
• ENST00000557511
• ENSP00000451429

Symbol

• AD3
• PS1
• PSNL1
• AD3
• FAD
• PS1
• PS-1
• S182
• ACNINV3

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
biological process	1
hub protein	0.98
molecular function	0.94
disease perturbation	0.93
kinase perturbation	0.91

Related Tools

Target Illumination GWAS Analytics (TIGA)

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GENEVA

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 4470.62   (req: < 5)

Gene RIFs: 498   (req: <= 3)

Antibodies: 853   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 4470.62   (req: >= 5)

Gene RIFs: 498   (req: > 3)

Antibodies: 853   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 84

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 91

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

Active Ligands (91)

Explore Active Ligands

1 – 10 of 91

CHEMBL392068

PSEN1Tchem Enzyme

EC50 : 9.94

CHEMBL2159511

PSEN1Tchem Enzyme

IC50 : 8.89

CHEMBL2159510

PSEN1Tchem Enzyme

IC50 : 8.52

CHEMBL2159509

PSEN1Tchem Enzyme

IC50 : 8.22

CHEMBL2159689

PSEN1Tchem Enzyme

IC50 : 8.1

CHEMBL2159687

PSEN1Tchem Enzyme

IC50 : 7.75

CHEMBL2159691

PSEN1Tchem Enzyme

IC50 : 7.66

CHEMBL2159690

PSEN1Tchem Enzyme

IC50 : 7.62

CHEMBL3397721

PSEN1Tchem Enzyme

IC50 : 6.2

CHEMBL3397717

PSEN1Tchem Enzyme

IC50 : 6.1

GWAS Traits (9)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
red blood cell distribution width	EFO_0005192	2	2	2		75.4
C-reactive protein measurement	EFO_0004458	1	1	1		72.3
alkaline phosphatase measurement	EFO_0004533	1	1	1		51.7
HbA1c measurement	EFO_0004541	1	1	1		47.7
cognitive function measurement	EFO_0008354	2	1	2		44.2

• Explore on Target Illumination GWAS Analytics (TIGA)

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
red blood cell distribution width	EFO_0005192	2		75.4
C-reactive protein measurement	EFO_0004458	1		72.3
alkaline phosphatase measurement	EFO_0004533	1		51.7
HbA1c measurement	EFO_0004541	1		47.7
cognitive function measurement	EFO_0008354	2		44.2

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Orthologs (16)

1 – 5 of 16

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	presenilin 1	VGNC:3326	739740
Macaque	presenilin 1		696274
Mouse	presenilin 1	MGI:1202717	19164
Rat	presenilin 1	RGD:3425	29192
Dog	presenilin 1	VGNC:45085	403408

Species	Name	OMA	EggNOG	Inparanoid
Chimp	presenilin 1
Macaque	presenilin 1
Mouse	presenilin 1
Rat	presenilin 1
Dog	presenilin 1

Protein Structure (7 Structures, 1 AlphaFold Model)

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Representation

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Color Scheme

  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

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More information can be found at RCSB PDB

AF-P49768-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

1 – 5 of 7

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (57)

Reactome (35)

KEGG (5)

PathwayCommons (13)

WikiPathways (4)

Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Activated NOTCH1 Transmits Signal to the Nucleus	31 targets	R-HSA-2122948
Reactome	Axon guidance	533 targets	R-HSA-422475
Reactome	Cell death signalling via NRAGE, NRIF and NADE	76 targets	R-HSA-204998
Reactome	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	58 targets	R-HSA-2894862
Reactome	Constitutive Signaling by NOTCH1 PEST Domain Mutants	58 targets	R-HSA-2644606

Name	Explore in Pharos	Explore in Source
Activated NOTCH1 Transmits Signal to the Nucleus	31 targets	R-HSA-2122948
Axon guidance	533 targets	R-HSA-422475
Cell death signalling via NRAGE, NRIF and NADE	76 targets	R-HSA-204998
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	58 targets	R-HSA-2894862
Constitutive Signaling by NOTCH1 PEST Domain Mutants	58 targets	R-HSA-2644606

Gene Ontology Terms (115)

Functions (7)

Components (31)

Processes (77)

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1 – 7 of 7

GO Term	Evidence	Assigned by
aspartic endopeptidase activity, intramembrane cleaving	Inferred from Direct Assay (IDA)	UniProtKB
endopeptidase activity	Inferred from Direct Assay (IDA)	MGI
beta-catenin binding	Inferred from Physical Interaction (IPI)	UniProtKB
PDZ domain binding	Inferred from Physical Interaction (IPI)	UniProtKB
calcium channel activity	Inferred from Mutant Phenotype (IMP)	UniProtKB
cadherin binding	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
aspartic-type endopeptidase activity	Traceable Author Statement (TAS)	Reactome

Protein-Protein Interactions (319)

Explore Interacting Targets

1 – 10 of 319

• See Interactions on String-DB

SPPL2B

Tchem

Family:  Enzyme

Novelty:  0.0274774

p_int:  0.919532316

p_ni:  0.080467683

Score:  0.458

Data Source:  BioPlex,STRINGDB

AIRE

Tbio

Family:  TF; Epigenetic

Novelty:  0.00158659

p_int:  0.889469508

p_ni:  0.110530492

Data Source:  BioPlex

CDH8

Tbio

Novelty:  0.04055999

p_int:  0.789766622

p_ni:  0.210233377

Score:  0.27

Data Source:  BioPlex,STRINGDB

PSENEN

Tchem

Family:  Enzyme

Novelty:  0.00118125

Score:  0.999

Data Source:  Reactome,STRINGDB

APH1A

Tbio

Family:  Enzyme

Novelty:  0.00794922

Score:  0.999

Data Source:  Reactome,STRINGDB

NCSTN

Tbio

Novelty:  0.00453935

Score:  0.999

Data Source:  Reactome,STRINGDB

APH1B

Tbio

Family:  Enzyme

Novelty:  0.03620802

Score:  0.999

Data Source:  Reactome,STRINGDB

APP

Tchem

Novelty:  0.00008964

Score:  0.998

Data Source:  STRINGDB

PSEN2

Tchem

Family:  Enzyme

Novelty:  0.00112188

Score:  0.998

Data Source:  STRINGDB

CTNNB1

Tchem

Novelty:  0.0000744

Score:  0.994

Data Source:  STRINGDB

Publication Statistics

PubMed Score  4470.62

PubMed score by year

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PubTator Score  1744.28

PubTator score by year

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Amino Acid Sequence

Residue Counts

Protein Sequence

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UniProt Keyword Find Similar Targets

No Header	No Header
3D-structure
Alternative splicing
Alzheimer disease
Amyloidosis
Apoptosis
Cardiomyopathy
Cell adhesion
Cell membrane
Complete proteome
Direct protein sequencing

GWAS Trait Find Similar Targets

No Header	No Header
alkaline phosphatase measurement
apolipoprotein B measurement
C-reactive protein measurement
cognitive function measurement
HbA1c measurement
mathematical ability
red blood cell distribution width
reticulocyte measurement
self reported educational attainment

MGI Phenotype Find Similar Targets

No Header	No Header
behavior/neurological phenotype
cardiovascular system phenotype
cellular phenotype
craniofacial phenotype
embryo phenotype
endocrine/exocrine gland phenotype
growth/size/body region phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype