Details of the Target

General Information of Target

Target ID LDTP04303
Target Name Presenilin-1 (PSEN1)
Gene Name PSEN1
Gene ID 5663
Synonyms
AD3; PS1; PSNL1; Presenilin-1; PS-1; EC 3.4.23.-; Protein S182) [Cleaved into: Presenilin-1 NTF subunit; Presenilin-1 CTF subunit; Presenilin-1 CTF12; PS1-CTF12)]
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
Target Type
Clinical trial
Target Bioclass
Enzyme
Family
Peptidase A22A family
Subcellular location
Endoplasmic reticulum
Function
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 presence of the other members of the gamma-secretase complex for protease activity. 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. 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). Under conditions of apoptosis or calcium influx, cleaves CDH1. 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. Required for normal embryonic brain and skeleton development, and for normal angiogenesis. Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis. Involved in the regulation of neurite outgrowth. Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression.
TTD ID
T93105
Uniprot ID
P49768
DrugMap ID
TTZ3S8C
Ensemble ID
ENST00000324501.10
HGNC ID
HGNC:9508
ChEMBL ID
CHEMBL2473

Target Site Mutations in Different Cell Lines

Cell line Mutation details Probe for labeling this protein in this cell
AN3CA Deletion: p.P284QfsTer13 .
HEC1 SNV: p.N30H .
Ishikawa (Heraklio) 02 ER SNV: p.S346R .
LNCaP clone FGC SNV: p.N331S .
MEWO SNV: p.R269C .
RKO Deletion: p.E69del .

Probe(s) Labeling This Target

ABPP Probe
Click To Hide/Show 2 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
OPA-S-S-alkyne
 Probe Info  		K109(2.61)  LDD3494  [1]
Alkyne-RA190
 Probe Info  		2.07  LDD0303  [2]
PAL-AfBPP Probe
Click To Hide/Show 4 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
C153
 Probe Info  		21.56  LDD1834  [3]
FFF probe11
 Probe Info  		20.00  LDD0471  [4]
FFF probe13
 Probe Info  		20.00  LDD0475  [4]
FFF probe14
 Probe Info  		20.00  LDD0477  [4]

Competitor(s) Related to This Target

Competitor ID Name Cell line Binding Site(Ratio) Interaction ID Ref
 LDCM0131  RA190 SK-MEL-5 2.07  LDD0303  [2]

The Interaction Atlas With This Target

The Protein(s) Related To This Target

Enzyme
Click To Hide/Show 9 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
5' exonuclease Apollo (DCLRE1B) DNA repair metallo-beta-lactamase (DRMBL) family Q9H816
Hyaluronidase-2 (HYAL2) Glycosyl hydrolase 56 family Q12891
L-lactate dehydrogenase A-like 6B (LDHAL6B) LDH family Q9BYZ2
Phospholipid phosphatase 1 (PLPP1) PA-phosphatase related phosphoesterase family O14494
Beta-secretase 1 (BACE1) Peptidase A1 family P56817
Ubiquitin thioesterase OTUB1 (OTUB1) Peptidase C65 family Q96FW1
Carboxypeptidase E (CPE) Peptidase M14 family P16870
Serine/threonine-protein kinase PLK1 (PLK1) Ser/Thr protein kinase family P53350
RING finger protein 112 (RNF112) GB1/RHD3 GTPase family Q9ULX5
Transporter and channel
Click To Hide/Show 6 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Amyloid-beta precursor protein (APP) APP family P05067
Bax inhibitor 1 (TMBIM6) BI1 family P55061
Sodium-dependent organic anion transporter (SLC10A6) Bile acid:sodium symporter (BASS) family Q3KNW5
Hsp90 co-chaperone Cdc37 (CDC37) CDC37 family Q16543
Transmembrane emp24 domain-containing protein 10 (TMED10) EMP24/GP25L family P49755
Amyloid-beta A4 precursor protein-binding family A member 1 (APBA1) . Q02410
Immunoglobulin
Click To Hide/Show 2 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Basigin (BSG) . P35613
Triggering receptor expressed on myeloid cells 2 (TREM2) . Q9NZC2
Cytokine and receptor
Click To Hide/Show 1 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) . O00300
Other
Click To Hide/Show 15 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT) ECSIT family Q9BQ95
Hsc70-interacting protein (ST13) FAM10 family P50502
Ferritin light chain (FTL) Ferritin family P02792
Histone H3.1 (H3C1; H3C2; H3C3; H3C4; H3C6; H3C7; H3C8; H3C10; H3C11; H3C12) Histone H3 family P68431
Keratin-associated protein 9-2 (KRTAP9-2) KRTAP type 9 family Q9BYQ4
MORF4 family-associated protein 1 (MRFAP1) MORF4 family-associated protein family Q9Y605
Nicastrin (NCSTN) Nicastrin family Q92542
Gamma-secretase subunit PEN-2 (PSENEN) PEN-2 family Q9NZ42
Oocyte-secreted protein 2 (OOSP2) PLAC1 family Q86WS3
Fasciculation and elongation protein zeta-2 (FEZ2) Zygin family Q9UHY8
PDZK1-interacting protein 1 (PDZK1IP1) . Q13113
Protein MGARP (MGARP) . Q8TDB4
RING1 and YY1-binding protein (RYBP) . Q8N488
Superkiller complex protein 8 (SKIC8) . Q9GZS3
Zinc finger matrin-type protein 2 (ZMAT2) . Q96NC0

The Drug(s) Related To This Target

Phase 2
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
R-flurbiprofen Small molecular drug D05FGR
Preclinical
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
(S)-flurbiprofen Small molecular drug D0G2IC
Investigative
Click To Hide/Show 9 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
(2s,3r)-2-(Benzyloxy)-3-methoxycyclohexanone Small molecular drug D0M2LV
(5r,6s)-5,6-bis(Benzyloxy)Cyclohex-2-enone Small molecular drug D00DFR
(5r,6s)-6-(Benzyloxy)-5-methoxycyclohex-2-enone Small molecular drug D04TWU
1-benzoyl-2-benzyl-1,2-dihydropyridin-3(6h)-one Small molecular drug D0I8BA
1-chloro-4-(1-phenyl-cyclohexanesulfonyl)-benzene Small molecular drug D0K8LN
Drug 311383 . D09HAD
Drug 311440 . D0XQ2T
Drug 311951 . D06TPT
Drug 311952 . D0V7YM

References

1 A chemical proteomics approach for global mapping of functional lysines on cell surface of living cell. Nat Commun. 2024 Apr 8;15(1):2997. doi: 10.1038/s41467-024-47033-w.
Mass spectrometry data entry: PXD042888
2 Physical and Functional Analysis of the Putative Rpn13 Inhibitor RA190. Cell Chem Biol. 2020 Nov 19;27(11):1371-1382.e6. doi: 10.1016/j.chembiol.2020.08.007. Epub 2020 Aug 27.
3 Large-scale chemoproteomics expedites ligand discovery and predicts ligand behavior in cells. Science. 2024 Apr 26;384(6694):eadk5864. doi: 10.1126/science.adk5864. Epub 2024 Apr 26.
Mass spectrometry data entry: PXD041587
4 Ligand and Target Discovery by Fragment-Based Screening in Human Cells. Cell. 2017 Jan 26;168(3):527-541.e29. doi: 10.1016/j.cell.2016.12.029. Epub 2017 Jan 19.