PSN1_CANLF
ID PSN1_CANLF Reviewed; 466 AA.
AC Q6RH31; Q6RH32;
DT 16-MAY-2006, integrated into UniProtKB/Swiss-Prot.
DT 16-MAY-2006, sequence version 2.
DT 03-AUG-2022, entry version 106.
DE RecName: Full=Presenilin-1;
DE Short=PS-1;
DE EC=3.4.23.-;
DE Contains:
DE RecName: Full=Presenilin-1 NTF subunit;
DE Contains:
DE RecName: Full=Presenilin-1 CTF subunit;
DE Contains:
DE RecName: Full=Presenilin-1 CTF12;
DE Short=PS1-CTF12;
GN Name=PSEN1;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS I-462 AND I-466).
RA Nakata M.;
RT "Sequence analysis and chromosomal mapping of presenilin-1 and amyloid
RT precursor protein genes in dogs.";
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP IDENTIFICATION IN COMPLEX WITH CDH1; CTNNB1; CTNND1 AND JUP.
RX PubMed=11226248; DOI=10.1073/pnas.041603398;
RA Baki L., Marambaud P., Efthimiopoulos S., Georgakopoulos A., Wen P.,
RA Cui W., Shioi J., Koo E., Ozawa M., Friedrich V.L., Robakis N.K.;
RT "Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120
RT association, and regulates stability and function of the cadherin/catenin
RT adhesion complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:2381-2386(2001).
CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an
CC endoprotease complex that catalyzes the intramembrane cleavage of
CC integral membrane proteins such as Notch receptors and APP (amyloid-
CC beta precursor protein). Requires the presence of the other members of
CC the gamma-secretase complex for protease activity. Plays a role in
CC Notch and Wnt signaling cascades and regulation of downstream processes
CC via its role in processing key regulatory proteins, and by regulating
CC cytosolic CTNNB1 levels. Stimulates cell-cell adhesion via its
CC interaction with CDH1; this stabilizes the complexes between CDH1 (E-
CC cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1
CC and JUP (gamma-catenin). Under conditions of apoptosis or calcium
CC influx, cleaves CDH1. This promotes the disassembly of the complexes
CC between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of
CC cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (By
CC similarity). Required for normal embryonic brain and skeleton
CC development, and for normal angiogenesis (By similarity). Mediates the
CC proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (By similarity). The
CC holoprotein functions as a calcium-leak channel that allows the passive
CC movement of calcium from endoplasmic reticulum to cytosol and is
CC therefore involved in calcium homeostasis. Involved in the regulation
CC of neurite outgrowth (By similarity). Is a regulator of presynaptic
CC facilitation, spike transmission and synaptic vesicles replenishment in
CC a process that depends on gamma-secretase activity. It acts through the
CC control of SYT7 presynaptic expression (By similarity).
CC {ECO:0000250|UniProtKB:P49768, ECO:0000250|UniProtKB:P49769}.
CC -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed
CC of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2),
CC nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex
CC is sufficient for secretase activity. Other components which are
CC associated with the complex include SLC25A64, SLC5A7 and PHB. As part
CC of the gamma-secretase complex, interacts with CRB2 (via transmembrane
CC domain) (By similarity). Predominantly heterodimer of a N-terminal
CC (NTF) and a C-terminal (CTF) endoproteolytical fragment. Associates
CC with proteolytic processed C-terminal fragments C83 and C99 of the
CC amyloid precursor protein (APP). Associates with NOTCH1. Associates
CC with cadherin/catenin adhesion complexes through direct binding to CDH1
CC or CDH2 (PubMed:11226248). Interaction with CDH1 stabilizes the complex
CC and stimulates cell-cell aggregation. Interaction with CDH2 is
CC essential for trafficking of CDH2 from the endoplasmic reticulum to the
CC plasma membrane. Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1,
CC FLNA, FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with
CC GFAP (By similarity). Interacts with DOCK3 (By similarity). Interacts
CC with UBQLN1 (By similarity). {ECO:0000250|UniProtKB:P49768,
CC ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:11226248}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:P49768}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P49768}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P49768}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:P49768}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P49768}. Cytoplasmic granule
CC {ECO:0000250|UniProtKB:P49768}. Cell membrane
CC {ECO:0000250|UniProtKB:P49768}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P49768}. Cell projection, growth cone
CC {ECO:0000250|UniProtKB:P49768}. Early endosome
CC {ECO:0000250|UniProtKB:P49768}. Early endosome membrane
CC {ECO:0000250|UniProtKB:P49768}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P49768}. Cell projection, neuron projection
CC {ECO:0000250|UniProtKB:P49768}. Cell projection, axon
CC {ECO:0000250|UniProtKB:Q4JIM4}. Synapse {ECO:0000250|UniProtKB:Q4JIM4}.
CC Note=Translocates with bound NOTCH1 from the endoplasmic reticulum
CC and/or Golgi to the cell surface. Colocalizes with CDH1/2 at sites of
CC cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum
CC and the proximity of the plasma membrane. Also present in azurophil
CC granules of neutrophils. Colocalizes with UBQLN1 in the cell membrane
CC and in cytoplasmic juxtanuclear structures called aggresomes.
CC {ECO:0000250|UniProtKB:P49768}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=I-466;
CC IsoId=Q6RH31-1; Sequence=Displayed;
CC Name=I-462;
CC IsoId=Q6RH31-2; Sequence=VSP_018569;
CC -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC {ECO:0000250|UniProtKB:P49768}.
CC -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between
CC PSEN1 transmembrane domains and via the first lumenal loop and the
CC cytoplasmic loop between the sixth and seventh transmembrane domains.
CC Substrate binding causes a conformation change and formation of an
CC intermolecular antiparallel beta-sheet between PSEN1 and its
CC substrates. {ECO:0000250|UniProtKB:P49768}.
CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF)
CC and C-terminal (CTF) fragments of approximately 35 and 20 kDa,
CC respectively. During apoptosis, the C-terminal fragment (CTF) is
CC further cleaved by caspase-3 to produce the fragment, PS1-CTF12.
CC {ECO:0000250|UniProtKB:P49768}.
CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is
CC phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on
CC Ser-345 inhibits endoproteolysis. {ECO:0000250|UniProtKB:P49768}.
CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}.
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DR EMBL; AY498704; AAR97724.1; -; mRNA.
DR EMBL; AY498705; AAR97725.1; -; mRNA.
DR RefSeq; NP_001002943.2; NM_001002943.2.
DR RefSeq; NP_001280213.1; NM_001293284.1.
DR AlphaFoldDB; Q6RH31; -.
DR SMR; Q6RH31; -.
DR CORUM; Q6RH31; -.
DR STRING; 9615.ENSCAFP00000024732; -.
DR MEROPS; A22.001; -.
DR PaxDb; Q6RH31; -.
DR GeneID; 403408; -.
DR KEGG; cfa:403408; -.
DR CTD; 5663; -.
DR eggNOG; KOG2736; Eukaryota.
DR InParanoid; Q6RH31; -.
DR Proteomes; UP000002254; Unplaced.
DR GO; GO:0016235; C:aggresome; ISS:UniProtKB.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0016324; C:apical plasma membrane; IBA:GO_Central.
DR GO; GO:0005938; C:cell cortex; IBA:GO_Central.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0035253; C:ciliary rootlet; IBA:GO_Central.
DR GO; GO:0043198; C:dendritic shaft; IBA:GO_Central.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0070765; C:gamma-secretase complex; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030426; C:growth cone; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IBA:GO_Central.
DR GO; GO:0045121; C:membrane raft; IBA:GO_Central.
DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0031594; C:neuromuscular junction; IBA:GO_Central.
DR GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005790; C:smooth endoplasmic reticulum; IEA:GOC.
DR GO; GO:0030018; C:Z disc; IBA:GO_Central.
DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; ISS:UniProtKB.
DR GO; GO:0008013; F:beta-catenin binding; IBA:GO_Central.
DR GO; GO:0045296; F:cadherin binding; IBA:GO_Central.
DR GO; GO:0004175; F:endopeptidase activity; IBA:GO_Central.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IBA:GO_Central.
DR GO; GO:0042982; P:amyloid precursor protein metabolic process; ISS:UniProtKB.
DR GO; GO:0034205; P:amyloid-beta formation; ISS:UniProtKB.
DR GO; GO:0050435; P:amyloid-beta metabolic process; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0006816; P:calcium ion transport; IBA:GO_Central.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IBA:GO_Central.
DR GO; GO:0007220; P:Notch receptor processing; IBA:GO_Central.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0043085; P:positive regulation of catalytic activity; ISS:UniProtKB.
DR GO; GO:0016485; P:protein processing; ISS:UniProtKB.
DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0010975; P:regulation of neuron projection development; ISS:UniProtKB.
DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IBA:GO_Central.
DR Gene3D; 1.10.472.100; -; 1.
DR InterPro; IPR002031; Pept_A22A_PS1.
DR InterPro; IPR001108; Peptidase_A22A.
DR InterPro; IPR006639; Preselin/SPP.
DR InterPro; IPR042524; Presenilin_C.
DR PANTHER; PTHR10202; PTHR10202; 1.
DR Pfam; PF01080; Presenilin; 1.
DR PRINTS; PR01072; PRESENILIN.
DR PRINTS; PR01073; PRESENILIN1.
DR SMART; SM00730; PSN; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Apoptosis; Cell adhesion; Cell membrane;
KW Cell projection; Endoplasmic reticulum; Endosome; Golgi apparatus;
KW Hydrolase; Membrane; Notch signaling pathway; Phosphoprotein; Protease;
KW Reference proteome; Synapse; Transmembrane; Transmembrane helix.
FT CHAIN 1..297
FT /note="Presenilin-1 NTF subunit"
FT /evidence="ECO:0000250"
FT /id="PRO_0000236052"
FT CHAIN 298..466
FT /note="Presenilin-1 CTF subunit"
FT /evidence="ECO:0000250"
FT /id="PRO_0000236053"
FT CHAIN 345..466
FT /note="Presenilin-1 CTF12"
FT /evidence="ECO:0000250"
FT /id="PRO_0000236054"
FT TOPO_DOM 1..81
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 82..102
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 103..131
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 132..152
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 153..165
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 166..188
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 189..193
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 194..215
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 216..219
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 220..240
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 241..247
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 248..271
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 272..379
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 380..400
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 401..406
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 407..427
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 428..431
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 432..452
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 453..466
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 1..66
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 287..289
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 304..335
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 321..449
FT /note="Required for interaction with CTNNB1"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 371..398
FT /note="Required for interaction with CTNND2"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 376..380
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 431..433
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 463..466
FT /note="Interaction with MTCH1"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOTIF 432..434
FT /note="PAL"
FT /evidence="ECO:0000305"
FT COMPBIAS 1..31
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 32..47
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 307..324
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 256
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT ACT_SITE 384
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 290..291
FT /note="Cleavage; alternate"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 291..292
FT /note="Cleavage; alternate"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 297..298
FT /note="Cleavage"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 344..345
FT /note="Cleavage; by caspase"
FT MOD_RES 50
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97887"
FT MOD_RES 309
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOD_RES 328
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P97887"
FT MOD_RES 330
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97887"
FT MOD_RES 345
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOD_RES 370
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49769"
FT VAR_SEQ 26..29
FT /note="Missing (in isoform I-462)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_018569"
SQ SEQUENCE 466 AA; 52417 MW; BB78A213744E1F79 CRC64;
MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DSREQHSSER RRRGNPEPLS NGRPQGSSHQ
VVEQDDEEDE ELTLKYGAKH VIMLFVPVTL CMVVVVATIK SVSFYTRKDG QLIYTPFTED
TETVGQRALH SILNAAIMIS VIVVMTILLV VLYKYRCYKV IHAWLIISSL LLLFLFSFIY
LGEVFKTYNV AMDYITVALL IWNFGVVGMI AIHWKGPLRL QQAYLIMISA LMALVFIKYL
PEWTAWLILA VISVYDLVAV LCPKGPLRML VETAQERNET LFPALIYSST MVWLVNMAEG
DPEAQRKVSK NSNYNAQSTE SETQDPVTES DDGGFSEEWE AQRDSRLGPH HSTTETRAAV
QELSSNILAS EDPEERGVKL GLGDFIFYSV LVGKASATAS GDWNTTIACF VAILIGLCLT
LLLLAIFKKA LPALPISITF GLVFYFATDY LVQPFMDQLA FHQFYI
