PSN1_MICMU
ID PSN1_MICMU Reviewed; 467 AA.
AC P79802;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 03-AUG-2022, entry version 118.
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; Synonyms=PS1, PSNL1;
OS Microcebus murinus (Gray mouse lemur) (Lemur murinus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Strepsirrhini; Lemuriformes;
OC Cheirogaleidae; Microcebus.
OX NCBI_TaxID=30608;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS I-463 AND I-467), AND TISSUE
RP SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=8920931; DOI=10.1006/bbrc.1996.1678;
RA Calenda A., Mestre-Frances N., Czech C., Pradier L., Bons N., Bellis M.;
RT "Molecular cloning, sequencing, and brain expression of the presenilin 1
RT gene in Microcebus murinus.";
RL Biochem. Biophys. Res. Commun. 228:430-439(1996).
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. Interaction with CDH1 stabilizes the complex and stimulates
CC cell-cell aggregation. Interaction with CDH2 is essential for
CC trafficking of CDH2 from the endoplasmic reticulum to the plasma
CC membrane. Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1, FLNA,
CC FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with GFAP
CC (By similarity). Interacts with DOCK3 (By similarity). Interacts with
CC UBQLN1 (By similarity). {ECO:0000250|UniProtKB:P49768,
CC ECO:0000250|UniProtKB:P49769}.
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-467;
CC IsoId=P79802-1; Sequence=Displayed;
CC Name=I-463;
CC IsoId=P79802-2; Sequence=VSP_005193;
CC -!- TISSUE SPECIFICITY: Found predominantly in neurons of the different
CC cortical layers and hippocampus but also in subcortical structures.
CC {ECO:0000269|PubMed:8920931}.
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-346 inhibits endoproteolysis. {ECO:0000250|UniProtKB:P49768}.
CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}.
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DR EMBL; Z71333; CAA95930.1; -; mRNA.
DR PIR; JC5080; JC5080.
DR PIR; JC5081; JC5081.
DR RefSeq; NP_001296874.1; NM_001309945.1. [P79802-1]
DR AlphaFoldDB; P79802; -.
DR SMR; P79802; -.
DR MEROPS; A22.001; -.
DR GeneID; 105858213; -.
DR KEGG; mmur:105858213; -.
DR CTD; 5663; -.
DR OrthoDB; 797738at2759; -.
DR Proteomes; UP000694394; Unplaced.
DR GO; GO:0016235; C:aggresome; ISS:UniProtKB.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
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:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0043005; C:neuron projection; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; ISS:UniProtKB.
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:0006915; P:apoptotic process; IEA:UniProtKB-KW.
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: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 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..298
FT /note="Presenilin-1 NTF subunit"
FT /evidence="ECO:0000250"
FT /id="PRO_0000025593"
FT CHAIN 299..467
FT /note="Presenilin-1 CTF subunit"
FT /evidence="ECO:0000250"
FT /id="PRO_0000025594"
FT CHAIN 346..467
FT /note="Presenilin-1 CTF12"
FT /evidence="ECO:0000250"
FT /id="PRO_0000236057"
FT TOPO_DOM 1..82
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 83..103
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 104..132
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 133..153
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 154..166
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 167..189
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 190..194
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 195..216
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 217..220
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 221..241
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 242..248
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 249..272
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 273..380
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 381..401
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 402..407
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 408..428
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 429..432
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TRANSMEM 433..453
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT TOPO_DOM 454..467
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 1..69
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 288..290
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 305..354
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 322..450
FT /note="Required for interaction with CTNNB1"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 372..399
FT /note="Required for interaction with CTNND2"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 377..381
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 432..434
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT REGION 464..467
FT /note="Interaction with MTCH1"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOTIF 433..435
FT /note="PAL"
FT /evidence="ECO:0000305"
FT COMPBIAS 1..30
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 31..47
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 310..325
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 257
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT ACT_SITE 385
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 291..292
FT /note="Cleavage; alternate"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 292..293
FT /note="Cleavage; alternate"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 298..299
FT /note="Cleavage"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT SITE 345..346
FT /note="Cleavage; by caspase"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOD_RES 51
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97887"
FT MOD_RES 310
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOD_RES 346
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOD_RES 367
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49768"
FT MOD_RES 371
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49769"
FT VAR_SEQ 26..29
FT /note="Missing (in isoform I-463)"
FT /evidence="ECO:0000303|PubMed:8920931"
FT /id="VSP_005193"
SQ SEQUENCE 467 AA; 52385 MW; D986FF2CA7F2975C CRC64;
MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNREQQDHGD RRRLGNPEPL SNGRPQGNSG
PVVERDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE
DTETVGQRAL HSVLNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI
YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY
LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE
GDPEAQRRVS KNTKYNAQGT EREAQASVPE NDDGGFSEEW EAQRDSQLGP HRSTSVSRAA
VQEISSSIPA SEDPEERGVK LGLGDFVFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL
TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI
