PSEN1

Presenilin-1 ;
PS-1 ;
Protein S182 ;
[Cleaved into: Presenilin-1 NTF subunit ;
Presenilin-1 CTF subunit ;
Presenilin-1 CTF12 ;
PS1-CTF12 ;
]

disease:Defects in PSEN1 are a cause of Alzheimer disease type 3 (AD3) [MIM:607822]. AD3 is a familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia , loss of cognitve abilities , and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles , extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s) , derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP , are also implicated in neuronal death. ,disease:Defects in PSEN1 are a cause of frontotemporal dementia [MIM:600274]. ,domain:The PAL motif is required for normal active site conformation. ,function: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 (beta-amyloid 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. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx , cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin , thus negatively regulating Wnt signaling. May also play a role in hematopoiesis. ,online information:Presenilins mutations ,PTM:After endoproteolysis , the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis. ,PTM:Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa , respectively. During apoptosis , the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment , PS1-CTF12. ,similarity:Belongs to the peptidase A22A family. ,subcellular location:Bound to NOTCH1 also at the cell surface. Colocalizes with CDH1/2 at sites of cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the proximity of the plasma membrane. Also present in azurophil granules of neutrophils. ,subunit: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. Other components which are associated with the complex include SLC25A64 , SLC5A7 , PHB and PSEN1 isoform 3. Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment. Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) . Associates with NOTCH1. Component of cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2. Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation. Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane. Interacts with CTNND2 , CTNNB1 , HERPUD1 , FLNA , FLNB , MTCH1 , PKP4 and PARL. Interacts through its N-terminus with isoform 3 of GFAP. Interacts with DOCK3. ,tissue specificity:Expressed in a wide range of tissues including various regions of the brain , liver , spleen and lymph nodes. ,

autophagic vacuole formation , MAPKKK cascade , activation of MAPKK activity , skeletal system development , regulation of neurotransmitter levels , blood vessel development , cell fate specification , somitogenesis , neuron migration , cell activation , regulation of protein amino acid phosphorylation , negative regulation of protein amino acid phosphorylation , positive regulation of protein amino acid phosphorylation , hair follicle development , vasculature development , heart looping , hemopoietic progenitor cell differentiation , activation of immune response , cell activation during immune response , lymphocyte activation during immune response , T cell activation during immune response ,leukocyte activation during immune response , immune response-activating cell surface receptor signaling pathway ,immune system development , leukocyte differentiation , myeloid leukocyte differentiation , positive regulation of immune system process , immune response-activating signal transduction , immune response-regulating signal transduction , immune response-regulating cell surface receptor signaling pathway , generation of a signal involved in cell-cell signaling , regionalization , heart morphogenesis , protein amino acid phosphorylation , negative regulation of protein kinase activity , protein amino acid glycosylation , proteolysis , membrane protein ectodomain proteolysis ,glycoprotein catabolic process , phosphorus metabolic process , phosphate metabolic process , ion transport , cation transport , anion transport , neurotransmitter transport , mitochondrial transport , amino acid transport , cellular ion homeostasis , cellular calcium ion homeostasis , cellular metal ion homeostasis , exocytosis , vesicle targeting ,autophagy , apoptosis , anti-apoptosis , induction of apoptosis , cell motion , immune response , response to DNA damage stimulus , response to oxidative stress , vacuole organization , chromosome segregation , cell adhesion , cell surface receptor linked signal transduction , regulation of epidermal growth factor receptor activity , Notch signaling pathway ,Notch receptor processing , intracellular signaling cascade , protein kinase cascade , cell-cell signaling , synaptic transmission , neurotransmitter secretion , pattern specification process , ectoderm development , heart development ,behavior , learning or memory , memory , protein localization , cell death , cell proliferation , epidermis development ,induction of apoptosis by extracellular signals , macromolecule catabolic process , glycoprotein metabolic process ,glycoprotein biosynthetic process , cellular response to starvation , post-embryonic development , embryonic development ending in birth or egg hatching , anterior/posterior pattern formation , dorsal/ventral pattern formation ,response to extracellular stimulus , regulation of receptor activity , positive regulation of phosphorus metabolic process ,negative regulation of phosphorus metabolic process , positive regulation of macromolecule metabolic process ,negative regulation of macromolecule metabolic process , negative regulation of cell development , regulation of cell morphogenesis involved in differentiation , regulation of cell death , positive regulation of cell death , regulation of neuron projection development , programmed cell death , induction of programmed cell death , protein transport ,organic cation transport , quaternary ammonium group transport , organic anion transport , acidic amino acid transport ,L-glutamate transport , amine transport , organic acid transport , organic alcohol transport , choline transport , synaptic vesicle exocytosis , synaptic vesicle targeting , vesicle-mediated transport , macroautophagy , death , phosphorylation ,cell-cell adhesion , cell migration , protein processing , regulation of phosphate metabolic process , transmission of nerve impulse , cellular homeostasis , neural tube patterning , telencephalon development , pallium development ,developmental maturation , cerebral cortex cell migration , Cajal-Retzius cell differentiation , forebrain cell migration ,cerebral cortex neuron differentiation , dorsal/ventral neural tube patterning , neural tube development , cerebral cortex development , telencephalon cell migration , molting cycle process , hair cycle process , regulation of cell morphogenesis ,biological adhesion , cellular cation homeostasis , cellular di- , tri-valent inorganic cation homeostasis , hemopoiesis ,myeloid cell differentiation , protein catabolic process , neuron differentiation , embryonic limb morphogenesis , forebrain development , membrane protein intracellular domain proteolysis , regulation of cell projection organization , negative regulation of cell projection organization , regulation of protein modification process , negative regulation of protein modification process , positive regulation of protein modification process , regulation of neurological system process ,response to nutrient levels , cellular response to extracellular stimulus , cellular response to nutrient levels , activation of protein kinase activity , regulation of cellular protein metabolic process , negative regulation of cellular protein metabolic process , positive regulation of cellular protein metabolic process , endoplasmic reticulum calcium ion homeostasis , secretion by cell , cellular response to stress , membrane protein proteolysis , negative regulation of kinase activity , positive regulation of kinase activity , appendage morphogenesis , limb morphogenesis , embryonic appendage morphogenesis , tube morphogenesis , segmentation , tube development , growth , regulation of epidermal growth factor receptor signaling pathway , T cell activation , molting cycle , regulation of phosphorylation , negative regulation of phosphorylation , positive regulation of phosphorylation , regulation of membrane potential , homeostatic process , response to starvation , hair cycle , anagen , regulation of apoptosis , amyloid precursor protein metabolic process , amyloid precursor protein catabolic process , chordate embryonic development , positive regulation of apoptosis , negative regulation of apoptosis , regulation of programmed cell death , positive regulation of programmed cell death , negative regulation of programmed cell death , positive regulation of catalytic activity , negative regulation of catalytic activity , regulation of protein binding , regulation of MAP kinase activity , positive regulation of MAP kinase activity , biopolymer glycosylation , regulation of neuron apoptosis , negative regulation of neuron apoptosis , regulation of kinase activity , regulation of system process , negative regulation of molecular function , positive regulation of molecular function , cellular protein catabolic process , cellular macromolecule catabolic process , cell fate commitment ,establishment of protein localization , leukocyte activation , negative regulation of cell differentiation , regulation of neuron differentiation , regulation of protein kinase activity , positive regulation of protein kinase activity , negative regulation of phosphate metabolic process , positive regulation of phosphate metabolic process , lymphocyte activation ,secretion , intracellular transport , carboxylic acid transport , regulation of synaptic plasticity , synaptic vesicle transport ,hemopoietic or lymphoid organ development , thymus development , positive regulation of response to stimulus ,developmental growth , embryonic morphogenesis , neuron development , skeletal system morphogenesis , appendage development , hair follicle maturation , brain morphogenesis , cell motility , chemical homeostasis , beta-amyloid metabolic process , epithelial cell proliferation , regulation of neurogenesis , negative regulation of neurogenesis , regulation of axonogenesis , negative regulation of axonogenesis , positive regulation of immune response , ion homeostasis ,regulation of synaptic transmission , regulation of coagulation , positive regulation of coagulation , antigen receptor-mediated signaling pathway , T cell receptor signaling pathway , neurological system process , cognition , regulation of binding , negative regulation of cellular component organization , regulation of phosphorus metabolic process , positive regulation of multicellular organismal process , positive regulation of protein metabolic process , negative regulation of protein metabolic process , regulation of transferase activity , positive regulation of transferase activity , negative regulation of transferase activity , neuron apoptosis , smooth endoplasmic reticulum calcium ion homeostasis ,proteolysis involved in cellular protein catabolic process , protein maturation , protein maturation by peptide bond cleavage , organelle localization , vesicle localization , establishment of vesicle localization , establishment of organelle localization , localization of cell , regulation of nervous system development , regulation of synaptic transmission , glutamatergic , regulation of transmission of nerve impulse , metal ion homeostasis , di- , tri-valent inorganic cation homeostasis , calcium ion homeostasis , cation homeostasis , cellular chemical homeostasis , regulation of resting membrane potential , limb development , regulation of cell development , negative regulation of cell death ,glycosylation ,

Endoplasmic reticulum . Endoplasmic reticulum membrane ; Multi-pass membrane protein . Golgi apparatus membrane ; Multi-pass membrane protein . Cytoplasmic granule . Cell membrane ; Multi-pass membrane protein . Cell projection , growth cone . Early endosome . Early endosome membrane ; Multi-pass membrane protein . Cell projection , neuron projection . Cell projection , axon . Cell junction , synapse . Translocates with bound NOTCH1 from the endoplasmic reticulum and/or Golgi to the cell surface (PubMed:10593990) . Colocalizes with CDH1/2 at sites of cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the proximity of the plasma membrane (PubMed:9738936) . Also present in azurophil granules of neutrophils (PubMed:11987239) . Colocalizes with UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures called aggresomes (PubMed:21143716) . .