motifs/domains
| nine transmembrane segments (9TM), and role of TMD9 in the formation of the catalytic pore and the substrate entry, crucial to the unusual mode of intramembrane proteolysis by gamma-secretase  |
|
cytoplasmic N (NTF) and C terminal (CTF) fragments |
|
a large cytoplasmic loop (HL-VI) between transmembrane segments 6 and 7, including two aspartates, endoproteolytically processed within the region of HL-VI, interacting with Rab11 |
|
a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin-binding domain (UBD), mediating non-covalent binding to Lysine 63-linked polyubiquitin chains |
|
C-terminal PAL sequence implicated in active site conformation and catalytic activity , and the hydrophobic C-terminal tip, both being critical for the catalytic activity and the formation of the gamma-secretase complex |
SUBCELLULAR LOCALIZATION
| plasma membrane
|
| intracellular
|
|
| intracellular,cytoplasm,organelle,mitochondria
|
|
| intracellular,cytoplasm,organelle,membrane
|
|
| intracellular,cytoplasm,organelle,endoplasmic reticulum
|
|
| intracellular,cytoplasm,organelle,Golgi
|
|
| intracellular,cytoplasm,organelle,lysosome
|
|
| intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
|
|
| intracellular,nucleus,chromatin/chromosome,kinetochore
|
| text
| ubiquitous transmembrane protein |
|
expressed in mitochondria-associated membranes (MAM) - a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria |
| basic FUNCTION
| plays a widespread role in embryogenesis |
|
required for efficient proteolysis of both Notch and beta-amyloid precursor protein within their trans- membrane domains |
|
plays a pivotal role in the production of the amyloid-beta protein |
|
an effective antiapoptotic molecule capable of significantly inhibiting p53-dependent and p53-independent cell death |
|
controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis |
|
regulates the gamma-secretase proteolysis of the amyloid precursor protein (APP) C-terminal fragment (APP-C100) |
|
membrane receptor for GDI1 and involved in the cleavage activity of APP (generation of A beta 42/43)and, independently endoproteolysis of NOTCHs |
|
involved in the cleavage activity of APP or indirectly and NOTCH either by putative intrinsic aspartyl protease (gamma secretase) activity |
|
essential components of the gamma-secretase complex, which cleaves APP to affect Abeta processing |
|
participating to the regulation of neurite growth and stabilization in both developing and differentiated neurons |
|
essential for efficient trafficking of N-cadherin (CDH2) from the ER to the plasma membrane |
|
member of the gamma-secretase complex, playing a role, with PSENEN, NCSTN, APH1A, necessary and sufficient to reconstitute gamma-secretase activity |
|
plays a critical role in the gamma-secretase processing of the amyloid precursor protein to generate the beta-amyloid peptide, which accumulates in plaques in the pathogenesis of Alzheimer's disease (AD) |
|
essential roles in synaptic plasticity, learning and memory, and neuronal survival in the adult cerebral cortex |
|
may prevent development of Alzheimer's disease by activating PI3K/Akt signaling pathway |
|
can modifie lipid raft composition of neuronal membranes |
|
essential role in the maturation and trafficking of the v-ATPase responsible for lysosome acidification and proteolysis during autophagy |
|
required for lysosomal turnover of autophagic and endocytic protein substrates |
|
PSEN1 function is required to control the spatiotemporal pattern of axonal responses to Netrin by coordinating the activity of different signaling pathways |
|
directly influences Netrin/DCC signaling with cell type precision and spatiotemporal specificity, and is a key neural circuit builder that gates the spatiotemporal pattern of guidance signaling, thereby ensuring neural projections occur with high fidelity |
|
not modulating the Ca2+ shuttling between ER and mitochondria |
|
physiological role in adult neurogenesis, and potential target for the manipulation of neural progenitor cell differentiation |
|
phosphorylated PSEN1 can promote the down-regulation of insulin signaling, which may be a positive feed-forward mechanism inhibiting insulin signaling |
|
intramembrane aspartyl protease that regulate important biological functions |
|
regulates the constitutive turnover of the fibronectin matrix in endothelial cells |
|
PSEN1, PSEN2 are novel substrates for TRAF6-mediated K63-linked ubiquitination and ubiquitination of presenilins by TRAF6 increases presenilin holoprotein levels and reduced TRAF6 ubiquitination of presenilins results in reduction of calcium release from the endoplasmic reticulum |
|
PSEN1, PSEN2 regulates calcium homeostasis and synaptic function via ryanodine receptor (RyR), suggesting that disruption of intracellular calcium homeostasis may be an early pathogenic event leading to presynaptic dysfunction in Alzheimer disease |
|
PSEN1, PSEN2 encode the major component of gamma-secretase, which is responsible for sequential proteolytic cleavages of amyloid precursor proteins and the subsequent formation of amyloid-beta peptides |
|
PSEN1, PSEN2 regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer disease |
