Phospho-Presenilin 1 (Ser353) Antibody - #AF8304

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 (By similarity). 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 (By similarity).

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.

After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.

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.
Note: 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).

Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level). Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes.

Homodimer. The functional gamma-secretase complex is composed of at least four polypeptides: 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) (via transmembrane domain). Associates with NOTCH1 (via transmembrane domain). Associates with 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, CTNND1, JUP, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with isoform 3 of GFAP. Interacts with DOCK3 (By similarity). Interacts with isoform 1 and isoform 3 of UBQLN1.

The PAL motif is required for normal active site conformation.

Substrates, such as NOTCH1 and APP peptides, are bound between PSEN1 transmembrane domains and via the first lumenal loop and the cytoplasmic loop between the sixth and seventh transmembrane domains. Substrate binding causes a conformation change and formation of an intermolecular antiparallel beta-sheet between PSEN1 and its substrates.

Belongs to the peptidase A22A family.