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App

Developmental stage

Expressed in 4 to 24 week old mice.

Domain

The transmembrane helix undergoes a conformation change and unravels partially when bound to PSEN1, facilitating cleavage by PSEN1.

The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.

The GFLD subdomain binds Cu(2+) ions; this promotes homodimerization.

The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The YENPXY site is also involved in clathrin-mediated endocytosis.

The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers.

The OX-2 motif shows some similarity to a region in the N-terminus of CD200/MOX2.

Function

Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). By acting as a kinesin I membrane receptor, plays a role in axonal anterograde transport of cargo towards synapses in axons (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons (By similarity). Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.

Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse amyloid-beta peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Amyloid-beta protein 42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also binds GPC1 in lipid rafts (By similarity).

The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.

Post-translational modifications

Proteolytically processed under normal cellular conditions (PubMed:11553691, PubMed:23931995). Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99 (PubMed:11553691, PubMed:23931995). Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid-beta proteins, amyloid-beta protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase (By similarity).

Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either CASP6, CASP8 or CASP9 results in the production of the neurotoxic C31 peptide and the increased production of amyloid-beta peptides.

N- and O-glycosylated.

Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific (By similarity). Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins (By similarity). Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta (By similarity). The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (By similarity). In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis (PubMed:28720718). Phosphorylation on Tyr-757 is required for SHC binding (By similarity). Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP (By similarity). This phosphorylation is inhibited by heparin (By similarity).

Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond.

Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP).

Amyloid-beta peptides are degraded by IDE.

Sulfated on tyrosine residues.

Sequence Similarities

Belongs to the APP family.

Tissue Specificity

Expressed in the brain with expression in cortex, cerebellum, hippocampus, olfactory bulb, neurons, astrocytes and microglia (at protein level) (PubMed:25757569, PubMed:26260791, PubMed:28720718). Expressed in the retinal lens (PubMed:25757569). Expressed at a low level in muscle cells (at protein level) (PubMed:25757569).

Isoform APP770

Expressed in kidney.

Isoform APP751

Widely expressed (PubMed:8510506). Expressed in several different brain regions including hippocampus, substantia nigra pars compacta and cerebellum (PubMed:8510506). Within the cerebellum, abundantly expressed in Purkinje cells (PubMed:8510506).

Isoform APP695

Expressed in the brain, kidney and liver (PubMed:8510506). Expressed in several different brain regions including hippocampus, substantia nigra pars compacta and cerebellum (PubMed:8510506). Within the cerebellum, abundantly expressed in Purkinje cells (PubMed:8510506).

Isoform APP714

Expressed in several different brain regions including hippocampus, substantia nigra pars compacta and cerebellum (PubMed:8510506). Within the cerebellum, abundantly expressed in Purkinje cells (PubMed:8510506).

Cellular localization

Alternative names

A4, AD1, App, Amyloid-beta precursor protein, ABPP, Alzheimer disease amyloid A4 protein homolog, Alzheimer disease amyloid protein, Amyloid precursor protein, Amyloid-beta (A4) precursor protein, Amyloid-beta A4 protein, Amyloidogenic glycoprotein, APP, AG

swissprot:P12023 entrezGene:11820