Reviewed,
UniProtKB/Swiss-Prot P12023 (A4_MOUSE)
Last modified
July 22, 2008.
Version 118.
History...
Clusters with 100%,
90%,
50% identity |
Documents (4) |
Third-party data |
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Names and origin
| Protein names | Recommended name: Amyloid beta A4 protein Alternative name(s): Alzheimer disease amyloid A4 protein homolog ABPP Short name(s)=APP Amyloidogenic glycoprotein Short name(s)=AG Cleaved into 12 chains: Recommended name: Soluble APP-alpha Short name(s)=S-APP-alpha Recommended name: Soluble APP-beta Short name(s)=S-APP-beta Recommended name: C99 Alternative name(s): APP-C99 Recommended name: Beta-amyloid protein 42 Alternative name(s): Beta-APP42 Recommended name: Beta-amyloid protein 40 Alternative name(s): Beta-APP40 Recommended name: C83 Recommended name: P3(42) Recommended name: P3(40) Recommended name: Gamma-secretase C-terminal fragment 59 Alternative name(s): Gamma-CTF(59) Amyloid intracellular domain 59 Short name(s)=AID(59) APP-C59 Recommended name: Gamma-secretase C-terminal fragment 57 Alternative name(s): Gamma-CTF(57) Amyloid intracellular domain 57 Short name(s)=AID(57) APP-C57 Recommended name: Gamma-secretase C-terminal fragment 50 Alternative name(s): Gamma-CTF(50) Amyloid intracellular domain 50 Short name(s)=AID(50) Recommended name: C31 | ||
| Gene names |
| ||
| Organism | Mus musculus (Mouse) | ||
| Taxonomic identifier | 10090 [NCBI] | ||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus |
Protein attributes
| Sequence length | 770 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is further processed into a mature form. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1/Tip60 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. 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 By similarity. Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation By similarity. The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis. |
| Subunit structure | Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1, Numb and Dab1. Binding to Dab1 inhibits its serine phosphorylation. Also interacts with GPCR-like protein BPP, FPRL1, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1 By similarity. In vitro, it binds MAPT via the MT-binding domains By similarity. Associates with microtubules in the presence of ATP and in a kinesin-dependent manner By similarity. Interacts, through a C-terminal domain, with GNAO1 By similarity. Amyloid beta-42 binds CHRNA7 in hippocampal neurons By similarity. Beta-amyloid associates with HADH2 By similarity. Interacts with ANKS1B By similarity. Interacts with CPEB1. |
| Subcellular location | Membrane; Single-pass type I membrane protein. Membrane › clathrin-coated pit. Note= Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with Fe65. Beta-APP42 associates with FPRL1 at the cell surface and the complex is then rapidly internalized By similarity. APP sorts to the basolateral surface in epithelial cells By similarity. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment By similarity. |
| Tissue specificity | Isoform APP770 is expressed in kidney. Isoform APP751 is widely expressed. Isoform APP695 is expressed in brain, kidney and liver. Isoform APP695, isoform APP714 and isoform APP751 are expressed in several different brain regions including hippocampus, substania nigra pars compacta and cerebellum. In the cerebellum, these isoforms are abundantly expressed in Purkinje cells. |
| Domain | The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells. 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 NPXY site is also involved in clathrin-mediated endocytosis By similarity. |
| Post-translational modification | Proteolytically processed under normal cellular conditions. Cleavage by alpha-secretase or alternatively by beta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, respectively, and the retention of corresponding membrane-anchored C-terminal fragments, C83 and C99. Subsequent processing of 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 40 (Abeta40) and amyloid-beta 42 (Abeta42), major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides By similarity. N- and O-glycosylated By similarity. Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members By similarity. Phosphorylation on Tyr-757 is required for SHC binding 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 By similarity. |
| Miscellaneous | Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. Rat and mouse beta-amyloid peptides have an arginine residue substituted for the bridging histidine residue and are thus less capable of forming amyloid aggegates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding By similarity. |
| Sequence similarities | Belongs to the APP family. Contains 1 BPTI/Kunitz inhibitor domain. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| Apba2 | P98084 | 1 | EBI-78814,EBI-81669 | |
| Apbb1 | Q9QXJ1 | 1 | EBI-78814,EBI-81338 | |
| Dab1 | P97318 | 1 | EBI-78814,EBI-81680 | |
| MAPK8IP1 | Q9UQF2 | 1 | EBI-78814,EBI-78404 | From a different organism. |
| MAPK8IP1 | Q9UQF2 | 1 | EBI-286828,EBI-78404 | From a different organism. |
| Mapk8ip1 | Q9WVI9 | 2 | EBI-78814,EBI-74515 | |
| Mapk8ip1 | Q9WVI9-1 | 2 | EBI-78814,EBI-288461 | |
| Mapk8ip1 | Q9WVI9-1 | 1 | EBI-286828,EBI-288461 | |
| Shc3 | Q61120 | 1 | EBI-78814,EBI-79107 |
Alternative products
| This entry describes 4 isoforms produced by alternative splicing. [Align] [Select] Notes: Additional isoforms seem to exist. | |||||
| Isoform APP770 (identifier: P12023-1) This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. | |||||
| Isoform APP695 (identifier: P12023-2) The sequence of this isoform differs from the canonical sequence as follows: 289-289: E → V 290-364: Missing. | |||||
| Isoform APP751 (identifier: P12023-3) The sequence of this isoform differs from the canonical sequence as follows: 346-380: Missing. | |||||
| Isoform APP714 (identifier: P12023-4) The sequence of this isoform is not available. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | ||||||
Molecule processing | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Signal peptide | 1 – 17 | 17 | By similarity | |||||||
| Chain | 18 – 770 | 753 | Amyloid beta A4 protein | |||||||
| Chain | 18 – 687 | 670 | Soluble APP-alpha Potential | |||||||
| Chain | 18 – 671 | 654 | Soluble APP-beta Potential | |||||||
| Chain | 672 – 770 | 99 | C99 By similarity | |||||||
| Chain | 672 – 713 | 42 | Beta-amyloid protein 42 By similarity | |||||||
| Chain | 672 – 711 | 40 | Beta-amyloid protein 40 By similarity | |||||||
| Chain | 688 – 770 | 83 | C83 By similarity | |||||||
| Peptide | 688 – 713 | 26 | P3(42) By similarity | |||||||
| Peptide | 688 – 711 | 24 | P3(40) By similarity | |||||||
| Chain | 712 – 770 | 59 | Gamma-secretase C-terminal fragment 59 | |||||||
| Chain | 714 – 770 | 57 | Gamma-secretase C-terminal fragment 57 | |||||||
| Chain | 721 – 770 | 50 | Gamma-secretase C-terminal fragment 50 | |||||||
| Chain | 740 – 770 | 31 | C31 By similarity | |||||||
Regions | ||||||||||
| Topological domain | 18 – 699 | 682 | Extracellular Potential | |||||||
| Transmembrane | 700 – 723 | 24 | Potential | |||||||
| Topological domain | 724 – 770 | 47 | Cytoplasmic Potential | |||||||
| Domain | 291 – 341 | 51 | BPTI/Kunitz inhibitor | |||||||
| Region | 96 – 110 | 15 | Heparin-binding By similarity | |||||||
| Region | 181 – 188 | 8 | Zinc-binding By similarity | |||||||
| Region | 391 – 423 | 33 | Heparin-binding By similarity | |||||||
| Region | 491 – 522 | 32 | Heparin-binding By similarity | |||||||
| Region | 523 – 540 | 18 | Collagen-binding By similarity | |||||||
| Region | 732 – 751 | 20 | Interaction with G(o)-alpha By similarity | |||||||
| Motif | 724 – 734 | 11 | Basolateral sorting signal | |||||||
| Motif | 759 – 762 | 4 | NPXY motif; contains endocytosis signal | |||||||
| Compositional bias | 230 – 260 | 31 | Asp/Glu-rich (acidic) | |||||||
| Compositional bias | 274 – 280 | 7 | Poly-Thr | |||||||
Sites | ||||||||||
| Metal binding | 137 | 1 | Copper By similarity | |||||||
| Metal binding | 147 | 1 | Copper By similarity | |||||||
| Metal binding | 149 | 1 | Copper By similarity | |||||||
| Metal binding | 151 | 1 | Copper Probable | |||||||
| Metal binding | 677 | 1 | Copper or zinc By similarity | |||||||
| Metal binding | 685 | 1 | Copper or zinc By similarity | |||||||
| Site | 144 | 1 | Required for Cu(2+) reduction By similarity | |||||||
| Site | 301 – 302 | 2 | Reactive bond By similarity | |||||||
| Site | 671 – 672 | 2 | Cleavage; by beta-secretase By similarity | |||||||
| Site | 672 – 673 | 2 | Cleavage; by caspase-6 By similarity | |||||||
| Site | 687 – 688 | 2 | Cleavage; by alpha-secretase By similarity | |||||||
| Site | 704 | 1 | Implicated in free radical propagation By similarity | |||||||
| Site | 706 | 1 | Susceptible to oxidation By similarity | |||||||
| Site | 711 – 712 | 2 | Cleavage; by gamma-secretase; site 1 By similarity | |||||||
| Site | 713 – 714 | 2 | Cleavage; by gamma-secretase; site 2 By similarity | |||||||
| Site | 720 – 721 | 2 | Cleavage; by gamma-secretase; site 3 By similarity | |||||||
| Site | 739 – 740 | 2 | Cleavage; by caspase-6, caspase-8 or caspase-9 By similarity | |||||||
Amino acid modifications | ||||||||||
| Modified residue | 198 | 1 | Phosphoserine; by CK2 By similarity | |||||||
| Modified residue | 206 | 1 | Phosphoserine; by CK1 By similarity | |||||||
| Modified residue | 729 | 1 | Phosphothreonine By similarity | |||||||
| Modified residue | 730 | 1 | Phosphoserine; by APP-kinase I By similarity | |||||||
| Modified residue | 743 | 1 | Phosphothreonine; by CDK5 and MAPK10 | |||||||
| Modified residue | 757 | 1 | Phosphotyrosine By similarity | |||||||
| Glycosylation | 542 | 1 | N-linked (GlcNAc...) Probable | |||||||
| Glycosylation | 571 | 1 | N-linked (GlcNAc...) Probable | |||||||
| Disulfide bond | 144 ↔ 158 | By similarity | ||||||||
| Disulfide bond | 291 ↔ 341 | By similarity | ||||||||
| Disulfide bond | 300 ↔ 324 | By similarity | ||||||||
| Disulfide bond | 316 ↔ 337 | By similarity | ||||||||
Natural variations | ||||||||||
| Alternative sequence | 289 | 1 | E → V in isoform APP695. | |||||||
| Alternative sequence | 290 – 364 | 75 | Missing in isoform APP695. | |||||||
| Alternative sequence | 346 – 380 | 35 | Missing in isoform APP751. | |||||||
Experimental info | ||||||||||

Clusters with