Reviewed, UniProtKB/Swiss-Prot P12023 (A4_MOUSE)

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

Name:

App

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

Keywords
Biological process	Apoptosis Cell adhesion Endocytosis Notch signaling pathway
Cellular component	Coated pit Membrane
Coding sequence diversity	Alternative splicing
Disease	Amyloid
Domain	Signal Transmembrane
Ligand	Copper Heparin-binding Iron Metal-binding Zinc
Molecular function	Protease inhibitor Serine protease inhibitor
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	G2 phase of mitotic cell cycle Inferred from mutant phenotype. Source: MGI adult locomotory behavior Inferred from mutant phenotype. Source: MGI axon cargo transport Inferred from mutant phenotype. Source: MGI axon midline choice point recognition Inferred from mutant phenotype. Source: MGI cellular copper ion homeostasis Inferred from mutant phenotype. Source: MGI collateral sprouting in the absence of injury Inferred from genetic interaction. Source: MGI dendrite development Inferred from mutant phenotype. Source: MGI endocytosis Inferred from mutant phenotype. Source: MGI extracellular matrix organization and biogenesis Inferred from genetic interaction. Source: MGI forebrain development Inferred from mutant phenotype. Source: MGI ionotropic glutamate receptor signaling pathway Inferred from mutant phenotype. Source: MGI mRNA polyadenylation Ref.16 Inferred from direct assay. Source: MGI mating behavior Inferred from genetic interaction. Source: MGI neuromuscular process controlling balance Inferred from genetic interaction. Source: MGI neuron remodeling Inferred from mutant phenotype. Source: MGI positive regulation of mitotic cell cycle Inferred from mutant phenotype. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: MGI protein amino acid phosphorylation Inferred from mutant phenotype. Source: MGI regulation of epidermal growth factor receptor activity Inferred from genetic interaction. Source: MGI regulation of multicellular organism growth Inferred from mutant phenotype. Source: MGI regulation of synapse structure and activity Inferred from mutant phenotype. Source: MGI regulation of translation Ref.16 Inferred from direct assay. Source: MGI smooth endoplasmic reticulum calcium ion homeostasis Inferred from genetic interaction. Source: MGI suckling behavior Inferred from genetic interaction. Source: MGI synaptic growth at neuromuscular junction Inferred from genetic interaction. Source: MGI visual learning Inferred from mutant phenotype. Source: MGI
Cellular component	Golgi apparatus Inferred from direct assay. Source: MGI apical part of cell Inferred from direct assay. Source: MGI axon Inferred from direct assay. Source: MGI ciliary rootlet Inferred from direct assay. Source: MGI cytoplasmic vesicle Inferred from direct assay. Source: MGI integral to membrane Inferred from direct assay. Source: MGI membrane fraction Inferred from direct assay. Source: MGI neuromuscular junction Inferred from direct assay. Source: MGI perinuclear region of cytoplasm Inferred from direct assay. Source: MGI spindle midzone Inferred from direct assay. Source: MGI
Molecular function	DNA binding Inferred from direct assay. Source: MGI protein binding Ref.12 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

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