InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: App

Summary

InnateDB Protein

IDBP-172956.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

App

Protein Name

amyloid beta (A4) precursor protein

Synonyms

Abeta; Abpp; Adap; Ag; betaApp; Cvap; E030013M08Rik;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000005406

InnateDB Gene

IDBG-172954 (App)

Protein Structure

UniProt Annotation

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-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. 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. {ECO:0000250, ECO:0000269PubMed:15677459}.Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds 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. Also bind GPC1 in lipid rafts (By similarity). {ECO:0000250}.The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis. {ECO:0000269PubMed:15677459}.N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6). {ECO:0000250}.

Subcellular Localization

Membrane {ECO:0000269PubMed:15677459}; Single-pass type I membrane protein {ECO:0000269PubMed:15677459}. Membrane, clathrin-coated pit {ECO:0000269PubMed:15677459}. 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 APBB1 (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. Associates with GPC1 in perinuclear compartments. {ECO:0000250}.

Disease Associations

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. {ECO:0000269PubMed:8510506}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 63 experimentally validated interaction(s) in this database.
They are also associated with 1813 interaction(s) predicted by orthology.

Experimentally validated
Total	63 [view]
Protein-Protein	57 [view]
Protein-DNA	6 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	1813 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003677	DNA binding
GO:0004867	serine-type endopeptidase inhibitor activity
GO:0005102	receptor binding
GO:0005515	protein binding
GO:0008201	heparin binding
GO:0016504	peptidase activator activity
GO:0019899	enzyme binding
GO:0033130	acetylcholine receptor binding
GO:0042802	identical protein binding
GO:0046914	transition metal ion binding
GO:0051425	PTB domain binding
GO:0070851	growth factor receptor binding

Biological Process

GO:0001967	suckling behavior
GO:0006378	mRNA polyadenylation
GO:0006417	regulation of translation
GO:0006468	protein phosphorylation
GO:0006878	cellular copper ion homeostasis
GO:0006897	endocytosis
GO:0006979	response to oxidative stress
GO:0007155	cell adhesion
GO:0007176	regulation of epidermal growth factor-activated receptor activity
GO:0007219	Notch signaling pathway
GO:0007409	axonogenesis
GO:0007617	mating behavior
GO:0007626	locomotory behavior
GO:0008088	axon cargo transport
GO:0008203	cholesterol metabolic process
GO:0008344	adult locomotory behavior
GO:0008542	visual learning
GO:0010468	regulation of gene expression
GO:0010951	negative regulation of endopeptidase activity
GO:0010952	positive regulation of peptidase activity
GO:0010971	positive regulation of G2/M transition of mitotic cell cycle
GO:0016199	axon midline choice point recognition
GO:0016322	neuron remodeling
GO:0016358	dendrite development
GO:0030198	extracellular matrix organization
GO:0030900	forebrain development
GO:0031175	neuron projection development
GO:0035235	ionotropic glutamate receptor signaling pathway
GO:0040014	regulation of multicellular organism growth
GO:0043393	regulation of protein binding
GO:0045665	negative regulation of neuron differentiation
GO:0045931	positive regulation of mitotic cell cycle
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0048669	collateral sprouting in absence of injury
GO:0050803	regulation of synapse structure and activity
GO:0050885	neuromuscular process controlling balance
GO:0051124	synaptic growth at neuromuscular junction
GO:0051260	protein homooligomerization
GO:0051402	neuron apoptotic process
GO:0051563	smooth endoplasmic reticulum calcium ion homeostasis

Cellular Component

GO:0005615	extracellular space
GO:0005641	nuclear envelope lumen
GO:0005737	cytoplasm
GO:0005794	Golgi apparatus
GO:0005886	plasma membrane
GO:0005905	coated pit
GO:0005911	cell-cell junction
GO:0009986	cell surface
GO:0016020	membrane
GO:0016021	integral component of membrane
GO:0030134	ER to Golgi transport vesicle
GO:0030424	axon
GO:0031410	cytoplasmic vesicle
GO:0031594	neuromuscular junction
GO:0035253	ciliary rootlet
GO:0043005	neuron projection
GO:0043197	dendritic spine
GO:0043198	dendritic shaft
GO:0043231	intracellular membrane-bounded organelle
GO:0043235	receptor complex
GO:0045121	membrane raft
GO:0045177	apical part of cell
GO:0045202	synapse
GO:0048471	perinuclear region of cytoplasm
GO:0051233	spindle midzone
GO:0070062	extracellular vesicular exosome

Protein Structure and Domains

PDB ID

MGI:88059

InterPro

IPR008154 Amyloidogenic glycoprotein, extracellular
IPR008155 Amyloidogenic glycoprotein
IPR011178 Amyloidogenic glycoprotein, copper-binding
IPR013803 Amyloidogenic glycoprotein, amyloid-beta peptide
IPR015849 Amyloidogenic glycoprotein, heparin-binding
IPR019543 Beta-amyloid precursor protein C-terminal
IPR024329 Amyloidogenic glycoprotein, E2 domain

PFAM

PF12924
PF03494
PF02177
PF10515
PF12925

PRINTS

PR00203
PR00204

PIRSF

SMART

SM00006

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt