InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: APP

Summary

InnateDB Protein

IDBP-1104.7

Last Modified

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

Gene Symbol

APP

Protein Name

amyloid beta (A4) precursor protein

Synonyms

AAA; ABETA; ABPP; AD1; APPI; CTFgamma; CVAP; PN-II; PN2;

Species

Homo sapiens

Ensembl Protein

ENSP00000351796

InnateDB Gene

IDBG-1100 (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 inhibits 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. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. 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. 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}.Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. {ECO:0000250}.The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).

Subcellular Localization

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 APBB1 (Fe65). Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. 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. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions.

Disease Associations

Alzheimer disease 1 (AD1) [MIM:104300]: A familial early- onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. {ECO:0000269PubMed:10097173, ECO:0000269PubMed:10631141, ECO:0000269PubMed:10665499, ECO:0000269PubMed:10867787, ECO:0000269PubMed:11063718, ECO:0000269PubMed:11528419, ECO:0000269PubMed:12034808, ECO:0000269PubMed:1302033, ECO:0000269PubMed:1303239, ECO:0000269PubMed:1303275, ECO:0000269PubMed:1415269, ECO:0000269PubMed:15201367, ECO:0000269PubMed:15365148, ECO:0000269PubMed:15668448, ECO:0000269PubMed:1671712, ECO:0000269PubMed:1678058, ECO:0000269PubMed:1908231, ECO:0000269PubMed:1925564, ECO:0000269PubMed:1944558, ECO:0000269PubMed:8267572, ECO:0000269PubMed:8290042, ECO:0000269PubMed:8476439, ECO:0000269PubMed:8577393, ECO:0000269PubMed:9328472, ECO:0000269PubMed:9754958}. Note=The disease is caused by mutations affecting the gene represented in this entry.Cerebral amyloid angiopathy, APP-related (CAA-APP) [MIM:605714]: A hereditary localized amyloidosis due to amyloid- beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque- like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex- opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra- striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non- neuronal cells. Isoform APP751 is the most abundant form in T- lymphocytes. Appican is expressed in astrocytes. {ECO:0000269PubMed:12859342, ECO:0000269PubMed:1406936}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 2628 experimentally validated interaction(s) in this database.
They are also associated with 31 interaction(s) predicted by orthology.

Experimentally validated
Total	2628 [view]
Protein-Protein	2625 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	31 [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:0019899	enzyme binding
GO:0033130	acetylcholine receptor binding
GO:0042802	identical protein binding
GO:0046914	transition metal ion binding
GO:0051425	PTB domain binding

Biological Process

GO:0000085	mitotic G2 phase
GO:0002576	platelet degranulation
GO:0006378	mRNA polyadenylation
GO:0006417	regulation of translation
GO:0006468	protein phosphorylation
GO:0006878	cellular copper ion homeostasis
GO:0006897	endocytosis
GO:0007155	cell adhesion
GO:0007176	regulation of epidermal growth factor-activated receptor activity
GO:0007219	Notch signaling pathway
GO:0007399	nervous system development
GO:0007409	axonogenesis
GO:0007596	blood coagulation
GO:0007617	mating behavior
GO:0007626	locomotory behavior
GO:0008088	axon cargo transport
GO:0008344	adult locomotory behavior
GO:0008542	visual learning
GO:0010951	negative regulation of endopeptidase activity
GO:0016199	axon midline choice point recognition
GO:0016322	neuron remodeling
GO:0016358	dendrite development
GO:0030168	platelet activation
GO:0030198	extracellular matrix organization
GO:0031175	neuron projection development
GO:0035235	ionotropic glutamate receptor signaling pathway
GO:0035872	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
GO:0040014	regulation of multicellular organism growth
GO:0045087	innate immune response
GO:0045931	positive regulation of mitotic cell cycle
GO:0048669	collateral sprouting in absence of injury
GO:0050803	regulation of synapse structure and activity
GO:0051402	neuron apoptotic process

Cellular Component

GO:0005576	extracellular region
GO:0005615	extracellular space
GO:0005641	nuclear envelope lumen
GO:0005737	cytoplasm
GO:0005794	Golgi apparatus
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0005905	coated pit
GO:0009986	cell surface
GO:0016021	integral component of membrane
GO:0030424	axon
GO:0031093	platelet alpha granule lumen
GO:0043197	dendritic spine
GO:0043198	dendritic shaft
GO:0043231	intracellular membrane-bounded organelle
GO:0043235	receptor complex
GO:0045121	membrane raft
GO:0045202	synapse
GO:0048471	perinuclear region of cytoplasm
GO:0070062	extracellular vesicular exosome

Protein Structure and Domains

PDB ID

InterPro

IPR002223 Proteinase inhibitor I2, Kunitz metazoa
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

PF00014
PF12924
PF03494
PF02177
PF10515
PF12925

PRINTS

PR00759
PR00203
PR00204

PIRSF

SMART

SM00131
SM00006

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt