MGP Database

New search | Record Overview | Ontology/Pathway Information | Domain Information | UniProt Annotations | Related Proteins
MGP000176

UniProt Annotations

Entry Information
Gene Nameamyloid beta (A4) precursor protein
Protein EntryA4_HUMAN
UniProt IDP05067
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=11; Comment=Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.; Name=APP770; Synonyms=PreA4 770; IsoId=P05067-1; Sequence=Displayed; Note=A major isoform.; Name=APP305; IsoId=P05067-2; Sequence=VSP_000005, VSP_000006; Name=L-APP677; IsoId=P05067-3; Sequence=VSP_000002, VSP_000004, VSP_000009; Note=The L-isoforms are referred to as appicans.; Name=APP695; Synonyms=PreA4 695; IsoId=P05067-4; Sequence=VSP_000002, VSP_000004; Note=A major isoform.; Name=L-APP696; IsoId=P05067-5; Sequence=VSP_000002, VSP_000003, VSP_000009; Note=The L-isoforms are referred to as appicans.; Name=APP714; IsoId=P05067-6; Sequence=VSP_000002, VSP_000003; Name=L-APP733; IsoId=P05067-7; Sequence=VSP_000007, VSP_000008, VSP_000009; Note=The L-isoforms are referred to as appicans.; Name=APP751; Synonyms=PreA4 751; IsoId=P05067-8; Sequence=VSP_000007, VSP_000008; Note=A major isoform.; Name=L-APP752; IsoId=P05067-9; Sequence=VSP_000009; Name=APP639; IsoId=P05067-10; Sequence=VSP_009116, VSP_009117, VSP_009118; Name=11; IsoId=P05067-11; Sequence=VSP_045446, VSP_045447;
DiseaseAlzheimer 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:0000269|PubMed:10097173, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10665499, ECO:0000269|PubMed:10867787, ECO:0000269|PubMed:11063718, ECO:0000269|PubMed:11528419, ECO:0000269|PubMed:12034808, ECO:0000269|PubMed:1302033, ECO:0000269|PubMed:1303239, ECO:0000269|PubMed:1303275, ECO:0000269|PubMed:1415269, ECO:0000269|PubMed:15201367, ECO:0000269|PubMed:15365148, ECO:0000269|PubMed:15668448, ECO:0000269|PubMed:1671712, ECO:0000269|PubMed:1678058, ECO:0000269|PubMed:1908231, ECO:0000269|PubMed:1925564, ECO:0000269|PubMed:1944558, ECO:0000269|PubMed:8267572, ECO:0000269|PubMed:8290042, ECO:0000269|PubMed:8476439, ECO:0000269|PubMed:8577393, ECO:0000269|PubMed:9328472, ECO:0000269|PubMed:9754958}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseCerebral 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.
DomainThe basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells. {ECO:0000269|PubMed:8576160}.
DomainThe 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. {ECO:0000269|PubMed:8576160}.
FunctionAppicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. {ECO:0000250}.
FunctionBeta-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.
FunctionFunctions 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}.
FunctionN-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).
FunctionThe gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.
InductionIncreased levels during neuronal differentiation.
InteractionSelf; NbExp=104; IntAct=EBI-77613, EBI-77613; Q306T3:- (xeno); NbExp=3; IntAct=EBI-77613, EBI-8294101; P31696:AGRN (xeno); NbExp=3; IntAct=EBI-2431589, EBI-457650; Q02410:APBA1; NbExp=3; IntAct=EBI-77613, EBI-368690; O00213:APBB1; NbExp=5; IntAct=EBI-77613, EBI-81694; Q92870:APBB2; NbExp=2; IntAct=EBI-77613, EBI-79277; P51693:APLP1; NbExp=2; IntAct=EBI-302641, EBI-74648; Q06481:APLP2; NbExp=2; IntAct=EBI-302641, EBI-79306; P02647:APOA1; NbExp=5; IntAct=EBI-77613, EBI-701692; Q13867:BLMH; NbExp=2; IntAct=EBI-302641, EBI-718504; P15253:CALR (xeno); NbExp=3; IntAct=EBI-77613, EBI-9005200; P27797:CALR; NbExp=2; IntAct=EBI-77613, EBI-1049597; Q8K3H7:CALR (xeno); NbExp=2; IntAct=EBI-3894543, EBI-9005068; P39060:COL18A1; NbExp=2; IntAct=EBI-821758, EBI-2566375; P07339:CTSD; NbExp=2; IntAct=EBI-77613, EBI-2115097; O75955:FLOT1; NbExp=5; IntAct=EBI-77613, EBI-603643; P01100:FOS; NbExp=3; IntAct=EBI-77613, EBI-852851; P46089:GPR3; NbExp=2; IntAct=EBI-302641, EBI-3909653; Q9NSC5:HOMER3; NbExp=3; IntAct=EBI-302661, EBI-748420; Q99714:HSD17B10; NbExp=4; IntAct=EBI-77613, EBI-79964; O43736:ITM2A; NbExp=3; IntAct=EBI-302641, EBI-2431769; P05412:JUN; NbExp=2; IntAct=EBI-77613, EBI-852823; Q99683:MAP3K5; NbExp=2; IntAct=EBI-77613, EBI-476263; P10636:MAPT; NbExp=9; IntAct=EBI-77613, EBI-366182; Q93074:MED12; NbExp=2; IntAct=EBI-77613, EBI-394357; P03897:MT-ND3; NbExp=2; IntAct=EBI-821758, EBI-1246249; P07196:NEFL; NbExp=2; IntAct=EBI-77613, EBI-475646; P21359:NF1; NbExp=3; IntAct=EBI-77613, EBI-1172917; P08138:NGFR; NbExp=2; IntAct=EBI-77613, EBI-1387782; P07174:Ngfr (xeno); NbExp=2; IntAct=EBI-2431589, EBI-1038810; P61457:PCBD1; NbExp=2; IntAct=EBI-77613, EBI-740475; Q15113:PCOLCE; NbExp=3; IntAct=EBI-821758, EBI-8869614; P30101:PDIA3; NbExp=3; IntAct=EBI-77613, EBI-979862; Q13526:PIN1; NbExp=2; IntAct=EBI-302641, EBI-714158; P04156:PRNP; NbExp=3; IntAct=EBI-77613, EBI-977302; P49768:PSEN1; NbExp=6; IntAct=EBI-77613, EBI-297277; P29353:SHC1; NbExp=5; IntAct=EBI-77613, EBI-78835; Q92529:SHC3; NbExp=2; IntAct=EBI-77613, EBI-79084; Q9NP59:SLC40A1; NbExp=4; IntAct=EBI-77613, EBI-725153; Q8BGY9:Slc5a7 (xeno); NbExp=2; IntAct=EBI-77613, EBI-2010752; Q9HCB6:SPON1; NbExp=3; IntAct=EBI-302641, EBI-2431846; P01137:TGFB1; NbExp=3; IntAct=EBI-77613, EBI-779636; P61812:TGFB2; NbExp=7; IntAct=EBI-77613, EBI-779581; O75509:TNFRSF21; NbExp=3; IntAct=EBI-77613, EBI-2313231; Q13625:TP53BP2; NbExp=3; IntAct=EBI-77613, EBI-77642;
Mass SpectrometryMass=5752.5; Method=MALDI; Range=719-767; Evidence={ECO:0000269|PubMed:12214090};
Mass SpectrometryMass=6436.8; Method=MALDI; Range=715-769; Evidence={ECO:0000269|PubMed:12214090};
Mass SpectrometryMass=6451.6; Method=MALDI; Range=714-770; Evidence={ECO:0000269|PubMed:12214090};
Mass SpectrometryMass=6461.6; Method=MALDI; Range=712-767; Evidence={ECO:0000269|PubMed:12214090};
MiscellaneousChelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. The affinity for copper is much higher than for other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding.
PtmBeta-amyloid peptides are degraded by IDE.
PtmExtracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond. In vitro, the APP-Cu(+) complex in the presence of hydrogen peroxide results in an increased production of beta-amyloid-containing peptides.
PtmN- and O-glycosylated. O-glycosylation on Ser and Thr residues with core 1 or possibly core 8 glycans. Partial tyrosine glycosylation (Tyr-681) is found on some minor, short beta-amyloid peptides (beta-amyloid 1-15, 1-16, 1-17, 1-18, 1-19 and 1-20) but not found on beta-amyloid 38, beta-amyloid 40 nor on beta-amyloid 42. Modification on a tyrosine is unusual and is more prevelant in AD patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr, Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O- AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is O- acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac 2,8Neu5Ac linked. O-glycosylations in the vicinity of the cleavage sites may influence the proteolytic processing. Appicans are L-APP isoforms with O-linked chondroitin sulfate. {ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:21712440, ECO:0000269|PubMed:22576872}.
PtmPhosphorylation 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. 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. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin. {ECO:0000269|PubMed:10341243, ECO:0000269|PubMed:11146006, ECO:0000269|PubMed:11517218, ECO:0000269|PubMed:11877420, ECO:0000269|PubMed:8131745, ECO:0000269|PubMed:8999878}.
PtmProteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-6, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides.
PtmProteolytically processed under normal cellular conditions. 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. 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 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). Many other minor beta-amyloid peptides, beta-amyloid 1-X peptides, are found in cerebral spinal fluid (CSF) including the beta-amyloid X- 15 peptides, produced from the cleavage by alpha-secretase and all terminatiing at Gln-686.
PtmTrophic-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).
Sequence CautionSequence=AAA58727.1; Type=Miscellaneous discrepancy; Note=Contamination by an Alu repeat.; Evidence={ECO:0000305};
SimilarityBelongs to the APP family. {ECO:0000305}.
SimilarityContains 1 BPTI/Kunitz inhibitor domain. {ECO:0000255|PROSITE-ProRule:PRU00031}.
Subcellular LocationMembrane; 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.
SubunitBinds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and, NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, FPRL1, APPBP1, IB1, KNS2 (via its TPR domains) (By similarity), APPBP2 (via BaSS) and DDB1. 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. Amyloid beta-42 binds CHRNA7 in hippocampal neurons. Beta-amyloid associates with HADH2. Soluble APP binds, via its N-terminal head, to FBLN1. Interacts with CPEB1 and AGER (By similarity). Interacts with ANKS1B and TNFRSF21. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; this is promoted by heparin binding. Beta-amyloid protein 40 interacts with S100A9. CTF-alpha product of APP interacts with GSAP. Interacts with SORL1. Interacts with PLD3. {ECO:0000250, ECO:0000269|PubMed:10681545, ECO:0000269|PubMed:10816430, ECO:0000269|PubMed:11238726, ECO:0000269|PubMed:11278849, ECO:0000269|PubMed:11438549, ECO:0000269|PubMed:11517218, ECO:0000269|PubMed:11544248, ECO:0000269|PubMed:11689470, ECO:0000269|PubMed:11724784, ECO:0000269|PubMed:11877420, ECO:0000269|PubMed:11943163, ECO:0000269|PubMed:15347684, ECO:0000269|PubMed:16174740, ECO:0000269|PubMed:17051221, ECO:0000269|PubMed:17895381, ECO:0000269|PubMed:18468999, ECO:0000269|PubMed:19225519, ECO:0000269|PubMed:19366692, ECO:0000269|PubMed:19901339, ECO:0000269|PubMed:20212142, ECO:0000269|PubMed:20811458, ECO:0000269|PubMed:22457725, ECO:0000269|PubMed:24336208, ECO:0000269|PubMed:8446172, ECO:0000269|PubMed:8626687, ECO:0000269|PubMed:8855266, ECO:0000269|PubMed:8887653, ECO:0000269|PubMed:9300481, ECO:0000269|PubMed:9338779, ECO:0000269|PubMed:9843960, ECO:0000269|PubMed:9890987}.
Tissue SpecificityExpressed 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:0000269|PubMed:12859342, ECO:0000269|PubMed:1406936}.
Web ResourceName=AD mutations; URL="http://www.molgen.ua.ac.be/ADmutations/";
Web ResourceName=Alzforum; Note=APP mutations; URL="http://alzforum.org/mutations/search?genes%5B%5D=348";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/app/";
Web ResourceName=Wikipedia; Note=Amyloid beta entry; URL="http://en.wikipedia.org/wiki/Amyloid_beta";
  logo