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Protein

Amyloid-beta A4 protein

Gene

APP

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Interaction between APP molecules on neighboring cells promotes synaptogenesis (PubMed:25122912). 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 Cu2+-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 Cu2+ ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.By similarity1 Publication
Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu2+ and Fe3+ to Cu+ and Fe2+, respectively. Amyloid-beta protein 42 is a more effective reductant than amyloid-beta protein 40. Amyloid-beta peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. APP42-beta may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity. Also binds GPC1 in lipid rafts.
Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.By similarity
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).

Miscellaneous

Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-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.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi147Copper 1PROSITE-ProRule annotationCombined sources2 Publications1
Metal bindingi151Copper 1PROSITE-ProRule annotationCombined sources2 Publications1
Metal bindingi168Copper 1PROSITE-ProRule annotationCombined sources1 Publication1
Sitei170Required for Cu(2+) reductionPROSITE-ProRule annotation1
Sitei301 – 302Reactive bond2
Metal bindingi677Copper or zinc 22 Publications1
Metal bindingi681Copper or zinc 22 Publications1
Metal bindingi684Copper or zinc 23 Publications1
Metal bindingi685Copper or zinc 22 Publications1
Sitei704Implicated in free radical propagationBy similarity1
Sitei706Susceptible to oxidation1 Publication1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionHeparin-binding, Protease inhibitor, Serine protease inhibitor
Biological processApoptosis, Cell adhesion, Endocytosis, Notch signaling pathway
LigandCopper, Iron, Metal-binding, Zinc

Enzyme and pathway databases

BioCyciMetaCyc:ENSG00000142192-MONOMER
ReactomeiR-HSA-114608 Platelet degranulation
R-HSA-3000178 ECM proteoglycans
R-HSA-381426 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-416476 G alpha (q) signalling events
R-HSA-418594 G alpha (i) signalling events
R-HSA-432720 Lysosome Vesicle Biogenesis
R-HSA-444473 Formyl peptide receptors bind formyl peptides and many other ligands
R-HSA-445989 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
R-HSA-844456 The NLRP3 inflammasome
R-HSA-879415 Advanced glycosylation endproduct receptor signaling
R-HSA-8862803 Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models
R-HSA-8957275 Post-translational protein phosphorylation
R-HSA-933542 TRAF6 mediated NF-kB activation
R-HSA-977225 Amyloid fiber formation
SABIO-RKiP05067
SIGNORiP05067

Protein family/group databases

MEROPSiI02.015
TCDBi1.C.50.1.2 the amyloid Beta-protein peptide (aBetapp) family

Names & Taxonomyi

Protein namesi
Recommended name:
Amyloid-beta A4 protein
Alternative name(s):
ABPP
APPI
Short name:
APP
Alzheimer disease amyloid protein
Amyloid precursor proteinCurated
Amyloid-beta precursor proteinCurated
Cerebral vascular amyloid peptide
Short name:
CVAP
PreA4
Protease nexin-II
Short name:
PN-II
Cleaved into the following 14 chains:
Soluble APP-alpha
Short name:
S-APP-alpha
Soluble APP-beta
Short name:
S-APP-beta
Alternative name(s):
Beta-secretase C-terminal fragment
Short name:
Beta-CTF
Amyloid-beta protein 42
Short name:
Abeta42
Alternative name(s):
Beta-APP42
Amyloid-beta protein 40
Short name:
Abeta40
Alternative name(s):
Beta-APP40
Alternative name(s):
Alpha-secretase C-terminal fragment
Short name:
Alpha-CTF
Alternative name(s):
Amyloid intracellular domain 59
Short name:
AICD-59
Short name:
AID(59)
Gamma-CTF(59)
Alternative name(s):
Amyloid intracellular domain 57
Short name:
AICD-57
Short name:
AID(57)
Gamma-CTF(57)
Alternative name(s):
Amyloid intracellular domain 50
Short name:
AICD-50
Short name:
AID(50)
Gamma-CTF(50)
Gene namesi
Name:APP
Synonyms:A4, AD1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 21

Organism-specific databases

EuPathDBiHostDB:ENSG00000142192.20
HGNCiHGNC:620 APP
MIMi104760 gene
neXtProtiNX_P05067

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini18 – 701ExtracellularCuratedAdd BLAST684
Transmembranei702 – 722Helical2 PublicationsAdd BLAST21
Topological domaini723 – 770CytoplasmicCuratedAdd BLAST48

Keywords - Cellular componenti

Amyloid, Cell membrane, Cell projection, Coated pit, Cytoplasmic vesicle, Endosome, Membrane

Pathology & Biotechi

Involvement in diseasei

Alzheimer disease 1 (AD1)26 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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 constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
See also OMIM:104300
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_000015670 – 671KM → NL in AD1. Corresponds to variant dbSNP:rs281865161Ensembl.2
Natural variantiVAR_044424678D → N in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750064EnsemblClinVar.1
Natural variantiVAR_000016692A → G in AD1; Flemish mutation; increases the solubility of processed amyloid-beta peptides and increases the stability of peptide oligomers. 3 PublicationsCorresponds to variant dbSNP:rs63750671EnsemblClinVar.1
Natural variantiVAR_014215693E → G in AD1. 2 PublicationsCorresponds to variant dbSNP:rs63751039EnsemblClinVar.1
Natural variantiVAR_000019713A → T in AD1. 2 PublicationsCorresponds to variant dbSNP:rs63750066EnsemblClinVar.1
Natural variantiVAR_032277714T → A in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750643EnsemblClinVar.1
Natural variantiVAR_014218714T → I in AD1; increased amyloid-beta protein 42/40 ratio. 2 PublicationsCorresponds to variant dbSNP:rs63750973EnsemblClinVar.1
Natural variantiVAR_010108715V → M in AD1; decreased amyloid-beta protein 40/total amyloid-beta. 1 PublicationCorresponds to variant dbSNP:rs63750734EnsemblClinVar.1
Natural variantiVAR_000020716I → V in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750399EnsemblClinVar.1
Natural variantiVAR_000023717V → F in AD1. 4 PublicationsCorresponds to variant dbSNP:rs63750264EnsemblClinVar.1
Natural variantiVAR_000022717V → G in AD1. 2 PublicationsCorresponds to variant dbSNP:rs63749964EnsemblClinVar.1
Natural variantiVAR_000021717V → I in AD1. 7 PublicationsCorresponds to variant dbSNP:rs63750264EnsemblClinVar.1
Natural variantiVAR_014219717V → L in AD1. 1 PublicationCorresponds to variant dbSNP:rs63750264EnsemblClinVar.1
Natural variantiVAR_010109723L → P in AD1. 1 PublicationCorresponds to variant dbSNP:rs63751122EnsemblClinVar.1
Cerebral amyloid angiopathy, APP-related (CAA-APP)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:605714
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_014216693E → K in CAA-APP; Italian type. 1 PublicationCorresponds to variant dbSNP:rs63750579EnsemblClinVar.1
Natural variantiVAR_000017693E → Q in CAA-APP; Dutch type. 1 PublicationCorresponds to variant dbSNP:rs63750579EnsemblClinVar.1
Natural variantiVAR_014217694D → N in CAA-APP; Iowa type. 2 PublicationsCorresponds to variant dbSNP:rs63749810EnsemblClinVar.1
Natural variantiVAR_032276705L → V in CAA-APP; Italian type. 1 PublicationCorresponds to variant dbSNP:rs63750921EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi99 – 102KRGR → NQGG: Reduced heparin-binding. 1 Publication4
Mutagenesisi108H → A: Loss of the copper binding site in the GFLD subdomain; when associated with A-110. 1 Publication1
Mutagenesisi110H → A: Loss of the copper binding site in the GFLD subdomain; when associated with A-108. 1 Publication1
Mutagenesisi137H → N: Binds copper. Forms dimer. 1 Publication1
Mutagenesisi141M → T: Binds copper. Forms dimer. 1 Publication1
Mutagenesisi144C → S: Binds copper. No dimer formation. No copper reducing activity. 2 Publications1
Mutagenesisi147 – 149HLH → ALA: 50% decrease in copper reducing activity. 1 Publication3
Mutagenesisi147H → A: Loss of a copper binding site; when associated with A-151. 1 Publication1
Mutagenesisi147H → A: Some decrease in copper reducing activity. 2 Publications1
Mutagenesisi147H → N: Binds copper. Forms dimer. 2 Publications1
Mutagenesisi147H → Y: Greatly reduced copper-mediated low-density lipoprotein oxidation. 2 Publications1
Mutagenesisi151H → A: Loss of a copper binding site; when associated with A-147. 1 Publication1
Mutagenesisi151H → K: Greatly reduced copper-mediated low-density lipoprotein oxidation. 2 Publications1
Mutagenesisi151H → N: Binds copper. Forms dimer. 2 Publications1
Mutagenesisi198S → A: Greatly reduced casein kinase phosphorylation. 2 Publications1
Mutagenesisi206S → A: Reduced casein kinase phosphorylation. 2 Publications1
Mutagenesisi499R → A: Reduced affinity for heparin; when associated with A-503. 1 Publication1
Mutagenesisi503K → A: Reduced affinity for heparin; when associated with A-499. 1 Publication1
Mutagenesisi656S → A: Abolishes chondroitin sulfate binding in L-APP733 isoform. 1 Publication1
Mutagenesisi676R → G: 60-70% zinc-induced amyloid-beta protein 28 aggregation. 1 Publication1
Mutagenesisi681Y → F: 60-70% zinc-induced amyloid-beta protein 28 aggregation. 1 Publication1
Mutagenesisi684H → R: Only 23% zinc-induced amyloid-beta protein 28 aggregation. 1 Publication1
Mutagenesisi704G → V: Reduced protein oxidation. No hippocampal neuron toxicity. 1
Mutagenesisi706M → L: Reduced lipid peroxidation inhibition. 2 Publications1
Mutagenesisi706M → V: No free radical production. No hippocampal neuron toxicity. 2 Publications1
Mutagenesisi717V → C or S: Unchanged amyloid-beta protein 42/total amyloid-beta ratio. 2 Publications1
Mutagenesisi717V → F, G or I: Increased amyloid-beta protein 42/40 ratio. 2 Publications1
Mutagenesisi717V → K: Decreased amyloid-beta protein 42/total amyloid-beta ratio. 2 Publications1
Mutagenesisi717V → M: Increased amyloid-beta protein 42/40 ratio. No change in apoptosis after caspase cleavage. 2 Publications1
Mutagenesisi728Y → A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in amyloid-beta protein 42 secretion. 3 Publications1
Mutagenesisi739D → A: No cleavage by caspases during apoptosis. 3 Publications1
Mutagenesisi739D → N: No effect on FADD-induced apoptosis. 3 Publications1
Mutagenesisi743T → A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension. 4 Publications1
Mutagenesisi743T → E: Reduced NGF-stimulated neurite extension. No effect on APP maturation. 4 Publications1
Mutagenesisi756G → A: APP internalization unchanged. No change in amyloid-beta protein 42 secretion. 1 Publication1
Mutagenesisi757Y → A: Little APP internalization. Reduced amyloid-beta protein 42 secretion. 4 Publications1
Mutagenesisi757Y → G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1. 4 Publications1
Mutagenesisi759N → A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced amyloid-beta protein 42 secretion. 2 Publications1
Mutagenesisi760P → A: Little APP internalization. Reduced amyloid-beta protein 42 secretion. 1 Publication1
Mutagenesisi762Y → A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in amyloid-beta protein 42 secretion. 2 Publications1

Keywords - Diseasei

Alzheimer disease, Amyloidosis, Disease mutation, Neurodegeneration

Organism-specific databases

DisGeNETi351
GeneReviewsiAPP
MalaCardsiAPP
MIMi104300 phenotype
605714 phenotype
OpenTargetsiENSG00000142192
Orphaneti324723 ABeta amyloidosis, Arctic type
100006 ABeta amyloidosis, Dutch type
324708 ABeta amyloidosis, Iowa type
324713 ABeta amyloidosis, Italian type
324718 ABetaA21G amyloidosis
324703 ABetaL34V amyloidosis
1020 Early-onset autosomal dominant Alzheimer disease
PharmGKBiPA24910

Chemistry databases

ChEMBLiCHEMBL2487
DrugBankiDB05150 CAD106
DB09148 Florbetaben (18F)
DB09149 Florbetapir (18F)
DB09151 Flutemetamol (18F)
DB02235 L-methionine (R)-S-oxide
DB05846 Mito-4509

Polymorphism and mutation databases

BioMutaiAPP
DMDMi112927

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 173 PublicationsAdd BLAST17
ChainiPRO_000000008818 – 770Amyloid-beta A4 proteinAdd BLAST753
ChainiPRO_000000008918 – 687Soluble APP-alphaAdd BLAST670
ChainiPRO_000000009018 – 671Soluble APP-betaAdd BLAST654
ChainiPRO_000038196618 – 286N-APPAdd BLAST269
ChainiPRO_0000000091672 – 770C99Add BLAST99
ChainiPRO_0000000092672 – 713Amyloid-beta protein 42Add BLAST42
ChainiPRO_0000000093672 – 711Amyloid-beta protein 40Add BLAST40
ChainiPRO_0000000094688 – 770C83Add BLAST83
PeptideiPRO_0000000095688 – 713P3(42)Add BLAST26
PeptideiPRO_0000000096688 – 711P3(40)Add BLAST24
ChainiPRO_0000384574691 – 770C80Add BLAST80
ChainiPRO_0000000097712 – 770Gamma-secretase C-terminal fragment 59Add BLAST59
ChainiPRO_0000000098714 – 770Gamma-secretase C-terminal fragment 57Add BLAST57
ChainiPRO_0000000099721 – 770Gamma-secretase C-terminal fragment 50By similarityAdd BLAST50
ChainiPRO_0000000100740 – 770C31Add BLAST31

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi38 ↔ 62PROSITE-ProRule annotationCombined sources
Disulfide bondi73 ↔ 117PROSITE-ProRule annotationCombined sources
Disulfide bondi98 ↔ 105PROSITE-ProRule annotationCombined sources
Disulfide bondi133 ↔ 187PROSITE-ProRule annotationCombined sources3 Publications
Disulfide bondi144 ↔ 174PROSITE-ProRule annotationCombined sources3 Publications
Disulfide bondi158 ↔ 186PROSITE-ProRule annotationCombined sources3 Publications
Modified residuei198Phosphoserine; by CK21 Publication1
Modified residuei206Phosphoserine; by CK11 Publication1
Disulfide bondi291 ↔ 341Combined sources
Disulfide bondi300 ↔ 324Combined sources
Disulfide bondi316 ↔ 337Combined sources
Modified residuei441Phosphoserine; by FAM20C1 Publication1
Modified residuei497Phosphotyrosine1 Publication1
Glycosylationi542N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi571N-linked (GlcNAc...) asparagineCurated1
Glycosylationi633O-linked (GalNAc...) threonine; partial2 Publications1
Glycosylationi651O-linked (GalNAc...) threonine; partial2 Publications1
Glycosylationi652O-linked (GalNAc...) threonine; partial2 Publications1
Glycosylationi656O-linked (Xyl...) (chondroitin sulfate) serine; in L-APP isoforms1 Publication1
Glycosylationi659O-linked (HexNAc...) threonine; partial1 Publication1
Glycosylationi663O-linked (GalNAc...) threonine; partial1 Publication1 Publication1
Glycosylationi667O-linked (GalNAc...) serine; partial1 Publication1 Publication1
Glycosylationi681O-linked (HexNAc...) tyrosine; partial1 Publication1
Modified residuei729PhosphothreonineBy similarity1
Modified residuei730Phosphoserine; by APP-kinase IBy similarity1
Modified residuei743Phosphothreonine; by CDK5 and MAPK10Combined sources1 Publication1
Modified residuei757Phosphotyrosine1 Publication1
Cross-linki763Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity

Post-translational modificationi

Proteolytically 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 protein 40 and amyloid-beta protein 42, major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). Many other minor amyloid-beta peptides, amyloid-beta 1-X peptides, are found in cerebral spinal fluid (CSF) including the amyloid-beta X-15 peptides, produced from the cleavage by alpha-secretase and all terminating at Gln-686.
Proteolytically 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 amyloid-beta peptides.
N-glycosylated (PubMed:2900137). N- 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 amyloid-beta peptides (amyloid-beta 1-15, 1-16, 1-17, 1-18, 1-19 and 1-20) but not found on amyloid-beta protein 38, amyloid-beta protein 40 nor on amyloid-beta protein 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.4 Publications
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. 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.6 Publications
Extracellular 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 amyloid-beta-containing peptides.
Trophic-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).
Amyloid-beta peptides are degraded by IDE.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei197 – 198Cleavage; by caspases1 Publication2
Sitei219 – 220Cleavage; by caspases1 Publication2
Sitei671 – 672Cleavage; by beta-secretase1 Publication2
Sitei672 – 673Cleavage; by caspase-6; when associated with variant 670-N-L-6712
Sitei687 – 688Cleavage; by alpha-secretase1 Publication2
Sitei690 – 691Cleavage; by theta-secretase1 Publication2
Sitei711 – 712Cleavage; by gamma-secretase; site 11 Publication2
Sitei713 – 714Cleavage; by gamma-secretase; site 21 Publication2
Sitei720 – 721Cleavage; by gamma-secretase; site 31 Publication2
Sitei739 – 740Cleavage; by caspase-6, caspase-8 or caspase-91 Publication2

Keywords - PTMi

Disulfide bond, Glycoprotein, Isopeptide bond, Oxidation, Phosphoprotein, Proteoglycan, Ubl conjugation

Proteomic databases

EPDiP05067
MaxQBiP05067
PaxDbiP05067
PeptideAtlasiP05067
PRIDEiP05067
ProteomicsDBi51774
51775 [P05067-10]
51776 [P05067-2]
51777 [P05067-3]
51778 [P05067-4]
51779 [P05067-5]
51780 [P05067-6]
51781 [P05067-7]
51782 [P05067-8]
51783 [P05067-9]

2D gel databases

SWISS-2DPAGEiP05067

PTM databases

GlyConnecti49
iPTMnetiP05067
PhosphoSitePlusiP05067
SwissPalmiP05067
UniCarbKBiP05067

Miscellaneous databases

PMAP-CutDBiP05067

Expressioni

Tissue specificityi

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.2 Publications

Inductioni

Increased levels during neuronal differentiation.

Gene expression databases

BgeeiENSG00000142192 Expressed in 242 organ(s), highest expression level in frontal cortex
ExpressionAtlasiP05067 baseline and differential
GenevisibleiP05067 HS

Organism-specific databases

HPAiCAB000157
HPA001462

Interactioni

Subunit structurei

Binds, 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), 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 protein 42 binds CHRNA7 in hippocampal neurons. Amyloid-beta 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; dimerization is enhanced in the presence of Cu2+ ions (PubMed:25122912). Can form homodimers; this is promoted by heparin binding. Amyloid-beta protein 40 interacts with S100A9. CTF-alpha product of APP interacts with GSAP. Interacts with SORL1. Interacts with PLD3. Interacts with VDAC1 (PubMed:25168729). Interacts with NSG1; could regulate APP processing (By similarity).By similarity33 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi106848, 2116 interactors
ComplexPortaliCPX-1062 Amyloid-beta protein 40/42 complex
CPX-1069 Amyloid-beta protein 40 complex
CPX-1070 Amyloid-beta protein 42 complex
CPX-1120 Amyloid-beta protein 40/42 oligomeric complex
CPX-1134 Amyloid-beta protein 42 oligomeric complex
CPX-1180 Amyloid-beta protein 40 oligomeric complex
CORUMiP05067
DIPiDIP-574N
ELMiP05067
IntActiP05067, 170 interactors
MINTiP05067
STRINGi9606.ENSP00000284981

Chemistry databases

BindingDBiP05067

Structurei

Secondary structure

1770
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP05067
SMRiP05067
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP05067

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini28 – 189E1PROSITE-ProRule annotationAdd BLAST162
Domaini291 – 341BPTI/Kunitz inhibitorPROSITE-ProRule annotationAdd BLAST51
Domaini374 – 565E2PROSITE-ProRule annotationAdd BLAST192

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni28 – 123GFLD subdomainPROSITE-ProRule annotationAdd BLAST96
Regioni96 – 110Heparin-bindingAdd BLAST15
Regioni131 – 189CuBD subdomainPROSITE-ProRule annotationAdd BLAST59
Regioni181 – 188Zinc-binding8
Regioni391 – 423Heparin-bindingAdd BLAST33
Regioni491 – 522Heparin-bindingAdd BLAST32
Regioni523 – 540Collagen-binding1 PublicationAdd BLAST18
Regioni732 – 751Interaction with G(o)-alphaAdd BLAST20

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi724 – 734Basolateral sorting signalAdd BLAST11
Motifi757 – 762YENPXY motif; contains endocytosis signal1 Publication6

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi230 – 260Asp/Glu-rich (acidic)Add BLAST31
Compositional biasi274 – 280Poly-Thr7

Domaini

The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.1 Publication
The GFLD subdomain binds Cu2+ ions; this promotes homodimerization.1 Publication
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 YENPXY site is also involved in clathrin-mediated endocytosis.1 Publication
The C-terminal region can bind zinc ions; this favors dimerization and formation of higher oligomers.2 Publications

Sequence similaritiesi

Belongs to the APP family.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3540 Eukaryota
ENOG410ZW2A LUCA
GeneTreeiENSGT00530000063252
HOGENOMiHOG000232190
HOVERGENiHBG000051
InParanoidiP05067
KOiK04520
OMAiKQCKTHA
OrthoDBiEOG091G0UW4
PhylomeDBiP05067
TreeFamiTF317274

Family and domain databases

CDDicd00109 KU, 1 hit
Gene3Di1.20.120.770, 1 hit
2.30.29.30, 1 hit
3.30.1490.140, 1 hit
3.90.570.10, 1 hit
4.10.230.10, 1 hit
4.10.410.10, 1 hit
InterProiView protein in InterPro
IPR036669 Amyloid_Cu-bd_sf
IPR008155 Amyloid_glyco
IPR013803 Amyloid_glyco_Abeta
IPR037071 Amyloid_glyco_Abeta_sf
IPR011178 Amyloid_glyco_Cu-bd
IPR024329 Amyloid_glyco_E2_domain
IPR008154 Amyloid_glyco_extra
IPR019744 Amyloid_glyco_extracell_CS
IPR015849 Amyloid_glyco_heparin-bd
IPR036454 Amyloid_glyco_heparin-bd_sf
IPR019745 Amyloid_glyco_intracell_CS
IPR028866 APP
IPR019543 APP_amyloid_C
IPR036176 E2_sf
IPR002223 Kunitz_BPTI
IPR036880 Kunitz_BPTI_sf
IPR011993 PH-like_dom_sf
IPR020901 Prtase_inh_Kunz-CS
PANTHERiPTHR23103 PTHR23103, 1 hit
PTHR23103:SF7 PTHR23103:SF7, 1 hit
PfamiView protein in Pfam
PF10515 APP_amyloid, 1 hit
PF12924 APP_Cu_bd, 1 hit
PF12925 APP_E2, 1 hit
PF02177 APP_N, 1 hit
PF03494 Beta-APP, 1 hit
PF00014 Kunitz_BPTI, 1 hit
PRINTSiPR00203 AMYLOIDA4
PR00759 BASICPTASE
PR00204 BETAAMYLOID
SMARTiView protein in SMART
SM00006 A4_EXTRA, 1 hit
SM00131 KU, 1 hit
SUPFAMiSSF109843 SSF109843, 1 hit
SSF56491 SSF56491, 1 hit
SSF57362 SSF57362, 1 hit
SSF89811 SSF89811, 1 hit
PROSITEiView protein in PROSITE
PS00319 APP_CUBD, 1 hit
PS51869 APP_E1, 1 hit
PS51870 APP_E2, 1 hit
PS00320 APP_INTRA, 1 hit
PS00280 BPTI_KUNITZ_1, 1 hit
PS50279 BPTI_KUNITZ_2, 1 hit

Sequences (11+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 11 isoformsi produced by alternative splicing. AlignAdd to basket
Note: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.

This entry has 11 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

Isoform APP770 (identifier: P05067-1) [UniParc]FASTAAdd to basket
Also known as: PreA4 770

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.

« Hide
        10         20         30         40         50
MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG
60 70 80 90 100
KWDSDPSGTK TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR
110 120 130 140 150
GRKQCKTHPH FVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW
160 170 180 190 200
HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDNVDSAD
210 220 230 240 250
AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE EADDDEDDED
260 270 280 290 300
GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
310 320 330 340 350
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL
360 370 380 390 400
KTTQEPLARD PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA
410 420 430 440 450
KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER
460 470 480 490 500
QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPRHV FNMLKKYVRA
510 520 530 540 550
EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN
560 570 580 590 600
VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
610 620 630 640 650
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL
660 670 680 690 700
TTRPGSGLTN IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG
710 720 730 740 750
AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS
760 770
KMQQNGYENP TYKFFEQMQN
Note: A major isoform.
Length:770
Mass (Da):86,943
Last modified:November 1, 1991 - v3
Checksum:iA12EE761403740F5
GO
Isoform APP305 (identifier: P05067-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     290-305: VCSEQAETGPCRAMIS → KWYKEVHSGQARWLML
     306-770: Missing.

Show »
Length:305
Mass (Da):34,358
Checksum:iD1CCD7237262687A
GO
Isoform L-APP677 (identifier: P05067-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-364: Missing.
     637-654: Missing.

Note: The L-isoforms are referred to as appicans.
Show »
Length:677
Mass (Da):76,760
Checksum:i48334D3EEF26990E
GO
Isoform APP695 (identifier: P05067-4) [UniParc]FASTAAdd to basket
Also known as: PreA4 695

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-364: Missing.