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P05067

- A4_HUMAN

UniProt

P05067 - A4_HUMAN

Protein

Amyloid beta A4 protein

Gene

APP

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 231 (01 Oct 2014)
      Sequence version 3 (01 Nov 1991)
      Previous versions | rss
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    Functioni

    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 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 similarity
    Beta-amyloid 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. 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.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).

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei144 – 1441Required for Cu(2+) reduction
    Metal bindingi147 – 1471Copper 1
    Metal bindingi151 – 1511Copper 1
    Metal bindingi168 – 1681Copper 1
    Sitei301 – 3022Reactive bond
    Sitei671 – 6722Cleavage; by beta-secretase
    Sitei672 – 6732Cleavage; by caspase-6; when associated with variant 670-N-L-671
    Metal bindingi677 – 6771Copper or zinc 2
    Metal bindingi681 – 6811Copper or zinc 2Curated
    Metal bindingi684 – 6841Copper or zinc 2
    Metal bindingi685 – 6851Copper or zinc 2
    Sitei687 – 6882Cleavage; by alpha-secretase
    Sitei690 – 6912Cleavage; by theta-secretase
    Sitei704 – 7041Implicated in free radical propagationBy similarity
    Sitei706 – 7061Susceptible to oxidation
    Sitei711 – 7122Cleavage; by gamma-secretase; site 1
    Sitei713 – 7142Cleavage; by gamma-secretase; site 2
    Sitei720 – 7212Cleavage; by gamma-secretase; site 3
    Sitei739 – 7402Cleavage; by caspase-6, caspase-8 or caspase-9

    GO - Molecular functioni

    1. acetylcholine receptor binding Source: UniProtKB
    2. DNA binding Source: UniProtKB
    3. enzyme binding Source: ParkinsonsUK-UCL
    4. heparin binding Source: UniProtKB-KW
    5. identical protein binding Source: IntAct
    6. peptidase activator activity Source: Ensembl
    7. protein binding Source: IntAct
    8. PTB domain binding Source: BHF-UCL
    9. receptor binding Source: BHF-UCL
    10. serine-type endopeptidase inhibitor activity Source: UniProtKB
    11. transition metal ion binding Source: InterPro

    GO - Biological processi

    1. adult locomotory behavior Source: UniProtKB
    2. axon cargo transport Source: UniProtKB
    3. axon midline choice point recognition Source: UniProtKB
    4. axonogenesis Source: UniProtKB
    5. blood coagulation Source: Reactome
    6. cell adhesion Source: UniProtKB-KW
    7. cellular copper ion homeostasis Source: UniProtKB
    8. cholesterol metabolic process Source: Ensembl
    9. collateral sprouting in absence of injury Source: UniProtKB
    10. dendrite development Source: UniProtKB
    11. endocytosis Source: UniProtKB
    12. extracellular matrix organization Source: UniProtKB
    13. forebrain development Source: Ensembl
    14. innate immune response Source: Reactome
    15. ionotropic glutamate receptor signaling pathway Source: UniProtKB
    16. locomotory behavior Source: UniProtKB
    17. mating behavior Source: UniProtKB
    18. mitotic G2 phase Source: UniProtKB
    19. mRNA polyadenylation Source: UniProtKB
    20. negative regulation of endopeptidase activity Source: GOC
    21. negative regulation of neuron differentiation Source: Ensembl
    22. neuromuscular process controlling balance Source: Ensembl
    23. neuron apoptotic process Source: UniProtKB
    24. neuron projection development Source: UniProtKB
    25. neuron remodeling Source: UniProtKB
    26. Notch signaling pathway Source: UniProtKB-KW
    27. nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway Source: Reactome
    28. platelet activation Source: Reactome
    29. platelet degranulation Source: Reactome
    30. positive regulation of G2/M transition of mitotic cell cycle Source: Ensembl
    31. positive regulation of mitotic cell cycle Source: UniProtKB
    32. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
    33. protein phosphorylation Source: UniProtKB
    34. regulation of epidermal growth factor-activated receptor activity Source: UniProtKB
    35. regulation of multicellular organism growth Source: UniProtKB
    36. regulation of protein binding Source: Ensembl
    37. regulation of synapse structure and activity Source: UniProtKB
    38. regulation of translation Source: UniProtKB
    39. response to oxidative stress Source: Ensembl
    40. smooth endoplasmic reticulum calcium ion homeostasis Source: Ensembl
    41. suckling behavior Source: Ensembl
    42. synaptic growth at neuromuscular junction Source: Ensembl
    43. visual learning Source: UniProtKB

    Keywords - Molecular functioni

    Protease inhibitor, Serine protease inhibitor

    Keywords - Biological processi

    Apoptosis, Cell adhesion, Endocytosis, Notch signaling pathway

    Keywords - Ligandi

    Copper, Heparin-binding, Iron, Metal-binding, Zinc

    Enzyme and pathway databases

    BioCyciMetaCyc:ENSG00000142192-MONOMER.
    ReactomeiREACT_118563. RIP-mediated NFkB activation via ZBP1.
    REACT_163906. ECM proteoglycans.
    REACT_18283. G alpha (q) signalling events.
    REACT_19231. G alpha (i) signalling events.
    REACT_21264. Formyl peptide receptors bind formyl peptides and many other ligands.
    REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_24969. TRAF6 mediated NF-kB activation.
    REACT_25195. Advanced glycosylation endproduct receptor signaling.
    REACT_75808. The NLRP3 inflammasome.
    REACT_75925. Amyloids.
    SABIO-RKP05067.

    Protein family/group databases

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

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Amyloid beta A4 protein
    Alternative name(s):
    ABPP
    APPI
    Short name:
    APP
    Alzheimer disease amyloid protein
    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-APP42
    Alternative name(s):
    Beta-APP40
    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
    ProteomesiUP000005640: Chromosome 21

    Organism-specific databases

    HGNCiHGNC:620. APP.

    Subcellular locationi

    Membrane; Single-pass type I membrane protein. Membraneclathrin-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.

    GO - Cellular componenti

    1. apical part of cell Source: Ensembl
    2. axon Source: UniProtKB
    3. cell surface Source: UniProtKB
    4. ciliary rootlet Source: Ensembl
    5. coated pit Source: UniProtKB-SubCell
    6. cytoplasm Source: UniProtKB
    7. cytosol Source: Reactome
    8. dendritic shaft Source: MGI
    9. dendritic spine Source: MGI
    10. extracellular region Source: Reactome
    11. extracellular space Source: UniProt
    12. extracellular vesicular exosome Source: UniProt
    13. Golgi apparatus Source: UniProtKB
    14. integral component of membrane Source: UniProtKB
    15. integral component of plasma membrane Source: ProtInc
    16. intracellular membrane-bounded organelle Source: HPA
    17. membrane raft Source: ParkinsonsUK-UCL
    18. neuromuscular junction Source: Ensembl
    19. nuclear envelope lumen Source: Alzheimers_University_of_Toronto
    20. perinuclear region of cytoplasm Source: UniProt
    21. plasma membrane Source: UniProtKB
    22. platelet alpha granule lumen Source: Reactome
    23. receptor complex Source: MGI
    24. spindle midzone Source: Ensembl
    25. synapse Source: MGI

    Keywords - Cellular componenti

    Amyloid, Coated pit, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    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.25 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti670 – 6712KM → NL in AD1.
    VAR_000015
    Natural varianti678 – 6781D → N in AD1. 1 Publication
    VAR_044424
    Natural varianti692 – 6921A → G in AD1; Flemish mutation; increases the solubility of processed beta-amyloid peptides and increases the stability of peptide oligomers. 2 Publications
    VAR_000016
    Natural varianti693 – 6931E → G in AD1. 2 Publications
    VAR_014215
    Natural varianti713 – 7131A → T in AD1. 2 Publications
    VAR_000019
    Natural varianti714 – 7141T → A in AD1. 1 Publication
    VAR_032277
    Natural varianti714 – 7141T → I in AD1; increased beta-APP42/beta-APP40 ratio. 2 Publications
    VAR_014218
    Natural varianti715 – 7151V → M in AD1; decreased beta-APP40/total APP-beta. 1 Publication
    VAR_010108
    Natural varianti716 – 7161I → V in AD1. 1 Publication
    VAR_000020
    Natural varianti717 – 7171V → F in AD1. 4 Publications
    VAR_000023
    Natural varianti717 – 7171V → G in AD1. 2 Publications
    VAR_000022
    Natural varianti717 – 7171V → I in AD1. 7 Publications
    VAR_000021
    Natural varianti717 – 7171V → L in AD1. 1 Publication
    VAR_014219
    Natural varianti723 – 7231L → P in AD1. 1 Publication
    VAR_010109
    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.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti693 – 6931E → K in CAA-APP; Italian type.
    VAR_014216
    Natural varianti693 – 6931E → Q in CAA-APP; Dutch type. 1 Publication
    VAR_000017
    Natural varianti694 – 6941D → N in CAA-APP; Iowa type. 2 Publications
    VAR_014217
    Natural varianti705 – 7051L → V in CAA-APP; Italian type. 1 Publication
    VAR_032276

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi99 – 1024KRGR → NQGG: Reduced heparin-binding. 1 Publication
    Mutagenesisi137 – 1371H → N: Binds copper. Forms dimer. 2 Publications
    Mutagenesisi141 – 1411M → T: Binds copper. Forms dimer. 2 Publications
    Mutagenesisi144 – 1441C → S: Binds copper. No dimer formation. No copper reducing activity. 3 Publications
    Mutagenesisi147 – 1493HLH → ALA: 50% decrease in copper reducing activity. 3 Publications
    Mutagenesisi147 – 1471H → A: Some decrease in copper reducing activity. 3 Publications
    Mutagenesisi147 – 1471H → N: Binds copper. Forms dimer. 3 Publications
    Mutagenesisi147 – 1471H → Y: Greatly reduced copper-mediated low-density lipoprotein oxidation. 3 Publications
    Mutagenesisi151 – 1511H → K: Greatly reduced copper-mediated low-density lipoprotein oxidation. 3 Publications
    Mutagenesisi151 – 1511H → N: Binds copper. Forms dimer. 3 Publications
    Mutagenesisi198 – 1981S → A: Greatly reduced casein kinase phosphorylation. 3 Publications
    Mutagenesisi206 – 2061S → A: Reduced casein kinase phosphorylation. 3 Publications
    Mutagenesisi499 – 4991R → A: Reduced affinity for heparin; when associated with A-503. 2 Publications
    Mutagenesisi503 – 5031K → A: Reduced affinity for heparin; when associated with A-499. 2 Publications
    Mutagenesisi656 – 6561S → A: Abolishes chondroitin sulfate binding in L-APP733 isoform. 2 Publications
    Mutagenesisi676 – 6761R → G: 60-70% zinc-induced beta-APP (28) peptide aggregation. 2 Publications
    Mutagenesisi681 – 6811Y → F: 60-70% zinc-induced beta-APP (28) peptide aggregation. 2 Publications
    Mutagenesisi684 – 6841H → R: Only 23% zinc-induced beta-APP (28) peptide aggregation. 2 Publications
    Mutagenesisi704 – 7041G → V: Reduced protein oxidation. No hippocampal neuron toxicity. 1 Publication
    Mutagenesisi706 – 7061M → L: Reduced lipid peroxidation inhibition. 3 Publications
    Mutagenesisi706 – 7061M → V: No free radical production. No hippocampal neuron toxicity. 3 Publications
    Mutagenesisi717 – 7171V → C or S: Unchanged beta-APP42/total APP-beta ratio. 3 Publications
    Mutagenesisi717 – 7171V → F, G or I: Increased beta-APP42/beta-APP40 ratio. 3 Publications
    Mutagenesisi717 – 7171V → K: Decreased beta-APP42/total APP-beta ratio. 3 Publications
    Mutagenesisi717 – 7171V → M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage. 3 Publications
    Mutagenesisi728 – 7281Y → A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion. 4 Publications
    Mutagenesisi739 – 7391D → A: No cleavage by caspases during apoptosis. 4 Publications
    Mutagenesisi739 – 7391D → N: No effect on FADD-induced apoptosis. 4 Publications
    Mutagenesisi743 – 7431T → A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension. 5 Publications
    Mutagenesisi743 – 7431T → E: Reduced NGF-stimulated neurite extension. No effect on APP maturation. 5 Publications
    Mutagenesisi756 – 7561G → A: APP internalization unchanged. No change in beta-APP42 secretion. 2 Publications
    Mutagenesisi757 – 7571Y → A: Little APP internalization. Reduced beta-APP42 secretion. 5 Publications
    Mutagenesisi757 – 7571Y → G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1. 5 Publications
    Mutagenesisi759 – 7591N → A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion. 3 Publications
    Mutagenesisi760 – 7601P → A: Little APP internalization. Reduced beta-APP42 secretion. 2 Publications
    Mutagenesisi762 – 7621Y → A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion. 3 Publications

    Keywords - Diseasei

    Alzheimer disease, Amyloidosis, Disease mutation, Neurodegeneration

    Organism-specific databases

    MIMi104300. phenotype.
    605714. phenotype.
    Orphaneti1020. Early-onset autosomal dominant Alzheimer disease.
    324723. Hereditary cerebral hemorrhage with amyloidosis, Arctic type.
    100006. Hereditary cerebral hemorrhage with amyloidosis, Dutch type.
    324718. Hereditary cerebral hemorrhage with amyloidosis, Flemish type.
    324708. Hereditary cerebral hemorrhage with amyloidosis, Iowa type.
    324713. Hereditary cerebral hemorrhage with amyloidosis, Italian type.
    324703. Hereditary cerebral hemorrhage with amyloidosis, Piedmont type.
    PharmGKBiPA24910.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 17173 PublicationsAdd
    BLAST
    Chaini18 – 770753Amyloid beta A4 proteinPRO_0000000088Add
    BLAST
    Chaini18 – 687670Soluble APP-alphaPRO_0000000089Add
    BLAST
    Chaini18 – 671654Soluble APP-betaPRO_0000000090Add
    BLAST
    Chaini18 – 286269N-APPPRO_0000381966Add
    BLAST
    Chaini672 – 77099C99PRO_0000000091Add
    BLAST
    Chaini672 – 71342Beta-amyloid protein 42PRO_0000000092Add
    BLAST
    Chaini672 – 71140Beta-amyloid protein 40PRO_0000000093Add
    BLAST
    Chaini688 – 77083C83PRO_0000000094Add
    BLAST
    Peptidei688 – 71326P3(42)PRO_0000000095Add
    BLAST
    Peptidei688 – 71124P3(40)PRO_0000000096Add
    BLAST
    Chaini691 – 77080C80PRO_0000384574Add
    BLAST
    Chaini712 – 77059Gamma-secretase C-terminal fragment 59PRO_0000000097Add
    BLAST
    Chaini714 – 77057Gamma-secretase C-terminal fragment 57PRO_0000000098Add
    BLAST
    Chaini721 – 77050Gamma-secretase C-terminal fragment 50By similarityPRO_0000000099Add
    BLAST
    Chaini740 – 77031C31PRO_0000000100Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi38 ↔ 62
    Disulfide bondi73 ↔ 117
    Disulfide bondi98 ↔ 105
    Disulfide bondi133 ↔ 187
    Disulfide bondi144 ↔ 174
    Disulfide bondi158 ↔ 186
    Modified residuei198 – 1981Phosphoserine; by CK21 Publication
    Modified residuei206 – 2061Phosphoserine; by CK11 Publication
    Disulfide bondi291 ↔ 341
    Disulfide bondi300 ↔ 324
    Disulfide bondi316 ↔ 337
    Glycosylationi542 – 5421N-linked (GlcNAc...)1 Publication
    Glycosylationi571 – 5711N-linked (GlcNAc...)Curated
    Glycosylationi614 – 6141O-linked (GalNAc...)1 Publication
    Glycosylationi623 – 6231O-linked (GalNAc...)1 Publication
    Glycosylationi628 – 6281O-linked (GalNAc...)1 Publication
    Glycosylationi633 – 6331O-linked (GalNAc...)1 Publication
    Glycosylationi651 – 6511O-linked (GalNAc...)1 Publication
    Glycosylationi652 – 6521O-linked (GalNAc...)1 Publication
    Glycosylationi656 – 6561O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms1 Publication
    Glycosylationi659 – 6591O-linked (GalNAc...)
    Glycosylationi663 – 6631O-linked (GalNAc...)1 Publication
    Glycosylationi667 – 6671O-linked (GalNAc...)1 Publication
    Glycosylationi679 – 6791O-linked (GalNAc...)1 Publication
    Glycosylationi697 – 6971O-linked (GalNAc...)1 Publication
    Modified residuei729 – 7291PhosphothreonineBy similarity
    Modified residuei730 – 7301Phosphoserine; by APP-kinase IBy similarity
    Modified residuei743 – 7431Phosphothreonine; by CDK5 and MAPK101 Publication
    Modified residuei757 – 7571Phosphotyrosine1 Publication

    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 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.
    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 beta-amyloid peptides.
    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 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.3 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 beta-amyloid-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).
    Beta-amyloid peptides are degraded by IDE.

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Phosphoprotein, Proteoglycan

    Proteomic databases

    MaxQBiP05067.
    PaxDbiP05067.
    PRIDEiP05067.

    2D gel databases

    SWISS-2DPAGEP05067.

    PTM databases

    PhosphoSiteiP05067.
    UniCarbKBiP05067.

    Miscellaneous databases

    PMAP-CutDBP05067.

    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

    ArrayExpressiP05067.
    BgeeiP05067.
    GenevestigatoriP05067.

    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) 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.By similarity31 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    itself104EBI-77613,EBI-77613
    Q306T33EBI-77613,EBI-8294101From a different organism.
    AGRNP316963EBI-2431589,EBI-457650From a different organism.
    APBA1Q024103EBI-77613,EBI-368690
    APBB1O002135EBI-77613,EBI-81694
    APBB2Q928702EBI-77613,EBI-79277
    APLP1P516932EBI-302641,EBI-74648
    APLP2Q064812EBI-302641,EBI-79306
    APOA1P026475EBI-77613,EBI-701692
    BLMHQ138672EBI-302641,EBI-718504
    CALRP152533EBI-77613,EBI-9005200From a different organism.
    CALRP277972EBI-77613,EBI-1049597
    CALRQ8K3H72EBI-3894543,EBI-9005068From a different organism.
    COL18A1P390602EBI-821758,EBI-2566375
    CTSDP073392EBI-77613,EBI-2115097
    FLOT1O759555EBI-77613,EBI-603643
    FOSP011003EBI-77613,EBI-852851
    GPR3P460892EBI-302641,EBI-3909653
    HOMER3Q9NSC53EBI-302661,EBI-748420
    HSD17B10Q997144EBI-77613,EBI-79964
    ITM2AO437363EBI-302641,EBI-2431769
    JUNP054122EBI-77613,EBI-852823
    MAP3K5Q996832EBI-77613,EBI-476263
    MAPTP106369EBI-77613,EBI-366182
    MED12Q930742EBI-77613,EBI-394357
    MT-ND3P038972EBI-821758,EBI-1246249
    NEFLP071962EBI-77613,EBI-475646
    NF1P213593EBI-77613,EBI-1172917
    NGFRP081382EBI-77613,EBI-1387782
    NgfrP071742EBI-2431589,EBI-1038810From a different organism.
    PCBD1P614572EBI-77613,EBI-740475
    PCOLCEQ151133EBI-821758,EBI-8869614
    PDIA3P301013EBI-77613,EBI-979862
    PIN1Q135262EBI-302641,EBI-714158
    PRNPP041563EBI-77613,EBI-977302
    PSEN1P497686EBI-77613,EBI-297277
    SHC1P293535EBI-77613,EBI-78835
    SHC3Q925292EBI-77613,EBI-79084
    SLC40A1Q9NP594EBI-77613,EBI-725153
    Slc5a7Q8BGY92EBI-77613,EBI-2010752From a different organism.
    SPON1Q9HCB63EBI-302641,EBI-2431846
    TGFB1P011373EBI-77613,EBI-779636
    TGFB2P618127EBI-77613,EBI-779581
    TNFRSF21O755093EBI-77613,EBI-2313231
    TP53BP2Q136253EBI-77613,EBI-77642

    Protein-protein interaction databases

    BioGridi106848. 1971 interactions.
    DIPiDIP-574N.
    IntActiP05067. 117 interactions.
    MINTiMINT-150767.

    Structurei

    Secondary structure

    1
    770
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi33 – 353
    Beta strandi43 – 453
    Turni47 – 493
    Beta strandi52 – 543
    Helixi66 – 7611
    Beta strandi82 – 876
    Beta strandi92 – 943
    Beta strandi97 – 993
    Helixi100 – 1023
    Beta strandi103 – 1064
    Beta strandi110 – 1123
    Beta strandi115 – 1195
    Beta strandi134 – 1396
    Helixi147 – 16014
    Beta strandi163 – 17412
    Turni175 – 1773
    Beta strandi178 – 18811
    Helixi288 – 2925
    Beta strandi299 – 3013
    Beta strandi304 – 3107
    Turni311 – 3144
    Beta strandi315 – 3217
    Beta strandi323 – 3253
    Beta strandi331 – 3333
    Helixi334 – 3418
    Helixi374 – 3807
    Helixi389 – 41830
    Beta strandi421 – 4233
    Helixi425 – 48056
    Beta strandi482 – 4843
    Helixi487 – 51832
    Helixi520 – 54627
    Helixi547 – 5504
    Helixi552 – 56615
    Helixi673 – 6753
    Beta strandi679 – 6824
    Beta strandi683 – 6853
    Beta strandi688 – 6914
    Helixi695 – 6973
    Beta strandi698 – 7003
    Beta strandi702 – 7054
    Beta strandi707 – 7126
    Helixi744 – 75411
    Beta strandi755 – 7584
    Beta strandi763 – 7653

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1AAPX-ray1.50A/B287-344[»]
    1AMBNMR-A672-699[»]
    1AMCNMR-A672-699[»]
    1AMLNMR-A672-711[»]
    1BA4NMR-A672-711[»]
    1BA6NMR-A672-711[»]
    1BJBNMR-A672-699[»]
    1BJCNMR-A672-699[»]
    1BRCX-ray2.50I287-342[»]
    1CA0X-ray2.10D/I289-342[»]
    1HZ3NMR-A681-706[»]
    1IYTNMR-A672-713[»]
    1MWPX-ray1.80A28-123[»]
    1OWTNMR-A124-189[»]
    1QCMNMR-A696-706[»]
    1QWPNMR-A696-706[»]
    1QXCNMR-A696-706[»]
    1QYTNMR-A696-706[»]
    1TAWX-ray1.80B287-344[»]
    1TKNNMR-A460-569[»]
    1UO7model-A672-713[»]
    1UO8model-A672-713[»]
    1UOAmodel-A672-713[»]
    1UOImodel-A672-713[»]
    1X11X-ray2.50C/D754-766[»]
    1Z0QNMR-A672-713[»]
    1ZE7NMR-A672-687[»]
    1ZE9NMR-A672-687[»]
    1ZJDX-ray2.60B289-344[»]
    2BEGNMR-A/B/C/D/E672-713[»]
    2BOMmodel-A/B681-713[»]
    2BP4NMR-A672-687[»]
    2FJZX-ray1.61A133-189[»]
    2FK1X-ray1.60A133-189[»]
    2FK2X-ray1.65A133-189[»]
    2FK3X-ray2.40A/B/C/D/E/F/G/H133-189[»]
    2FKLX-ray2.50A/B124-189[»]
    2FMAX-ray0.85A133-189[»]
    2G47X-ray2.10C/D672-711[»]
    2IPUX-ray1.65P/Q672-679[»]
    2LFMNMR-A672-711[»]
    2LLMNMR-A686-726[»]
    2LMNNMR-A/B/C/D/E/F/G/H/I/J/K/L672-711[»]
    2LMONMR-A/B/C/D/E/F/G/H/I/J/K/L672-711[»]
    2LMPNMR-A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R672-711[»]
    2LMQNMR-A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R672-711[»]
    2LNQNMR-A/B/C/D/E/F/G/H672-711[»]
    2LOHNMR-A/B686-726[»]
    2LP1NMR-A671-770[»]
    2LZ3NMR-A/B699-726[»]
    2LZ4NMR-A/B699-726[»]
    2M4JNMR-A/B/C/D/E/F/G/H/I672-711[»]
    2M9RNMR-A672-711[»]
    2M9SNMR-A672-711[»]
    2OTKNMR-C672-711[»]
    2R0WX-ray2.50Q672-679[»]
    2WK3X-ray2.59C/D672-713[»]
    2Y29X-ray2.30A687-692[»]
    2Y2AX-ray1.91A687-692[»]
    2Y3JX-ray1.99A/B/C/D/E/F/G/H701-706[»]
    2Y3KX-ray1.90A/B/C/D/E/F/G/H706-713[»]
    2Y3LX-ray2.10A/B/C/G706-713[»]
    3AYUX-ray2.00B586-595[»]
    3BAEX-ray1.59A672-699[»]
    3BKJX-ray1.59A672-687[»]
    3DXCX-ray2.10B/D739-770[»]
    3DXDX-ray2.20B/D739-770[»]
    3DXEX-ray2.00B/D739-770[»]
    3GCIX-ray2.04P707-713[»]
    3IFLX-ray1.50P672-678[»]
    3IFNX-ray1.50P672-711[»]
    3IFOX-ray2.15P/Q672-678[»]
    3IFPX-ray2.95P/Q/R/S672-678[»]
    3JQ5X-ray2.03B672-679[»]
    3JQLX-ray1.20B687-692[»]
    3JTIX-ray1.80B699-706[»]
    3KTMX-ray2.70A/B/C/D/E/F/G/H18-190[»]
    3L33X-ray2.48E/F/G/H290-341[»]
    3L81X-ray1.60B761-767[»]
    3MOQX-ray2.05A/B/C/D689-712[»]
    3MXCX-ray2.00L754-762[»]
    3MXYX-ray2.30L754-762[»]
    3NYJX-ray3.20A365-567[»]
    3NYLX-ray2.80A365-570[»]
    3OVJX-ray1.80A/B/C/D687-692[»]
    3OW9X-ray1.80A/B687-692[»]
    3SV1X-ray3.30D/E/F754-767[»]
    3U0TX-ray2.50E/F701-711[»]
    3UMHX-ray2.00A370-575[»]
    3UMIX-ray2.40A370-575[»]
    3UMKX-ray2.60A370-575[»]
    4HIXX-ray2.20A672-699[»]
    4MDRX-ray1.85B758-767[»]
    4NGEX-ray2.70B/E672-711[»]
    4ONFX-ray2.00P672-678[»]
    4ONGX-ray2.20P672-711[»]
    ProteinModelPortaliP05067.
    SMRiP05067. Positions 26-192, 287-342, 385-567, 683-728, 741-768.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP05067.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini18 – 699682ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini724 – 77047CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei700 – 72324HelicalSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini291 – 34151BPTI/Kunitz inhibitorPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni96 – 11015Heparin-bindingAdd
    BLAST
    Regioni181 – 1888Zinc-binding
    Regioni391 – 42333Heparin-bindingAdd
    BLAST
    Regioni491 – 52232Heparin-bindingAdd
    BLAST
    Regioni523 – 54018Collagen-bindingAdd
    BLAST
    Regioni732 – 75120Interaction with G(o)-alphaAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi724 – 73411Basolateral sorting signalAdd
    BLAST
    Motifi759 – 7624NPXY motif; contains endocytosis signal

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi230 – 26031Asp/Glu-rich (acidic)Add
    BLAST
    Compositional biasi274 – 2807Poly-Thr

    Domaini

    The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.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 NPXY site is also involved in clathrin-mediated endocytosis.1 Publication

    Sequence similaritiesi

    Belongs to the APP family.Curated
    Contains 1 BPTI/Kunitz inhibitor domain.PROSITE-ProRule annotation

    Keywords - Domaini

    Signal, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiNOG289770.
    HOVERGENiHBG000051.
    InParanoidiP05067.
    KOiK04520.
    OMAiTHAHIVI.
    OrthoDBiEOG7RNJZP.
    PhylomeDBiP05067.
    TreeFamiTF317274.

    Family and domain databases

    Gene3Di3.30.1490.140. 1 hit.
    3.90.570.10. 1 hit.
    4.10.230.10. 1 hit.
    4.10.410.10. 1 hit.
    InterProiIPR008155. Amyloid_glyco.
    IPR013803. Amyloid_glyco_Abeta.
    IPR011178. Amyloid_glyco_Cu-bd.
    IPR024329. Amyloid_glyco_E2_domain.
    IPR008154. Amyloid_glyco_extra.
    IPR019744. Amyloid_glyco_extracell_CS.
    IPR015849. Amyloid_glyco_heparin-bd.
    IPR019745. Amyloid_glyco_intracell_CS.
    IPR028866. APP.
    IPR019543. APP_amyloid_C.
    IPR002223. Prot_inh_Kunz-m.
    IPR020901. Prtase_inh_Kunz-CS.
    [Graphical view]
    PANTHERiPTHR23103:SF7. PTHR23103:SF7. 1 hit.
    PfamiPF10515. 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.
    [Graphical view]
    PRINTSiPR00203. AMYLOIDA4.
    PR00759. BASICPTASE.
    PR00204. BETAAMYLOID.
    SMARTiSM00006. A4_EXTRA. 1 hit.
    SM00131. KU. 1 hit.
    [Graphical view]
    SUPFAMiSSF109843. SSF109843. 1 hit.
    SSF56491. SSF56491. 1 hit.
    SSF57362. SSF57362. 1 hit.
    SSF89811. SSF89811. 1 hit.
    PROSITEiPS00319. A4_EXTRA. 1 hit.
    PS00320. A4_INTRA. 1 hit.
    PS00280. BPTI_KUNITZ_1. 1 hit.
    PS50279. BPTI_KUNITZ_2. 1 hit.
    [Graphical view]

    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. Align

    Note: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.

    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

    MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG    50
    KWDSDPSGTK TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR 100
    GRKQCKTHPH FVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW 150
    HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDNVDSAD 200
    AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE EADDDEDDED 250
    GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC 300
    RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL 350
    KTTQEPLARD PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA 400
    KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER 450
    QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPRHV FNMLKKYVRA 500
    EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN 550
    VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET 600
    KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL 650
    TTRPGSGLTN IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG 700
    AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS 750
    KMQQNGYENP TYKFFEQMQN 770

    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.

    Note: A major isoform.

    Show »
    Length:695
    Mass (Da):78,663
    Checksum:i4F6EA0139F969D56
    GO
    Isoform L-APP696 (identifier: P05067-5) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         289-289: E → V
         290-345: Missing.
         637-654: Missing.

    Note: The L-isoforms are referred to as appicans.

    Show »
    Length:696
    Mass (Da):78,866
    Checksum:i66DFDFFCFDB75A72
    GO
    Isoform APP714 (identifier: P05067-6) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         289-289: E → V
         290-345: Missing.

    Show »
    Length:714
    Mass (Da):80,769
    Checksum:i124EA691773DC13B
    GO
    Isoform L-APP733 (identifier: P05067-7) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         345-345: M → I
         346-364: Missing.
         637-654: Missing.

    Note: The L-isoforms are referred to as appicans.

    Show »
    Length:733
    Mass (Da):82,916
    Checksum:i44528239D68A53EE
    GO
    Isoform APP751 (identifier: P05067-8) [UniParc]FASTAAdd to Basket

    Also known as: PreA4 751

    The sequence of this isoform differs from the canonical sequence as follows:
         345-345: M → I
         346-364: Missing.

    Note: A major isoform.

    Show »
    Length:751
    Mass (Da):84,819
    Checksum:iC987C557C5A3714E
    GO
    Isoform L-APP752 (identifier: P05067-9) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         637-654: Missing.

    Show »
    Length:752
    Mass (Da):85,040
    Checksum:i074CFF767CBED2E0
    GO
    Isoform APP639 (identifier: P05067-10) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         19-74: Missing.
         289-363: Missing.
         364-364: L → V

    Show »
    Length:639
    Mass (Da):72,553
    Checksum:iC4120DEC51A59A95
    GO
    Isoform 11 (identifier: P05067-11) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-19: MLPGLALLLLAAWTARALE → MDQLEDLLVLFINY
         345-364: MSQSLLKTTQEPLARDPVKL → I

    Show »
    Length:746
    Mass (Da):84,521
    Checksum:i843411EFBDEFACE3
    GO

    Sequence cautioni

    The sequence AAA58727.1 differs from that shown. Reason: Contamination by an Alu repeat.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti15 – 162AR → VW in CAA31830. (PubMed:2783775)Curated
    Sequence conflicti647 – 6471D → E in AAA51722. (PubMed:3035574)Curated
    Sequence conflicti724 – 7241Missing in AAB26263. (PubMed:8476439)Curated
    Sequence conflicti724 – 7241Missing in AAB26264. (PubMed:8476439)Curated
    Sequence conflicti731 – 7311I → N in AAB26263. (PubMed:8476439)Curated
    Sequence conflicti731 – 7311I → N in AAB26264. (PubMed:8476439)Curated
    Sequence conflicti731 – 7311I → N in AAB26265. (PubMed:8476439)Curated
    Sequence conflicti757 – 7571Y → S in AAA35540. (PubMed:3810169)Curated

    Mass spectrometryi

    Molecular mass is 6461.6 Da from positions 712 - 767. Determined by MALDI. 1 Publication
    Molecular mass is 6451.6 Da from positions 714 - 770. Determined by MALDI. 1 Publication
    Molecular mass is 6436.8 Da from positions 715 - 769. Determined by MALDI. 1 Publication
    Molecular mass is 5752.5 Da from positions 719 - 767. Determined by MALDI. 1 Publication

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti501 – 5011E → K.1 Publication
    Corresponds to variant rs45588932 [ dbSNP | Ensembl ].
    VAR_022315
    Natural varianti665 – 6651E → D in a patient with late onset Alzheimer disease. 1 Publication
    VAR_010107
    Natural varianti670 – 6712KM → NL in AD1.
    VAR_000015
    Natural varianti678 – 6781D → N in AD1. 1 Publication
    VAR_044424
    Natural varianti692 – 6921A → G in AD1; Flemish mutation; increases the solubility of processed beta-amyloid peptides and increases the stability of peptide oligomers. 2 Publications
    VAR_000016
    Natural varianti693 – 6931E → G in AD1. 2 Publications
    VAR_014215
    Natural varianti693 – 6931E → K in CAA-APP; Italian type.
    VAR_014216
    Natural varianti693 – 6931E → Q in CAA-APP; Dutch type. 1 Publication
    VAR_000017
    Natural varianti694 – 6941D → N in CAA-APP; Iowa type. 2 Publications
    VAR_014217
    Natural varianti705 – 7051L → V in CAA-APP; Italian type. 1 Publication
    VAR_032276
    Natural varianti713 – 7131A → T in AD1. 2 Publications
    VAR_000019
    Natural varianti713 – 7131A → V in one chronic schizophrenia patient; unknown pathological significance. 1 Publication
    Corresponds to variant rs1800557 [ dbSNP | Ensembl ].
    VAR_000018
    Natural varianti714 – 7141T → A in AD1. 1 Publication
    VAR_032277
    Natural varianti714 – 7141T → I in AD1; increased beta-APP42/beta-APP40 ratio. 2 Publications
    VAR_014218
    Natural varianti715 – 7151V → M in AD1; decreased beta-APP40/total APP-beta. 1 Publication
    VAR_010108
    Natural varianti716 – 7161I → V in AD1. 1 Publication
    VAR_000020
    Natural varianti717 – 7171V → F in AD1. 4 Publications
    VAR_000023
    Natural varianti717 – 7171V → G in AD1. 2 Publications
    VAR_000022
    Natural varianti717 – 7171V → I in AD1. 7 Publications
    VAR_000021
    Natural varianti717 – 7171V → L in AD1. 1 Publication
    VAR_014219
    Natural varianti723 – 7231L → P in AD1. 1 Publication
    VAR_010109

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 1919MLPGL…ARALE → MDQLEDLLVLFINY in isoform 11. 1 PublicationVSP_045446Add
    BLAST
    Alternative sequencei19 – 7456Missing in isoform APP639. 1 PublicationVSP_009116Add
    BLAST
    Alternative sequencei289 – 36375Missing in isoform APP639. 1 PublicationVSP_009117Add
    BLAST
    Alternative sequencei289 – 2891E → V in isoform APP695, isoform L-APP696, isoform L-APP677 and isoform APP714. 1 PublicationVSP_000002
    Alternative sequencei290 – 36475Missing in isoform APP695 and isoform L-APP677. 1 PublicationVSP_000004Add
    BLAST
    Alternative sequencei290 – 34556Missing in isoform L-APP696 and isoform APP714. CuratedVSP_000003Add
    BLAST
    Alternative sequencei290 – 30516VCSEQ…RAMIS → KWYKEVHSGQARWLML in isoform APP305. 1 PublicationVSP_000005Add
    BLAST
    Alternative sequencei306 – 770465Missing in isoform APP305. 1 PublicationVSP_000006Add
    BLAST
    Alternative sequencei345 – 36420MSQSL…DPVKL → I in isoform 11. 1 PublicationVSP_045447Add
    BLAST
    Alternative sequencei345 – 3451M → I in isoform L-APP733 and isoform APP751. 3 PublicationsVSP_000007
    Alternative sequencei346 – 36419Missing in isoform L-APP733 and isoform APP751. 3 PublicationsVSP_000008Add
    BLAST
    Alternative sequencei364 – 3641L → V in isoform APP639. 1 PublicationVSP_009118
    Alternative sequencei637 – 65418Missing in isoform L-APP677, isoform L-APP696, isoform L-APP733 and isoform L-APP752. 1 PublicationVSP_000009Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    Y00264 mRNA. Translation: CAA68374.1.
    X13466
    , X13467, X13468, X13469, X13470, X13471, X13472, X13473, X13474, X13475, X13476, X13477, X13478, X13479, X13487, X13488 Genomic DNA. Translation: CAA31830.1.
    X06989 mRNA. Translation: CAA30050.1.
    M33112
    , M34862, M34863, M34864, M34865, M34866, M34867, M34868, M34869, M34870, M34871, M34872, M34873, M34874, M34876, M34877, M34878, M34879 Genomic DNA. Translation: AAB59502.1.
    M34875
    , M34862, M34863, M34864, M34865, M34866, M34867, M34868, M34869, M34870, M34871, M34872, M34873 Genomic DNA. Translation: AAB59501.1. Different termination.
    D87675 Genomic DNA. Translation: BAA22264.1.
    AK312326 mRNA. Translation: BAG35248.1.
    AK295621 mRNA. Translation: BAG58500.1.
    AY919674 Genomic DNA. Translation: AAW82435.1.
    AP001439 Genomic DNA. No translation available.
    AP001440 Genomic DNA. No translation available.
    AP001441 Genomic DNA. No translation available.
    AP001442 Genomic DNA. No translation available.
    AP001443 Genomic DNA. No translation available.
    CH471079 Genomic DNA. Translation: EAX09958.1.
    CH471079 Genomic DNA. Translation: EAX09959.1.
    CH471079 Genomic DNA. Translation: EAX09960.1.
    CH471079 Genomic DNA. Translation: EAX09961.1.
    CH471079 Genomic DNA. Translation: EAX09963.1.
    CH471079 Genomic DNA. Translation: EAX09965.1.
    BC004369 mRNA. Translation: AAH04369.1.
    BC065529 mRNA. Translation: AAH65529.1.
    M35675 mRNA. Translation: AAA60163.1. Sequence problems.
    M24547, M24546 Genomic DNA. Translation: AAC13654.1.
    M28373 mRNA. Translation: AAA58727.1. Sequence problems.
    X06982 mRNA. Translation: CAA30042.1.
    X06981 mRNA. Translation: CAA30041.1.
    M18734 mRNA. Translation: AAA51726.1.
    M29270, M29269 Genomic DNA. Translation: AAA51768.1.
    AB066441 mRNA. Translation: