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P12023

- A4_MOUSE

UniProt

P12023 - A4_MOUSE

Protein

Amyloid beta A4 protein

Gene

App

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 184 (01 Oct 2014)
      Sequence version 3 (09 May 2003)
      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 inhibit Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity By similarity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV By similarity. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons By similarity. Provides 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
    Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also bind GPC1 in lipid rafts By similarity.By similarity
    The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.1 Publication
    N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei144 – 1441Required for Cu(2+) reductionBy similarity
    Metal bindingi147 – 1471Copper 1By similarity
    Metal bindingi151 – 1511Copper 1By similarity
    Metal bindingi168 – 1681Copper 1By similarity
    Sitei301 – 3022Reactive bondBy similarity
    Sitei671 – 6722Cleavage; by beta-secretaseBy similarity
    Sitei672 – 6732Cleavage; by caspase-6By similarity
    Metal bindingi677 – 6771Copper or zinc 2By similarity
    Metal bindingi685 – 6851Copper or zinc 2By similarity
    Sitei687 – 6882Cleavage; by alpha-secretaseBy similarity
    Sitei690 – 6912Cleavage; by theta-secretaseBy similarity
    Sitei704 – 7041Implicated in free radical propagationBy similarity
    Sitei706 – 7061Susceptible to oxidationBy similarity
    Sitei711 – 7122Cleavage; by gamma-secretase; site 1By similarity
    Sitei713 – 7142Cleavage; by gamma-secretase; site 2By similarity
    Sitei720 – 7212Cleavage; by gamma-secretase; site 3By similarity
    Sitei739 – 7402Cleavage; by caspase-6, caspase-8 or caspase-9By similarity

    GO - Molecular functioni

    1. DNA binding Source: MGI
    2. heparin binding Source: UniProtKB-KW
    3. peptidase activator activity Source: Ensembl
    4. protein binding Source: IntAct
    5. serine-type endopeptidase inhibitor activity Source: UniProtKB-KW
    6. transition metal ion binding Source: InterPro

    GO - Biological processi

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

    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

    ReactomeiREACT_196606. ECM proteoglycans.
    REACT_198563. Amyloids.
    REACT_198647. Advanced glycosylation endproduct receptor signaling.
    REACT_202898. TRAF6 mediated NF-kB activation.
    REACT_207651. G alpha (q) signalling events.
    REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_222971. RIP-mediated NFkB activation via ZBP1.

    Protein family/group databases

    MEROPSiI02.015.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Amyloid beta A4 protein
    Alternative name(s):
    ABPP
    Short name:
    APP
    Alzheimer disease amyloid A4 protein homolog
    Amyloidogenic glycoprotein
    Short name:
    AG
    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):
    APP-C99
    Alternative name(s):
    Beta-APP42
    Alternative name(s):
    Beta-APP40
    Alternative name(s):
    APP-C59
    Amyloid intracellular domain 59
    Short name:
    AID(59)
    Gamma-CTF(59)
    Alternative name(s):
    APP-C57
    Amyloid intracellular domain 57
    Short name:
    AID(57)
    Gamma-CTF(57)
    Alternative name(s):
    Amyloid intracellular domain 50
    Short name:
    AID(50)
    Gamma-CTF(50)
    Gene namesi
    Name:App
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 16

    Organism-specific databases

    MGIiMGI:88059. App.

    Subcellular locationi

    Membrane 1 Publication; Single-pass type I membrane protein 1 Publication. Membraneclathrin-coated pit 1 Publication
    Note: Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Beta-APP42 associates with FPRL1 at the cell surface and the complex is then rapidly internalized By similarity. APP sorts to the basolateral surface in epithelial cells By similarity. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments.By similarity

    GO - Cellular componenti

    1. apical part of cell Source: MGI
    2. axon Source: MGI
    3. cell-cell junction Source: MGI
    4. cell surface Source: Ensembl
    5. ciliary rootlet Source: MGI
    6. coated pit Source: UniProtKB-SubCell
    7. cytoplasm Source: MGI
    8. cytoplasmic vesicle Source: MGI
    9. dendritic shaft Source: Ensembl
    10. dendritic spine Source: Ensembl
    11. ER to Golgi transport vesicle Source: MGI
    12. Golgi apparatus Source: MGI
    13. integral component of membrane Source: MGI
    14. membrane Source: MGI
    15. neuromuscular junction Source: MGI
    16. neuron projection Source: MGI
    17. perinuclear region of cytoplasm Source: MGI
    18. plasma membrane Source: MGI
    19. receptor complex Source: MGI
    20. spindle midzone Source: MGI

    Keywords - Cellular componenti

    Amyloid, Coated pit, Membrane

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi728 – 7281Y → A: No effect on MAPK8IP1 binding. 1 Publication
    Mutagenesisi732 – 7332HH → GL or GP: Almost complete loss of binding to G(o) alpha subunit. No inhibition of GTPase activity.
    Mutagenesisi743 – 7431T → E: No effect on MAPK8IP1 binding. 1 Publication
    Mutagenesisi756 – 7561G → F, H, N, S or W: Greatly impairs interaction with DAB2. 1 Publication
    Mutagenesisi756 – 7561G → Y: Impairs interaction with DAB2. 1 Publication
    Mutagenesisi757 – 7571Y → F: Greatly promotes interaction with DAB2. 2 Publications
    Mutagenesisi757 – 7571Y → G, H or V: Greatly impairs interaction with DAB2. 2 Publications
    Mutagenesisi757 – 7571Y → G: No MAPK8IP1 nor APBA1 nor APBB1 nor DAB1 binding. 2 Publications
    Mutagenesisi757 – 7571Y → I or W: Impairs interaction with DAB2. 2 Publications
    Mutagenesisi759 – 7591N → A: No MAPK8IP1 nor APBA1 nor Dab1 binding. No effect on APBB1 binding. 2 Publications
    Mutagenesisi759 – 7591N → G, L, M or P: Greatly impairs interaction with DAB2. 2 Publications
    Mutagenesisi760 – 7601P → E, F, I, K, L, Q, R, V, W or Y: Greatly impairs interaction with DAB2. 1 Publication
    Mutagenesisi762 – 7621Y → A: No MAPK8IP1 nor APBA1 nor Dab1 binding. No effect on APBB1 binding. 2 Publications
    Mutagenesisi762 – 7621Y → W: Greatly impairs interaction with DAB2. 2 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 1717By similarityAdd
    BLAST
    Chaini18 – 770753Amyloid beta A4 proteinPRO_0000000114Add
    BLAST
    Chaini18 – 687670Soluble APP-alphaSequence AnalysisPRO_0000000115Add
    BLAST
    Chaini18 – 671654Soluble APP-betaSequence AnalysisPRO_0000000116Add
    BLAST
    Chaini18 – 286269N-APPBy similarityPRO_0000381968Add
    BLAST
    Chaini672 – 77099C99By similarityPRO_0000000117Add
    BLAST
    Chaini672 – 71342Beta-amyloid protein 42By similarityPRO_0000000118Add
    BLAST
    Chaini672 – 71140Beta-amyloid protein 40By similarityPRO_0000000119Add
    BLAST
    Chaini688 – 77083C83By similarityPRO_0000000120Add
    BLAST
    Peptidei688 – 71326P3(42)By similarityPRO_0000000121Add
    BLAST
    Peptidei688 – 71124P3(40)By similarityPRO_0000000122Add
    BLAST
    Chaini691 – 77080C80PRO_0000384576Add
    BLAST
    Chaini712 – 77059Gamma-secretase C-terminal fragment 59PRO_0000000123Add
    BLAST
    Chaini714 – 77057Gamma-secretase C-terminal fragment 57PRO_0000000124Add
    BLAST
    Chaini721 – 77050Gamma-secretase C-terminal fragment 50PRO_0000000125Add
    BLAST
    Chaini740 – 77031C31By similarityPRO_0000000126Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi38 ↔ 62PROSITE-ProRule annotation
    Disulfide bondi73 ↔ 117PROSITE-ProRule annotation
    Disulfide bondi98 ↔ 105PROSITE-ProRule annotation
    Disulfide bondi133 ↔ 187PROSITE-ProRule annotation
    Disulfide bondi144 ↔ 174PROSITE-ProRule annotation
    Disulfide bondi158 ↔ 186PROSITE-ProRule annotation
    Modified residuei198 – 1981Phosphoserine; by CK2By similarity
    Modified residuei206 – 2061Phosphoserine; by CK1By similarity
    Disulfide bondi291 ↔ 341PROSITE-ProRule annotation
    Disulfide bondi300 ↔ 324PROSITE-ProRule annotation
    Disulfide bondi316 ↔ 337PROSITE-ProRule annotation
    Glycosylationi542 – 5421N-linked (GlcNAc...)Curated
    Glycosylationi571 – 5711N-linked (GlcNAc...)Curated
    Modified residuei729 – 7291PhosphothreonineBy similarity
    Modified residuei730 – 7301Phosphoserine; by APP-kinase IBy similarity
    Modified residuei743 – 7431Phosphothreonine; by CDK5 and MAPK101 Publication
    Modified residuei757 – 7571Phosphotyrosine; by ABL12 Publications

    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) By similarity.By similarity
    Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides By similarity.By similarity
    N- and O-glycosylated.By similarity
    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. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members By similarity. Phosphorylation on Tyr-757 is required for SHC binding By similarity.By similarity
    Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond.By similarity
    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).By similarity
    Beta-amyloid peptides are degraded by IDE.By similarity

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Phosphoprotein

    Proteomic databases

    MaxQBiP12023.
    PaxDbiP12023.
    PRIDEiP12023.

    PTM databases

    PhosphoSiteiP12023.

    Expressioni

    Tissue specificityi

    Isoform APP770 is expressed in kidney. Isoform APP751 is widely expressed. Isoform APP695 is expressed in brain, kidney and liver. Isoform APP695, isoform APP714 and isoform APP751 are expressed in several different brain regions including hippocampus, substania nigra pars compacta and cerebellum. In the cerebellum, these isoforms are abundantly expressed in Purkinje cells.1 Publication

    Gene expression databases

    ArrayExpressiP12023.
    BgeeiP12023.
    CleanExiMM_APP.
    GenevestigatoriP12023.

    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, NUMB and DAB1. Binding to DAB1 inhibits its serine phosphorylation. 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 By similarity. 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 By similarity. Amyloid beta-42 binds CHRNA7 in hippocampal neurons By similarity. Beta-amyloid associates with HADH2 By similarity. Interacts with ANKS1B, TNFRSF21 and AGER By similarity. Interacts with CPEB1. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; this is promoted by heparin binding By similarity. Beta-amyloid protein 40 interacts with S100A9 By similarity. CTF-alpha product of APP interacts with GSAP By similarity. Interacts with SORL1. Interacts with PLD3 By similarity.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Apba2P980842EBI-78814,EBI-81669
    Apbb1Q9QXJ12EBI-78814,EBI-81338
    Aplp1Q031574EBI-78814,EBI-399929
    Aplp2Q063353EBI-78814,EBI-446708
    CALRP152532EBI-78814,EBI-9005200From a different organism.
    CalrP142114EBI-78814,EBI-644340
    Dab1P973183EBI-78814,EBI-81680
    Dlg4Q621084EBI-78814,EBI-300895
    Lingo1Q9D1T02EBI-78814,EBI-2012981
    MAPK8IP1Q9UQF22EBI-78814,EBI-78404From a different organism.
    Mapk8ip1Q9WVI9-13EBI-78814,EBI-288461
    Shc3Q611202EBI-78814,EBI-79107
    Slc40a1Q9JHI92EBI-78814,EBI-2931424

    Protein-protein interaction databases

    BioGridi198167. 9 interactions.
    IntActiP12023. 77 interactions.
    MINTiMINT-208509.

    Structurei

    Secondary structure

    1
    770
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi744 – 75310

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2ROZNMR-A739-770[»]
    2YSZNMR-A739-770[»]
    2YT0NMR-A739-770[»]
    2YT1NMR-A739-770[»]
    ProteinModelPortaliP12023.
    SMRiP12023. Positions 26-192, 287-342, 371-566, 686-726, 741-768.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP12023.

    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-bindingBy similarityAdd
    BLAST
    Regioni181 – 1888Zinc-bindingBy similarity
    Regioni391 – 42333Heparin-bindingBy similarityAdd
    BLAST
    Regioni491 – 52232Heparin-bindingBy similarityAdd
    BLAST
    Regioni523 – 54018Collagen-bindingBy similarityAdd
    BLAST
    Regioni732 – 75120Interaction with G(o)-alphaBy similarityAdd
    BLAST
    Regioni756 – 77015Interaction with DAB2Add
    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.
    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 By similarity.By similarity

    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.
    HOGENOMiHOG000232190.
    HOVERGENiHBG000051.
    InParanoidiP12023.
    KOiK04520.
    OMAiTHAHIVI.
    OrthoDBiEOG7RNJZP.
    PhylomeDBiP12023.
    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 (4)i

    Sequence statusi: Complete.

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

    This entry describes 4 isoformsi produced by alternative splicing. Align

    Note: Additional isoforms seem to exist.

    Isoform APP770 (identifier: P12023-1) [UniParc]FASTAAdd to Basket

    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

    MLPSLALLLL AAWTVRALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG    50
    KWESDPSGTK TCIGTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR 100
    GRKQCKTHTH IVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW 150
    HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDSVDSAD 200
    AEEDDSDVWW GGADTDYADG GEDKVVEVAE EEEVADVEEE EADDDEDVED 250
    GDEVEEEAEE PYEEATERTT STATTTTTTT ESVEEVVREV CSEQAETGPC 300
    RAMISRWYFD VTEGKCVPFF YGGCGGNRNN FDTEEYCMAV CGSVSTQSLL 350
    KTTSEPLPQD PDKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA 400
    KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER 450
    QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPHHV FNMLKKYVRA 500
    EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN 550
    VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET 600
    KTTVELLPVN GEFSLDDLQP WHPFGVDSVP ANTENEVEPV DARPAADRGL 650
    TTRPGSGLTN IKTEEISEVK MDAEFGHDSG FEVRHQKLVF FAEDVGSNKG 700
    AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS 750
    KMQQNGYENP TYKFFEQMQN 770
    Length:770
    Mass (Da):86,722
    Last modified:May 9, 2003 - v3
    Checksum:i988D89E089092A3E
    GO
    Isoform APP695 (identifier: P12023-2) [UniParc]FASTAAdd to Basket

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

    Show »
    Length:695
    Mass (Da):78,443
    Checksum:i0DE93FA56FB20F3A
    GO
    Isoform APP751 (identifier: P12023-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         346-380: Missing.

    Show »
    Length:735
    Mass (Da):82,968
    Checksum:iBE4D5EC285943E89
    GO
    Isoform APP714 (identifier: P12023-4)

    Sequence is not available
    Length:
    Mass (Da):

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti211 – 2111G → V in AAA37139. (PubMed:3322280)Curated
    Sequence conflicti375 – 3751V → A in AAB41502. (PubMed:11235921)Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei289 – 2891E → V in isoform APP695. 3 PublicationsVSP_000012
    Alternative sequencei290 – 36475Missing in isoform APP695. 3 PublicationsVSP_000013Add
    BLAST
    Alternative sequencei346 – 38035Missing in isoform APP751. CuratedVSP_000014Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M18373 mRNA. Translation: AAA37139.1.
    X59379 mRNA. No translation available.
    U84012 mRNA. Translation: AAB41502.1.
    D10603 Genomic DNA. Translation: BAA01456.1.
    BC005490 mRNA. Translation: AAH05490.1.
    M24397 mRNA. Translation: AAA39929.1.
    X15210 mRNA. Translation: CAA33280.1.
    U82624 Genomic DNA. Translation: AAB40919.1.
    CCDSiCCDS28285.1. [P12023-2]
    PIRiA27485.
    A32282.
    S04855.
    RefSeqiNP_001185752.1. NM_001198823.1. [P12023-1]
    UniGeneiMm.277585.
    Mm.489029.
    Mm.490986.

    Genome annotation databases

    EnsembliENSMUST00000005406; ENSMUSP00000005406; ENSMUSG00000022892. [P12023-2]
    GeneIDi11820.
    KEGGimmu:11820.
    UCSCiuc007ztn.2. mouse. [P12023-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M18373 mRNA. Translation: AAA37139.1 .
    X59379 mRNA. No translation available.
    U84012 mRNA. Translation: AAB41502.1 .
    D10603 Genomic DNA. Translation: BAA01456.1 .
    BC005490 mRNA. Translation: AAH05490.1 .
    M24397 mRNA. Translation: AAA39929.1 .
    X15210 mRNA. Translation: CAA33280.1 .
    U82624 Genomic DNA. Translation: AAB40919.1 .
    CCDSi CCDS28285.1. [P12023-2 ]
    PIRi A27485.
    A32282.
    S04855.
    RefSeqi NP_001185752.1. NM_001198823.1. [P12023-1 ]
    UniGenei Mm.277585.
    Mm.489029.
    Mm.490986.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2ROZ NMR - A 739-770 [» ]
    2YSZ NMR - A 739-770 [» ]
    2YT0 NMR - A 739-770 [» ]
    2YT1 NMR - A 739-770 [» ]
    ProteinModelPortali P12023.
    SMRi P12023. Positions 26-192, 287-342, 371-566, 686-726, 741-768.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 198167. 9 interactions.
    IntActi P12023. 77 interactions.
    MINTi MINT-208509.

    Protein family/group databases

    MEROPSi I02.015.

    PTM databases

    PhosphoSitei P12023.

    Proteomic databases

    MaxQBi P12023.
    PaxDbi P12023.
    PRIDEi P12023.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000005406 ; ENSMUSP00000005406 ; ENSMUSG00000022892 . [P12023-2 ]
    GeneIDi 11820.
    KEGGi mmu:11820.
    UCSCi uc007ztn.2. mouse. [P12023-1 ]

    Organism-specific databases

    CTDi 351.
    MGIi MGI:88059. App.

    Phylogenomic databases

    eggNOGi NOG289770.
    HOGENOMi HOG000232190.
    HOVERGENi HBG000051.
    InParanoidi P12023.
    KOi K04520.
    OMAi THAHIVI.
    OrthoDBi EOG7RNJZP.
    PhylomeDBi P12023.
    TreeFami TF317274.

    Enzyme and pathway databases

    Reactomei REACT_196606. ECM proteoglycans.
    REACT_198563. Amyloids.
    REACT_198647. Advanced glycosylation endproduct receptor signaling.
    REACT_202898. TRAF6 mediated NF-kB activation.
    REACT_207651. G alpha (q) signalling events.
    REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
    REACT_222971. RIP-mediated NFkB activation via ZBP1.

    Miscellaneous databases

    ChiTaRSi app. mouse.
    EvolutionaryTracei P12023.
    NextBioi 279717.
    PROi P12023.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P12023.
    Bgeei P12023.
    CleanExi MM_APP.
    Genevestigatori P12023.

    Family and domain databases

    Gene3Di 3.30.1490.140. 1 hit.
    3.90.570.10. 1 hit.
    4.10.230.10. 1 hit.
    4.10.410.10. 1 hit.
    InterProi IPR008155. 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 ]
    PANTHERi PTHR23103:SF7. PTHR23103:SF7. 1 hit.
    Pfami 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.
    [Graphical view ]
    PRINTSi PR00203. AMYLOIDA4.
    PR00759. BASICPTASE.
    PR00204. BETAAMYLOID.
    SMARTi SM00006. A4_EXTRA. 1 hit.
    SM00131. KU. 1 hit.
    [Graphical view ]
    SUPFAMi SSF109843. SSF109843. 1 hit.
    SSF56491. SSF56491. 1 hit.
    SSF57362. SSF57362. 1 hit.
    SSF89811. SSF89811. 1 hit.
    PROSITEi PS00319. A4_EXTRA. 1 hit.
    PS00320. A4_INTRA. 1 hit.
    PS00280. BPTI_KUNITZ_1. 1 hit.
    PS50279. BPTI_KUNITZ_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Complementary DNA for the mouse homolog of the human amyloid beta protein precursor."
      Yamada T., Sasaki H., Furuya H., Miyata T., Goto I., Sakaki Y.
      Biochem. Biophys. Res. Commun. 149:665-671(1987) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
      Tissue: Brain.
    2. Yamada T.
      Submitted (MAR-1988) to the EMBL/GenBank/DDBJ databases
      Cited for: SEQUENCE REVISION.
    3. "The amyloid beta protein precursor or proteinase nexin II from mouse is closer related to its human homolog than previously reported."
      de Strooper B., van Leuven F., van den Berghe H.
      Biochim. Biophys. Acta 1129:141-143(1991) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
      Strain: BALB/c.
      Tissue: Brain.
    4. "Molecular cloning, expression, and regulation of hippocampal amyloid precursor protein of senescence accelerated mouse (SAMP8)."
      Kumar V.B., Vyas K., Franko M., Choudhary V., Buddhiraju C., Alvarez J., Morley J.E.
      Biochem. Cell Biol. 79:57-67(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
      Strain: SAMP8.
      Tissue: Hippocampus.
    5. "Positive and negative regulatory elements for the expression of the Alzheimer's disease amyloid precursor-encoding gene in mouse."
      Izumi R., Yamada T., Yoshikai S., Sasaki H., Hattori M., Sakai Y.
      Gene 112:189-195(1992) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-19.
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM APP770).
      Tissue: Mammary tumor.
    7. "Structure and expression of the alternatively-spliced forms of mRNA for the mouse homolog of Alzheimer's disease amyloid beta protein precursor."
      Yamada T., Sasaki H., Dohura K., Goto I., Sakaki Y.
      Biochem. Biophys. Res. Commun. 158:906-912(1989) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 281-380, ALTERNATIVE SPLICING.
      Tissue: Brain and Kidney.
    8. "Sequence of the protease inhibitor domain of the A4 amyloid protein precursor of Mus domesticus."
      Fukuchi K., Martin G.M., Deeb S.S.
      Nucleic Acids Res. 17:5396-5396(1989) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 289-364.
      Strain: CD-1.
      Tissue: Placenta.
    9. "Introduction of six mutations into the mouse genome using 'Hit and Run' gene-targeting: introduction of familial Alzheimer's disease mutations into the mouse amyloid precursor protein gene and humanization of the A-beta fragment."
      Wragg M.A., Busfield F., Duff K., Korenblat K., Capecchi M., Loring J.F., Goate A.M.
      Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 656-737.
      Strain: 129/Sv.
    10. "Regional distribution of the alternatively spliced isoforms of beta APP RNA transcript in the brain of normal, heterozygous and homozygous weaver mutant mice as revealed by in situ hybridization histochemistry."
      Sola C., Mengod G., Ghetti B., Palacios J.M., Triarhou L.C.
      Brain Res. Mol. Brain Res. 17:340-346(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY OF ALTERNATIVE SPLICED FORMS.
    11. "Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I."
      Kamal A., Stokin G.B., Yang Z., Xia C.-H., Goldstein L.S.
      Neuron 28:449-459(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH KNS2.
    12. "The beta-amyloid precursor protein APP is tyrosine-phosphorylated in cells expressing a constitutively active form of the Abl protoncogene."
      Zambrano N., Bruni P., Minopoli G., Mosca R., Molino D., Russo C., Schettini G., Sudol M., Russo T.
      J. Biol. Chem. 276:19787-19792(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT TYR-757.
    13. "C-jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK."
      Matsuda S., Yasukawa T., Homma Y., Ito Y., Niikura T., Hiraki T., Hirai S., Ohno S., Kita Y., Kawasumi M., Kouyama K., Yamamoto T., Kyriakis J.M., Nishimoto I.
      J. Neurosci. 21:6597-6607(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: C-TERMINAL PROTEIN-PROTEIN INTERACTION, MUTAGENESIS OF TYR-728; THR-743; TYR-757; ASN-759 AND TYR-762.
    14. "Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2."
      Morris S.M., Cooper J.A.
      Traffic 2:111-123(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH DAB2, MUTAGENESIS OF GLY-756; TYR-757; ASN-759; PRO-760 AND TYR-762.
    15. "Interaction of Alzheimer's beta-amyloid precursor family proteins with scaffold proteins of the JNK signaling cascade."
      Taru H., Iijima K., Hase M., Kirino Y., Yagi Y., Suzuki T.
      J. Biol. Chem. 277:20070-20078(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MAPK8IP1, PHOSPHORYLATION.
    16. "The gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds Numb and inhibits Notch signaling."
      Roncarati R., Sestan N., Scheinfeld M.H., Berechid B.E., Lopez P.A., Meucci O., McGlade J.C., Rakic P., D'Adamio L.
      Proc. Natl. Acad. Sci. U.S.A. 99:7102-7107(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION OF CTF PEPTIDES WITH NUMB.
    17. "The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurons in culture."
      Cupers P., Orlans I., Craessaerts K., Annaert W., De Strooper B.
      J. Neurochem. 78:1168-1178(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEOLYTIC PROCESSING BY GAMMA SECRETASE, INTERACTION WITH APBB1.
    18. "The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo."
      Cappai R., Cheng F., Ciccotosto G.D., Needham B.E., Masters C.L., Multhaup G., Fransson L.A., Mani K.
      J. Biol. Chem. 280:13913-13920(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, FUNCTION.
    19. "Amyloid precursor proteins anchor CPEB to membranes and promote polyadenylation-induced translation."
      Cao Q., Huang Y.-S., Kan M.-C., Richter J.D.
      Mol. Cell. Biol. 25:10930-10939(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CPEB1.
    20. Cited for: INTERACTION WITH APP.

    Entry informationi

    Entry nameiA4_MOUSE
    AccessioniPrimary (citable) accession number: P12023
    Secondary accession number(s): P97487, P97942, Q99K32
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1989
    Last sequence update: May 9, 2003
    Last modified: October 1, 2014
    This is version 184 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. Rat and mouse beta-amyloid peptides have an arginine residue substituted for the bridging histidine residue and are thus less capable of forming amyloid aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding By similarity.By similarity

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3