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P08592

- A4_RAT

UniProt

P08592 - A4_RAT

Protein

Amyloid beta A4 protein

Gene

App

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 176 (01 Oct 2014)
      Sequence version 2 (01 Dec 1992)
      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 By similarity. Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb By similarity. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 By similarity. 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 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.By similarity
    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 elicits inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also bind GPC1 in lipid rafts By similarity.By similarity
    Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.
    The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.By similarity
    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-6
    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
    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: UniProtKB
    2. growth factor receptor binding Source: RGD
    3. heparin binding Source: UniProtKB-KW
    4. peptidase activator activity Source: RGD
    5. protein binding Source: RGD
    6. serine-type endopeptidase inhibitor activity Source: UniProtKB-KW
    7. 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. cell adhesion Source: UniProtKB-KW
    6. cellular copper ion homeostasis Source: UniProtKB
    7. cholesterol metabolic process Source: Ensembl
    8. collateral sprouting in absence of injury Source: UniProtKB
    9. dendrite development Source: UniProtKB
    10. endocytosis Source: UniProtKB
    11. extracellular matrix organization Source: UniProtKB
    12. forebrain development Source: Ensembl
    13. ionotropic glutamate receptor signaling pathway Source: UniProtKB
    14. locomotory behavior Source: UniProtKB
    15. mating behavior Source: UniProtKB
    16. mitotic G2 phase Source: UniProtKB
    17. mRNA polyadenylation Source: UniProtKB
    18. negative regulation of neuron differentiation Source: Ensembl
    19. neuromuscular process controlling balance Source: Ensembl
    20. neuron apoptotic process Source: Ensembl
    21. neuron projection development Source: UniProtKB
    22. neuron remodeling Source: UniProtKB
    23. Notch signaling pathway Source: UniProtKB-KW
    24. positive regulation of G2/M transition of mitotic cell cycle Source: Ensembl
    25. positive regulation of mitotic cell cycle Source: UniProtKB
    26. positive regulation of peptidase activity Source: GOC
    27. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
    28. protein phosphorylation Source: UniProtKB
    29. regulation of epidermal growth factor-activated receptor activity Source: UniProtKB
    30. regulation of multicellular organism growth Source: UniProtKB
    31. regulation of protein binding Source: Ensembl
    32. regulation of synapse structure and activity Source: UniProtKB
    33. regulation of translation Source: UniProtKB
    34. response to oxidative stress Source: Ensembl
    35. smooth endoplasmic reticulum calcium ion homeostasis Source: Ensembl
    36. suckling behavior Source: Ensembl
    37. synaptic growth at neuromuscular junction Source: Ensembl
    38. 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

    ReactomeiREACT_194364. RIP-mediated NFkB activation via ZBP1.
    REACT_196231. Advanced glycosylation endproduct receptor signaling.
    REACT_198757. ECM proteoglycans.
    REACT_199225. Amyloids.

    Protein family/group databases

    MEROPSiI02.015.
    TCDBi1.C.50.1.1. the amyloid -protein peptide (app) family.

    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):
    Beta-APP42
    Alternative name(s):
    Beta-APP40
    Alternative name(s):
    Gamma-CTF(59)
    Alternative name(s):
    Gamma-CTF(57)
    Alternative name(s):
    Gamma-CTF(50)
    Gene namesi
    Name:App
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 11

    Organism-specific databases

    RGDi2139. 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). Associates with GPC1 in perinuclear compartments By similarity. 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-742 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body.By similarity

    GO - Cellular componenti

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

    Keywords - Cellular componenti

    Amyloid, Coated pit, Membrane

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi656 – 6561S → A: No chondroitin sulfate linkage to isoform L-APP733. 2 Publications
    Mutagenesisi704 – 7041G → V: Little oxidized neuronal proteins. Scarce beta-APP42 peptide aggregation. No neurotoxicity. 2 Publications
    Mutagenesisi732 – 7332HH → GL or GP: Almost complete loss of binding to GNAO1. No inhibition of GTPase activity. 1 Publication
    Mutagenesisi743 – 7431T → A: No effect on neurite growth and maturation. 2 Publications
    Mutagenesisi743 – 7431T → E: Inhibits neurite growth and maturation. 2 Publications
    Mutagenesisi757 – 7571Y → G: No DBB1 binding. 2 Publications
    Mutagenesisi759 – 7591N → A: Some DBB1 binding. 2 Publications
    Mutagenesisi762 – 7621Y → A: Some DBB1 binding. 2 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 1717By similarityAdd
    BLAST
    Chaini18 – 770753Amyloid beta A4 proteinPRO_0000000159Add
    BLAST
    Chaini18 – 687670Soluble APP-alphaBy similarityPRO_0000000160Add
    BLAST
    Chaini18 – 671654Soluble APP-betaSequence AnalysisPRO_0000000161Add
    BLAST
    Chaini18 – 286269N-APPBy similarityPRO_0000381971Add
    BLAST
    Chaini672 – 77099C99Sequence AnalysisPRO_0000000162Add
    BLAST
    Chaini672 – 71342Beta-amyloid protein 42By similarityPRO_0000000163Add
    BLAST
    Chaini672 – 71140Beta-amyloid protein 40By similarityPRO_0000000164Add
    BLAST
    Chaini688 – 77083C83By similarityPRO_0000000165Add
    BLAST
    Peptidei688 – 71326P3(42)By similarityPRO_0000000166Add
    BLAST
    Peptidei688 – 71124P3(40)By similarityPRO_0000000167Add
    BLAST
    Chaini691 – 77080C80PRO_0000384579Add
    BLAST
    Chaini712 – 77059Gamma-secretase C-terminal fragment 59PRO_0000000168Add
    BLAST
    Chaini714 – 77057Gamma-secretase C-terminal fragment 57PRO_0000000169Add
    BLAST
    Chaini721 – 77050Gamma-secretase C-terminal fragment 50PRO_0000000170Add
    BLAST
    Chaini740 – 77031C31By similarityPRO_0000000171Add
    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...)Sequence Analysis
    Glycosylationi571 – 5711N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi656 – 6561O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms
    Modified residuei729 – 7291Phosphothreonine
    Modified residuei730 – 7301Phosphoserine; by APP-kinase I1 Publication
    Modified residuei743 – 7431Phosphothreonine; by CDK5 and MAPK101 Publication
    Modified residuei757 – 7571Phosphotyrosine; by ABL1By 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 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
    N-glycosylated.
    O-glycosylated. O-linkage of chondroitin sulfate to the L-APP isoforms produces the APP proteoglycan core proteins, the appicans. The chondroitin sulfate chain of appicans contains 4-O-sulfated galactose in the linkage region and chondroitin sulfate E in the repeated disaccharide region.
    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. 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.4 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.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, Proteoglycan

    Proteomic databases

    PaxDbiP08592.
    PRIDEiP08592.

    PTM databases

    PhosphoSiteiP08592.

    Expressioni

    Tissue specificityi

    In the brain, non-L-APP isoforms are expressed in neurons, isoform APP695 being the predominant form. In astrocytes and microglial cells, almost 50% is L-isoform (appican).2 Publications

    Developmental stagei

    From 6 days to 7 months, levels of KPI-containing isoforms increase in the brain cortex and hippocampus. Levels of L-APP increase in all brain regions during the same period, but levels are low compared to non-L-APP isoforms.

    Inductioni

    Phosphorylation of mature, glycosylated APP occurs 48-72 hours after treatment of neuronal cells with nerve growth factor which correlates with the timing of neurite outgrowth.1 Publication

    Gene expression databases

    GenevestigatoriP08592.

    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) By similarity 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 By similarity. Beta-amyloid associates with HADH2 By similarity. Interacts with CPEB1, ANKS1B, TNFRSF21 and AGER By similarity. 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 By similarity. Interacts with PLD3 By similarity.By similarity

    Protein-protein interaction databases

    BioGridi248450. 2 interactions.
    DIPiDIP-6114N.
    DIP-618N.
    DIP-685N.
    IntActiP08592. 7 interactions.
    MINTiMINT-1521802.

    Structurei

    Secondary structure

    1
    770
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Turni679 – 6868
    Helixi687 – 6959

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1M7EX-ray2.45D/E/F755-763[»]
    1NMJNMR-A672-699[»]
    1OQNX-ray2.30C/D755-763[»]
    ProteinModelPortaliP08592.
    SMRiP08592. Positions 28-189, 287-342, 374-565, 672-699, 739-770.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP08592.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini18 – 699682ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini724 – 77047CytoplasmicBy similarityAdd
    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
    Regioni135 – 15521Copper-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)-alphaAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi724 – 73411Basolateral sorting signalBy similarityAdd
    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.

    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.
    GeneTreeiENSGT00530000063252.
    HOGENOMiHOG000232190.
    HOVERGENiHBG000051.
    InParanoidiP08592.
    KOiK04520.
    OMAiTHAHIVI.
    OrthoDBiEOG7RNJZP.
    PhylomeDBiP08592.
    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 (8)i

    Sequence statusi: Complete.

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

    This entry describes 8 isoformsi produced by alternative splicing. Align

    Isoform APP770 (identifier: P08592-1) [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 EESDSIDSAD 200
    AEEDDSDVWW GGADTDYADG GEDKVVEVAE EEEVADVEEE EAEDDEDVED 250
    GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC 300
    RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVSSQSLL 350
    KTTSEPLPQD PVKLPTTAAS 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):86,704
    Last modified:December 1, 1992 - v2
    Checksum:iC26C9D6BB2D929A7
    GO
    Isoform APP695 (identifier: P08592-2) [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):78,483
    Checksum:i61D21E1E941972DC
    GO
    Isoform L-APP677 (identifier: P08592-3)

    Sequence is not available

    Note: L-isoforms are referred to as appicans.

    Length:
    Mass (Da):
    Isoform L-APP696 (identifier: P08592-4)

    Sequence is not available

    Note: L-isoforms are referred to as appicans.

    Length:
    Mass (Da):
    Isoform APP714 (identifier: P08592-5)

    Sequence is not available
    Length:
    Mass (Da):
    Isoform L-APP733 (identifier: P08592-6)

    Sequence is not available

    Note: L-isoforms are referred to as appicans.

    Length:
    Mass (Da):
    Isoform APP751 (identifier: P08592-7)

    Sequence is not available
    Length:
    Mass (Da):
    Isoform L-APP752 (identifier: P08592-8)

    Sequence is not available

    Note: L-isoforms are referred to as appicans.

    Length:
    Mass (Da):

    Mass spectrometryi

    Molecular mass is 5911.3 Da from positions 721 - 770. Determined by MALDI. 1 Publication
    Molecular mass is 6024.4 Da from positions 720 - 770. Determined by MALDI. 1 Publication

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei289 – 2891E → V in isoform APP695. 1 PublicationVSP_000015
    Alternative sequencei290 – 36475Missing in isoform APP695. 1 PublicationVSP_000016Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X07648 mRNA. Translation: CAA30488.1.
    AF513015 mRNA. Translation: AAM90259.1.
    X14066 mRNA. Translation: CAA32229.1.
    PIRiS00550.
    S03607.
    S23094.
    RefSeqiNP_062161.1. NM_019288.2. [P08592-1]
    XP_006248073.1. XM_006248011.1. [P08592-2]
    UniGeneiRn.2104.

    Genome annotation databases

    EnsembliENSRNOT00000044081; ENSRNOP00000040243; ENSRNOG00000006997. [P08592-2]
    ENSRNOT00000048854; ENSRNOP00000041613; ENSRNOG00000006997. [P08592-1]
    GeneIDi54226.
    KEGGirno:54226.
    UCSCiRGD:2139. rat. [P08592-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X07648 mRNA. Translation: CAA30488.1 .
    AF513015 mRNA. Translation: AAM90259.1 .
    X14066 mRNA. Translation: CAA32229.1 .
    PIRi S00550.
    S03607.
    S23094.
    RefSeqi NP_062161.1. NM_019288.2. [P08592-1 ]
    XP_006248073.1. XM_006248011.1. [P08592-2 ]
    UniGenei Rn.2104.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1M7E X-ray 2.45 D/E/F 755-763 [» ]
    1NMJ NMR - A 672-699 [» ]
    1OQN X-ray 2.30 C/D 755-763 [» ]
    ProteinModelPortali P08592.
    SMRi P08592. Positions 28-189, 287-342, 374-565, 672-699, 739-770.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 248450. 2 interactions.
    DIPi DIP-6114N.
    DIP-618N.
    DIP-685N.
    IntActi P08592. 7 interactions.
    MINTi MINT-1521802.

    Protein family/group databases

    MEROPSi I02.015.
    TCDBi 1.C.50.1.1. the amyloid -protein peptide (app) family.

    PTM databases

    PhosphoSitei P08592.

    Proteomic databases

    PaxDbi P08592.
    PRIDEi P08592.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000044081 ; ENSRNOP00000040243 ; ENSRNOG00000006997 . [P08592-2 ]
    ENSRNOT00000048854 ; ENSRNOP00000041613 ; ENSRNOG00000006997 . [P08592-1 ]
    GeneIDi 54226.
    KEGGi rno:54226.
    UCSCi RGD:2139. rat. [P08592-1 ]

    Organism-specific databases

    CTDi 351.
    RGDi 2139. App.

    Phylogenomic databases

    eggNOGi NOG289770.
    GeneTreei ENSGT00530000063252.
    HOGENOMi HOG000232190.
    HOVERGENi HBG000051.
    InParanoidi P08592.
    KOi K04520.
    OMAi THAHIVI.
    OrthoDBi EOG7RNJZP.
    PhylomeDBi P08592.
    TreeFami TF317274.

    Enzyme and pathway databases

    Reactomei REACT_194364. RIP-mediated NFkB activation via ZBP1.
    REACT_196231. Advanced glycosylation endproduct receptor signaling.
    REACT_198757. ECM proteoglycans.
    REACT_199225. Amyloids.

    Miscellaneous databases

    EvolutionaryTracei P08592.
    NextBioi 610648.
    PROi P08592.

    Gene expression databases

    Genevestigatori P08592.

    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. "Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact."
      Shivers B.D., Hilbich C., Multhaup G., Salbaum J.M., Beyreuther K., Seeburg P.H.
      EMBO J. 7:1365-1370(1988) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
      Tissue: Brain.
    2. "A new beta amyloid precursor protein cDNA found in Rat6 embryo fibroblasts."
      Feng J., Song S., Zheng J.
      Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP770).
    3. "Amyloid beta protein precursor is possibly a heparan sulfate proteoglycan core protein."
      Schubert D., Schroeder R., LaCorbiere M., Saitoh T., Cole G.
      Science 241:223-226(1988) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 18-44.
    4. "Purification and tissue level of the beta-amyloid peptide precursor of rat brain."
      Potempska A., Styles J., Mehta P., Kim K.S., Miller D.L.
      J. Biol. Chem. 266:8464-8469(1991) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 18-32.
    5. "The sequence of the two extra exons in rat preA4."
      Kang J., Mueller-Hill B.
      Nucleic Acids Res. 17:2130-2130(1989) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 289-364.
      Tissue: Liver.
    6. "Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch."
      Gu Y., Misonou H., Sato T., Dohmae N., Takio K., Ihara Y.
      J. Biol. Chem. 276:35235-35238(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 720-730, MASS SPECTROMETRY.
    7. "APP gene family. Alternative splicing generates functionally related isoforms."
      Sandbrink R., Masters C.L., Beyreuther K.
      Ann. N. Y. Acad. Sci. 777:281-287(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: ALTERNATIVE SPLICING.
    8. "The Alzheimer amyloid precursor proteoglycan (appican) is present in brain and is produced by astrocytes but not by neurons in primary neural cultures."
      Shioi J., Pangalos M.N., Ripellino J.A., Vassilacopoulou D., Mytilineou C., Margolis R.U., Robakis N.K.
      J. Biol. Chem. 270:11839-11844(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY OF APPICAN.
    9. "Expression of the APP gene family in brain cells, brain development and aging."
      Sandbrink R., Monning U., Masters C.L., Beyreuther K.
      Gerontology 43:119-131(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY OF ISOFORMS.
    10. "A 127-kDa protein (UV-DDB) binds to the cytoplasmic domain of the Alzheimer's amyloid precursor protein."
      Watanabe T., Sukegawa J., Tomita S., Iijima K., Oguchi S., Suzuki T., Nairn A.C., Greengard P.
      J. Neurochem. 72:549-556(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH DDB1, MUTAGENESIS OF TYR-757; ASN-759 AND TYR-762.
    11. "The amyloid precursor protein interacts with Go heterotrimeric protein within a cell compartment specialized in signal transduction."
      Brouillet E., Trembleau A., Galanaud D., Volovitch M., Bouillot C., Valenza C., Prochiantz A., Allinquant B.
      J. Neurosci. 19:1717-1727(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH GNAO1, MUTAGENESIS OF 732-HIS-HIS-733.
    12. "The beta A4 amyloid precursor protein binding to copper."
      Hesse L., Beher D., Masters C.L., Multhaup G.
      FEBS Lett. 349:109-116(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: COPPER-BINDING.
    13. "The chondroitin sulfate attachment site of appican is formed by splicing out exon 15 of the amyloid precursor gene."
      Pangalos M.N., Efthimiopoulos S., Shioi J., Robakis N.K.
      J. Biol. Chem. 270:10388-10391(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERISTICS OF APPICAN, MUTAGENESIS OF SER-656.
    14. "The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction."
      Huang X., Atwood C.S., Hartshorn M.A., Multhaup G., Goldstein L.E., Scarpa R.C., Cuajungco M.P., Gray D.N., Lim J., Moir R.D., Tanzi R.E., Bush A.I.
      Biochemistry 38:7609-7616(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: BETA-AMYLOID METAL-BINDING.
    15. "Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease."
      Liu S.T., Howlett G., Barrow C.J.
      Biochemistry 38:9373-9378(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: BETA-AMYLOID ZINC-BINDING.
    16. "Role of glycine-33 and methionine-35 in Alzheimer's amyloid beta-peptide 1-42-associated oxidative stress and neurotoxicity."
      Kanski J., Varadarajan S., Aksenova M., Butterfield D.A.
      Biochim. Biophys. Acta 1586:190-198(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: IMPORTANCE OF GLY-704 IN FREE RADICAL PROPAGATION, MUTAGENESIS OF GLY-704.
    17. "The cytoplasmic domain of Alzheimer's amyloid precursor protein is phosphorylated at Thr654, Ser655, and Thr668 in adult rat brain and cultured cells."
      Oishi M., Nairn A.C., Czernik A.J., Lim G.S., Isohara T., Gandy S.E., Greengard P., Suzuki T.
      Mol. Med. 3:111-123(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION.
    18. "Phosphorylation of the cytoplasmic domain of Alzheimer's beta-amyloid precursor protein at Ser655 by a novel protein kinase."
      Isohara T., Horiuchi A., Watanabe T., Ando K., Czernik A.J., Uno I., Greengard P., Nairn A.C., Suzuki T.
      Biochem. Biophys. Res. Commun. 258:300-305(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-730.
    19. "Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation."
      Ando K., Oishi M., Takeda S., Iijima K., Isohara T., Nairn A.C., Kirino Y., Greengard P., Suzuki T.
      J. Neurosci. 19:4421-4427(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION, INDUCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-743.
    20. "Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5."
      Iijima K., Ando K., Takeda S., Satoh Y., Seki T., Itohara S., Greengard P., Kirino Y., Nairn A.C., Suzuki T.
      J. Neurochem. 75:1085-1091(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-743.
    21. "Appican, the proteoglycan form of the amyloid precursor protein, contains chondroitin sulfate E in the repeating disaccharide region and 4-O-sulfated galactose in the linkage region."
      Tsuchida K., Shioi J., Yamada S., Boghosian G., Wu A., Cai H., Sugahara K., Robakis N.K.
      J. Biol. Chem. 276:37155-37160(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE OF CARBOHYDRATE IN APPICAN.

    Entry informationi

    Entry nameiA4_RAT
    AccessioniPrimary (citable) accession number: P08592
    Secondary accession number(s): Q547B7
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: August 1, 1988
    Last sequence update: December 1, 1992
    Last modified: October 1, 2014
    This is version 176 of the entry and version 2 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, Direct protein sequencing, Reference proteome

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3