A4_RAT
ID A4_RAT Reviewed; 770 AA.
AC P08592; Q547B7;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 2.
DT 03-AUG-2022, entry version 241.
DE RecName: Full=Amyloid-beta precursor protein {ECO:0000312|RGD:2139};
DE AltName: Full=ABPP;
DE Short=APP;
DE AltName: Full=Alzheimer disease amyloid A4 protein homolog;
DE AltName: Full=Alzheimer disease amyloid protein;
DE AltName: Full=Amyloid precursor protein {ECO:0000305};
DE AltName: Full=Amyloid-beta (A4) precursor protein {ECO:0000312|RGD:2139};
DE AltName: Full=Amyloid-beta A4 protein {ECO:0000312|RGD:2139};
DE AltName: Full=Amyloidogenic glycoprotein;
DE Short=AG;
DE Contains:
DE RecName: Full=N-APP;
DE Contains:
DE RecName: Full=Soluble APP-alpha;
DE Short=S-APP-alpha;
DE Contains:
DE RecName: Full=Soluble APP-beta;
DE Short=S-APP-beta;
DE Contains:
DE RecName: Full=C99;
DE AltName: Full=Beta-secretase C-terminal fragment;
DE Short=Beta-CTF;
DE Contains:
DE RecName: Full=Amyloid-beta protein 42;
DE Short=Abeta42;
DE AltName: Full=Beta-APP42;
DE Contains:
DE RecName: Full=Amyloid-beta protein 40;
DE Short=Abeta40;
DE AltName: Full=Beta-APP40;
DE Contains:
DE RecName: Full=C83;
DE AltName: Full=Alpha-secretase C-terminal fragment;
DE Short=Alpha-CTF;
DE Contains:
DE RecName: Full=P3(42);
DE Contains:
DE RecName: Full=P3(40);
DE Contains:
DE RecName: Full=C80;
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 59;
DE AltName: Full=Gamma-CTF(59);
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 57;
DE AltName: Full=Gamma-CTF(57);
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 50;
DE AltName: Full=Gamma-CTF(50);
DE Contains:
DE RecName: Full=C31;
DE Flags: Precursor;
GN Name=App {ECO:0000312|RGD:2139};
GN Synonyms=A4 {ECO:0000250|UniProtKB:P05067},
GN AD1 {ECO:0000250|UniProtKB:P05067};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC TISSUE=Brain;
RX PubMed=2900758; DOI=10.1002/j.1460-2075.1988.tb02952.x;
RA Shivers B.D., Hilbich C., Multhaup G., Salbaum J.M., Beyreuther K.,
RA Seeburg P.H.;
RT "Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat
RT brain suggests a role in cell contact.";
RL EMBO J. 7:1365-1370(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP770).
RA Feng J., Song S., Zheng J.;
RT "A new beta amyloid precursor protein cDNA found in Rat6 embryo
RT fibroblasts.";
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PROTEIN SEQUENCE OF 18-44.
RX PubMed=2968652; DOI=10.1126/science.2968652;
RA Schubert D., Schroeder R., LaCorbiere M., Saitoh T., Cole G.;
RT "Amyloid beta protein precursor is possibly a heparan sulfate proteoglycan
RT core protein.";
RL Science 241:223-226(1988).
RN [4]
RP PROTEIN SEQUENCE OF 18-32.
RX PubMed=1673681; DOI=10.1016/s0021-9258(18)92997-2;
RA Potempska A., Styles J., Mehta P., Kim K.S., Miller D.L.;
RT "Purification and tissue level of the beta-amyloid peptide precursor of rat
RT brain.";
RL J. Biol. Chem. 266:8464-8469(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 289-364.
RC TISSUE=Liver;
RX PubMed=2648331; DOI=10.1093/nar/17.5.2130;
RA Kang J., Mueller-Hill B.;
RT "The sequence of the two extra exons in rat preA4.";
RL Nucleic Acids Res. 17:2130-2130(1989).
RN [6]
RP PROTEIN SEQUENCE OF 720-730, AND MASS SPECTROMETRY.
RX PubMed=11483588; DOI=10.1074/jbc.c100357200;
RA Gu Y., Misonou H., Sato T., Dohmae N., Takio K., Ihara Y.;
RT "Distinct intramembrane cleavage of the beta-amyloid precursor protein
RT family resembling gamma-secretase-like cleavage of Notch.";
RL J. Biol. Chem. 276:35235-35238(2001).
RN [7]
RP ALTERNATIVE SPLICING.
RX PubMed=8624099; DOI=10.1111/j.1749-6632.1996.tb34433.x;
RA Sandbrink R., Masters C.L., Beyreuther K.;
RT "APP gene family. Alternative splicing generates functionally related
RT isoforms.";
RL Ann. N. Y. Acad. Sci. 777:281-287(1996).
RN [8]
RP TISSUE SPECIFICITY OF APPICAN.
RX PubMed=7744833; DOI=10.1074/jbc.270.20.11839;
RA Shioi J., Pangalos M.N., Ripellino J.A., Vassilacopoulou D., Mytilineou C.,
RA Margolis R.U., Robakis N.K.;
RT "The Alzheimer amyloid precursor proteoglycan (appican) is present in brain
RT and is produced by astrocytes but not by neurons in primary neural
RT cultures.";
RL J. Biol. Chem. 270:11839-11844(1995).
RN [9]
RP TISSUE SPECIFICITY OF ISOFORMS.
RX PubMed=8996834; DOI=10.1159/000213840;
RA Sandbrink R., Monning U., Masters C.L., Beyreuther K.;
RT "Expression of the APP gene family in brain cells, brain development and
RT aging.";
RL Gerontology 43:119-131(1997).
RN [10]
RP INTERACTION WITH DDB1, AND MUTAGENESIS OF TYR-757; ASN-759 AND TYR-762.
RX PubMed=9930726; DOI=10.1046/j.1471-4159.1999.0720549.x;
RA Watanabe T., Sukegawa J., Tomita S., Iijima K., Oguchi S., Suzuki T.,
RA Nairn A.C., Greengard P.;
RT "A 127-kDa protein (UV-DDB) binds to the cytoplasmic domain of the
RT Alzheimer's amyloid precursor protein.";
RL J. Neurochem. 72:549-556(1999).
RN [11]
RP INTERACTION WITH GNAO1, AND MUTAGENESIS OF 732-HIS-HIS-733.
RX PubMed=10024358; DOI=10.1523/jneurosci.19-05-01717.1999;
RA Brouillet E., Trembleau A., Galanaud D., Volovitch M., Bouillot C.,
RA Valenza C., Prochiantz A., Allinquant B.;
RT "The amyloid precursor protein interacts with Go heterotrimeric protein
RT within a cell compartment specialized in signal transduction.";
RL J. Neurosci. 19:1717-1727(1999).
RN [12]
RP COPPER-BINDING.
RX PubMed=7913895; DOI=10.1016/0014-5793(94)00658-x;
RA Hesse L., Beher D., Masters C.L., Multhaup G.;
RT "The beta A4 amyloid precursor protein binding to copper.";
RL FEBS Lett. 349:109-116(1994).
RN [13]
RP CHARACTERISTICS OF APPICAN, AND MUTAGENESIS OF SER-656.
RX PubMed=7737970; DOI=10.1074/jbc.270.18.10388;
RA Pangalos M.N., Efthimiopoulos S., Shioi J., Robakis N.K.;
RT "The chondroitin sulfate attachment site of appican is formed by splicing
RT out exon 15 of the amyloid precursor gene.";
RL J. Biol. Chem. 270:10388-10391(1995).
RN [14]
RP AMYLOID-BETA METAL-BINDING.
RX PubMed=10386999; DOI=10.1021/bi990438f;
RA Huang X., Atwood C.S., Hartshorn M.A., Multhaup G., Goldstein L.E.,
RA Scarpa R.C., Cuajungco M.P., Gray D.N., Lim J., Moir R.D., Tanzi R.E.,
RA Bush A.I.;
RT "The A beta peptide of Alzheimer's disease directly produces hydrogen
RT peroxide through metal ion reduction.";
RL Biochemistry 38:7609-7616(1999).
RN [15]
RP AMYLOID-BETA ZINC-BINDING.
RX PubMed=10413512; DOI=10.1021/bi990205o;
RA Liu S.T., Howlett G., Barrow C.J.;
RT "Histidine-13 is a crucial residue in the zinc ion-induced aggregation of
RT the A beta peptide of Alzheimer's disease.";
RL Biochemistry 38:9373-9378(1999).
RN [16]
RP IMPORTANCE OF GLY-704 IN FREE RADICAL PROPAGATION, AND MUTAGENESIS OF
RP GLY-704.
RX PubMed=11959460; DOI=10.1016/s0925-4439(01)00097-7;
RA Kanski J., Varadarajan S., Aksenova M., Butterfield D.A.;
RT "Role of glycine-33 and methionine-35 in Alzheimer's amyloid-beta peptide
RT 1-42-associated oxidative stress and neurotoxicity.";
RL Biochim. Biophys. Acta 1586:190-198(2002).
RN [17]
RP PHOSPHORYLATION AT THR-729; SER-730 AND THR-743.
RX PubMed=9085254; DOI=10.1007/bf03401803;
RA Oishi M., Nairn A.C., Czernik A.J., Lim G.S., Isohara T., Gandy S.E.,
RA Greengard P., Suzuki T.;
RT "The cytoplasmic domain of Alzheimer's amyloid precursor protein is
RT phosphorylated at Thr654, Ser655, and Thr668 in adult rat brain and
RT cultured cells.";
RL Mol. Med. 3:111-123(1997).
RN [18]
RP PHOSPHORYLATION AT SER-730.
RX PubMed=10329382; DOI=10.1006/bbrc.1999.0637;
RA Isohara T., Horiuchi A., Watanabe T., Ando K., Czernik A.J., Uno I.,
RA Greengard P., Nairn A.C., Suzuki T.;
RT "Phosphorylation of the cytoplasmic domain of Alzheimer's beta-amyloid
RT precursor protein at Ser655 by a novel protein kinase.";
RL Biochem. Biophys. Res. Commun. 258:300-305(1999).
RN [19]
RP PHOSPHORYLATION, INDUCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP THR-743.
RX PubMed=10341243; DOI=10.1523/jneurosci.19-11-04421.1999;
RA Ando K., Oishi M., Takeda S., Iijima K., Isohara T., Nairn A.C., Kirino Y.,
RA Greengard P., Suzuki T.;
RT "Role of phosphorylation of Alzheimer's amyloid precursor protein during
RT neuronal differentiation.";
RL J. Neurosci. 19:4421-4427(1999).
RN [20]
RP PHOSPHORYLATION AT THR-743.
RX PubMed=10936190; DOI=10.1046/j.1471-4159.2000.0751085.x;
RA Iijima K., Ando K., Takeda S., Satoh Y., Seki T., Itohara S., Greengard P.,
RA Kirino Y., Nairn A.C., Suzuki T.;
RT "Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor
RT protein by cyclin-dependent kinase 5.";
RL J. Neurochem. 75:1085-1091(2000).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-441, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [22]
RP INTERACTION WITH KIF5B, AND TISSUE SPECIFICITY.
RX PubMed=23011729; DOI=10.1088/1478-3975/9/5/055005;
RA Seamster P.E., Loewenberg M., Pascal J., Chauviere A., Gonzales A.,
RA Cristini V., Bearer E.L.;
RT "Quantitative measurements and modeling of cargo-motor interactions during
RT fast transport in the living axon.";
RL Phys. Biol. 9:055005-055005(2012).
RN [23]
RP UBIQUITINATION AT LYS-763, AND MUTAGENESIS OF LYS-763.
RX PubMed=22847417; DOI=10.1073/pnas.1206786109;
RA El Ayadi A., Stieren E.S., Barral J.M., Boehning D.;
RT "Ubiquilin-1 regulates amyloid precursor protein maturation and degradation
RT by stimulating K63-linked polyubiquitination of lysine 688.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:13416-13421(2012).
RN [24]
RP PROTEOLYTIC PROCESSING, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=26479776; DOI=10.1021/acs.jproteome.5b00820;
RA Tsuchiya T., Osaki T., Minamino N., Sasaki K.;
RT "Peptidomics for studying limited proteolysis.";
RL J. Proteome Res. 14:4921-4931(2015).
RN [25]
RP STRUCTURE OF CARBOHYDRATE IN APPICAN, AND GLYCOSYLATION.
RX PubMed=11479316; DOI=10.1074/jbc.m105818200;
RA Tsuchida K., Shioi J., Yamada S., Boghosian G., Wu A., Cai H., Sugahara K.,
RA Robakis N.K.;
RT "Appican, the proteoglycan form of the amyloid precursor protein, contains
RT chondroitin sulfate E in the repeating disaccharide region and 4-O-sulfated
RT galactose in the linkage region.";
RL J. Biol. Chem. 276:37155-37160(2001).
CC -!- FUNCTION: Functions as a cell surface receptor and performs
CC physiological functions on the surface of neurons relevant to neurite
CC growth, neuronal adhesion and axonogenesis. Interaction between APP
CC molecules on neighboring cells promotes synaptogenesis. Involved in
CC cell mobility and transcription regulation through protein-protein
CC interactions (By similarity). Can promote transcription activation
CC through binding to APBB1-KAT5 and inhibit Notch signaling through
CC interaction with Numb (By similarity). Couples to apoptosis-inducing
CC pathways such as those mediated by G(o) and JIP. Inhibits G(o)-alpha
CC ATPase activity. Acts as a kinesin I membrane receptor, mediating the
CC axonal transport of beta-secretase and presenilin 1 (By similarity). By
CC acting as a kinesin I membrane receptor, plays a role in axonal
CC anterograde transport of cargo towards synapes in axons (By
CC similarity). May be involved in copper homeostasis/oxidative stress
CC through copper ion reduction. Can regulate neurite outgrowth through
CC binding to components of the extracellular matrix such as heparin and
CC collagen I and IV (By similarity). The splice isoforms that contain the
CC BPTI domain possess protease inhibitor activity. Induces a AGER-
CC dependent pathway that involves activation of p38 MAPK, resulting in
CC internalization of amyloid-beta peptide and leading to mitochondrial
CC dysfunction in cultured mitochondrial dysfunction in cultured cortical
CC neurons. Provides Cu(2+) ions for GPC1 which are required for release
CC of nitric oxide (NO) and subsequent degradation of the heparan sulfate
CC chains on GPC1 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P05067}.
CC -!- FUNCTION: Amyloid-beta peptides are lipophilic metal chelators with
CC metal-reducing activity. Binds transient metals such as copper, zinc
CC and iron. Rat and mouse amyloid-beta peptides bind only weakly
CC transient metals and have little reducing activity due to substitutions
CC of transient metal chelating residues. Amyloid-beta protein 42 may
CC activate mononuclear phagocytes in the brain and elicits inflammatory
CC responses. Promotes both tau aggregation and TPK II-mediated
CC phosphorylation. Also binds GPC1 in lipid rafts (By similarity).
CC {ECO:0000250}.
CC -!- FUNCTION: Appicans elicit adhesion of neural cells to the extracellular
CC matrix and may regulate neurite outgrowth in the brain.
CC -!- FUNCTION: The gamma-CTF peptides as well as the caspase-cleaved
CC peptides, including C31, are potent enhancers of neuronal apoptosis.
CC {ECO:0000250}.
CC -!- FUNCTION: N-APP binds TNFRSF21 triggering caspase activation and
CC degeneration of both neuronal cell bodies (via caspase-3) and axons
CC (via caspase-6). {ECO:0000250}.
CC -!- SUBUNIT: Binds, via its C-terminus, to the PID domain of several
CC cytoplasmic proteins, including APBB family members, the APBA family,
CC MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1
CC inhibits its serine phosphorylation (By similarity). Interacts (via
CC NPXY motif) with DAB2 (via PID domain); the interaction is impaired by
CC tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-
CC like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via
CC BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By
CC similarity). Associates with microtubules in the presence of ATP and in
CC a kinesin-dependent manner (By similarity). Interacts, through a C-
CC terminal domain, with GNAO1. Amyloid-beta protein 42 binds CHRNA7 in
CC hippocampal neurons (By similarity). Amyloid-beta associates with HADH2
CC (By similarity). Interacts with CPEB1, ANKS1B, TNFRSF21 and AGER (By
CC similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with
CC IDE. Can form homodimers; dimerization is enhanced in the presence of
CC Cu(2+) ions. Can form homodimers; this is promoted by heparin binding
CC (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By
CC similarity). CTF-alpha product of APP interacts with GSAP (By
CC similarity). Isoform APP695 interacts with SORL1 (via N-terminal
CC ectodomain); this interaction retains APP in the trans-Golgi network
CC and reduces processing into soluble APP-alpha and amyloid-beta peptides
CC (By similarity). The C99 fragment also interacts with SORL1 (By
CC similarity). Isoform APP751 interacts with SORL1 (By similarity).
CC Isoform APP770 interacts with SORL1 (By similarity). Interacts with
CC PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts
CC with NSG1; could regulate APP processing (By similarity). Amyloid-beta
CC protein 42 interacts with FPR2 (By similarity). Interacts with SYT7 (By
CC similarity). Interacts (via transmembrane region) with PSEN1; the
CC interaction is direct (By similarity). Interacts with LRRK2 (By
CC similarity). Interacts (via cytoplasmic domain) with KIF5B
CC (PubMed:23011729). Interacts (via C-terminus) with APBB2/FE65L1 (via C-
CC terminus) (By similarity). Interacts (via intracellular domain) with
CC APBB3 (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P05067,
CC ECO:0000250|UniProtKB:P12023, ECO:0000269|PubMed:23011729}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P05067};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:P05067}.
CC Membrane {ECO:0000250|UniProtKB:P05067}; Single-pass type I membrane
CC protein {ECO:0000250|UniProtKB:P05067}. Perikaryon
CC {ECO:0000269|PubMed:10341243}. Cell projection, growth cone
CC {ECO:0000269|PubMed:10341243}. Membrane, clathrin-coated pit
CC {ECO:0000250|UniProtKB:P05067}. Early endosome
CC {ECO:0000250|UniProtKB:P05067}. Cytoplasmic vesicle
CC {ECO:0000250|UniProtKB:P05067}. Note=Cell surface protein that rapidly
CC becomes internalized via clathrin-coated pits. Only a minor proportion
CC is present at the cell membrane; most of the protein is present in
CC intracellular vesicles. During maturation, the immature APP (N-
CC glycosylated in the endoplasmic reticulum) moves to the Golgi complex
CC where complete maturation occurs (O-glycosylated and sulfated). After
CC alpha-secretase cleavage, soluble APP is released into the
CC extracellular space and the C-terminal is internalized to endosomes and
CC lysosomes. Some APP accumulates in secretory transport vesicles leaving
CC the late Golgi compartment and returns to the cell surface. APP sorts
CC to the basolateral surface in epithelial cells (By similarity). During
CC neuronal differentiation, the Thr-742 phosphorylated form is located
CC mainly in growth cones, moderately in neurites and sparingly in the
CC cell body (PubMed:10341243). Casein kinase phosphorylation can occur
CC either at the cell surface or within a post-Golgi compartment.
CC Associates with GPC1 in perinuclear compartments. Colocalizes with
CC SORL1 in a vesicular pattern in cytoplasm and perinuclear regions (By
CC similarity). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000269|PubMed:10341243}.
CC -!- SUBCELLULAR LOCATION: [C83]: Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:P05067}. Golgi apparatus
CC {ECO:0000250|UniProtKB:P05067}. Early endosome
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [C99]: Early endosome
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [Amyloid-beta protein 42]: Cell surface.
CC Note=Associates with FPR2 at the cell surface and the complex is then
CC rapidly internalized. {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [Gamma-secretase C-terminal fragment 59]:
CC Nucleus. Cytoplasm. Note=Located to both the cytoplasm and nuclei of
CC neurons. It can be translocated to the nucleus through association with
CC APBB1 (Fe65) (By similarity). In dopaminergic neurons, the
CC phosphorylated Thr-743 form is localized to the nucleus (By
CC similarity). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000250|UniProtKB:P12023}.
CC -!- SUBCELLULAR LOCATION: [Soluble APP-beta]: Secreted
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=APP770;
CC IsoId=P08592-1; Sequence=Displayed;
CC Name=APP695;
CC IsoId=P08592-2; Sequence=VSP_000015, VSP_000016;
CC Name=L-APP677;
CC IsoId=P08592-3; Sequence=Not described;
CC Name=L-APP696;
CC IsoId=P08592-4; Sequence=Not described;
CC Name=APP714;
CC IsoId=P08592-5; Sequence=Not described;
CC Name=L-APP733;
CC IsoId=P08592-6; Sequence=Not described;
CC Name=APP751;
CC IsoId=P08592-7; Sequence=Not described;
CC Name=L-APP752;
CC IsoId=P08592-8; Sequence=Not described;
CC -!- TISSUE SPECIFICITY: Expressed in the brain (PubMed:23011729). In the
CC brain, non-L-APP isoforms are expressed in neurons, isoform APP695
CC being the predominant form. In astrocytes and microglial cells, almost
CC 50% is L-isoform (appican). {ECO:0000269|PubMed:23011729,
CC ECO:0000269|PubMed:7744833, ECO:0000269|PubMed:8996834}.
CC -!- DEVELOPMENTAL STAGE: From 6 days to 7 months, levels of KPI-containing
CC isoforms increase in the brain cortex and hippocampus. Levels of L-APP
CC increase in all brain regions during the same period, but levels are
CC low compared to non-L-APP isoforms.
CC -!- INDUCTION: Phosphorylation of mature, glycosylated APP occurs 48-72
CC hours after treatment of neuronal cells with nerve growth factor which
CC correlates with the timing of neurite outgrowth.
CC {ECO:0000269|PubMed:10341243}.
CC -!- DOMAIN: The transmembrane helix undergoes a conformation change and
CC unravels partially when bound to PSEN1, facilitating cleavage by PSEN1.
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- DOMAIN: The basolateral sorting signal (BaSS) is required for sorting
CC of membrane proteins to the basolateral surface of epithelial cells.
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- DOMAIN: The GFLD subdomain binds Cu(2+) ions; this promotes
CC homodimerization. {ECO:0000250|UniProtKB:P05067}.
CC -!- DOMAIN: The NPXY sequence motif found in many tyrosine-phosphorylated
CC proteins is required for the specific binding of the PID domain.
CC However, additional amino acids either N- or C-terminal to the NPXY
CC motif are often required for complete interaction. The PID domain-
CC containing proteins which bind APP require the YENPTY motif for full
CC interaction. These interactions are independent of phosphorylation on
CC the terminal tyrosine residue. The YENPXY site is also involved in
CC clathrin-mediated endocytosis. {ECO:0000250|UniProtKB:P05067}.
CC -!- DOMAIN: The C-terminal region can bind zinc ions; this favors
CC dimerization and formation of higher oligomers.
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- DOMAIN: The OX-2 motif shows some similarity to a region in the N-
CC terminus of CD200/MOX2. {ECO:0000250|UniProtKB:P05067}.
CC -!- PTM: Proteolytically processed under normal cellular conditions.
CC Cleavage either by alpha-secretase, beta-secretase or theta-secretase
CC leads to generation and extracellular release of soluble APP peptides,
CC S-APP-alpha and S-APP-beta, and the retention of corresponding
CC membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent
CC processing of C80 and C83 by gamma-secretase yields P3 peptides. This
CC is the major secretory pathway and is non-amyloidogenic. Alternatively,
CC presenilin/nicastrin-mediated gamma-secretase processing of C99
CC releases the amyloid-beta proteins, amyloid-beta protein 40 and
CC amyloid-beta protein 42, major components of amyloid plaques, and the
CC cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-
CC CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as
CC substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein
CC 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-
CC beta 1-X peptides, are found in cerebral spinal fluid (CSF) including
CC the amyloid-beta X-15 peptides, produced from the cleavage by alpha-
CC secretase. {ECO:0000250|UniProtKB:P05067}.
CC -!- PTM: Proteolytically cleaved by caspases during neuronal apoptosis.
CC Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the
CC production of the neurotoxic C31 peptide and the increased production
CC of amyloid-beta peptides. {ECO:0000250}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:P05067}.
CC -!- PTM: O-glycosylated. O-linkage of chondroitin sulfate to the L-APP
CC isoforms produces the APP proteoglycan core proteins, the appicans. The
CC chondroitin sulfate chain of appicans contains 4-O-sulfated galactose
CC in the linkage region and chondroitin sulfate E in the repeated
CC disaccharide region. {ECO:0000269|PubMed:11479316}.
CC -!- PTM: Phosphorylation in the C-terminal on tyrosine, threonine and
CC serine residues is neuron-specific (PubMed:9085254, PubMed:10329382,
CC PubMed:10341243). Phosphorylation can affect APP processing, neuronal
CC differentiation and interaction with other proteins (PubMed:10341243).
CC Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10,
CC in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with
CC maximal levels at the G2/M phase and, in vitro, by GSK-3-beta
CC (PubMed:10936190). The Thr-743 phosphorylated form causes a
CC conformational change which reduces binding of Fe65 family members (By
CC similarity). In dopaminergic (DA) neurons, phosphorylation on Thr-743
CC by LRKK2 promotes the production and the nuclear translocation of the
CC APP intracellular domain (AICD) which induces DA neuron apoptosis (By
CC similarity). Phosphorylation on Tyr-757 is required for SHC binding.
CC Phosphorylated in the extracellular domain by casein kinases on both
CC soluble and membrane-bound APP (By similarity). This phosphorylation is
CC inhibited by heparin (By similarity). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000269|PubMed:10329382, ECO:0000269|PubMed:10341243,
CC ECO:0000269|PubMed:10936190, ECO:0000269|PubMed:9085254}.
CC -!- PTM: Extracellular binding and reduction of copper, results in a
CC corresponding oxidation of Cys-144 and Cys-158, and the formation of a
CC disulfide bond. {ECO:0000250}.
CC -!- PTM: Trophic-factor deprivation triggers the cleavage of surface APP by
CC beta-secretase to release sAPP-beta which is further cleaved to release
CC an N-terminal fragment of APP (N-APP). {ECO:0000250}.
CC -!- PTM: Amyloid-beta peptides are degraded by IDE.
CC {ECO:0000250|UniProtKB:P12023}.
CC -!- PTM: Sulfated on tyrosine residues. {ECO:0000250|UniProtKB:P05067}.
CC -!- MASS SPECTROMETRY: [Gamma-secretase C-terminal fragment 50]:
CC Mass=5911.3; Method=MALDI; Evidence={ECO:0000269|PubMed:11483588};
CC -!- MISCELLANEOUS: Chelation of metal ions, notably copper, iron and zinc,
CC can induce histidine-bridging between amyloid-beta molecules resulting
CC in amyloid-beta-metal aggregates. Rat and mouse amyloid-beta peptides
CC have an arginine residue substituted for the bridging histidine residue
CC and are thus less capable of forming amyloid aggregates. Extracellular
CC zinc-binding increases binding of heparin to APP and inhibits collagen-
CC binding (By similarity). {ECO:0000250|UniProtKB:P05067, ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform L-APP677]: L-isoforms are referred to as
CC appicans. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform L-APP696]: L-isoforms are referred to as
CC appicans. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform L-APP733]: L-isoforms are referred to as
CC appicans. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform L-APP752]: L-isoforms are referred to as
CC appicans. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the APP family. {ECO:0000255|PROSITE-
CC ProRule:PRU01217}.
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DR EMBL; X07648; CAA30488.1; -; mRNA.
DR EMBL; AF513015; AAM90259.1; -; mRNA.
DR EMBL; X14066; CAA32229.1; -; mRNA.
DR PIR; S00550; S00550.
DR PIR; S03607; S03607.
DR PIR; S23094; S23094.
DR RefSeq; NP_062161.1; NM_019288.2. [P08592-1]
DR RefSeq; XP_006248073.1; XM_006248011.3. [P08592-2]
DR PDB; 1M7E; X-ray; 2.45 A; D/E/F=755-763.
DR PDB; 1NMJ; NMR; -; A=672-699.
DR PDB; 1OQN; X-ray; 2.30 A; C/D=755-763.
DR PDB; 2LI9; NMR; -; A/B=672-687.
DR PDBsum; 1M7E; -.
DR PDBsum; 1NMJ; -.
DR PDBsum; 1OQN; -.
DR PDBsum; 2LI9; -.
DR AlphaFoldDB; P08592; -.
DR BMRB; P08592; -.
DR SMR; P08592; -.
DR BioGRID; 248450; 4.
DR ComplexPortal; CPX-1108; Amyloid-beta protein 40/42 complex.
DR ComplexPortal; CPX-1109; Amyloid-beta protein 40 complex.
DR ComplexPortal; CPX-1110; Amyloid-beta protein 42 complex.
DR ComplexPortal; CPX-1182; Amyloid-beta protein 40 oligomeric complex.
DR ComplexPortal; CPX-1183; Amyloid-beta protein 42 oligomeric complex.
DR ComplexPortal; CPX-1184; Amyloid-beta protein 40/42 oligomeric complex.
DR DIP; DIP-618N; -.
DR ELM; P08592; -.
DR IntAct; P08592; 13.
DR STRING; 10116.ENSRNOP00000041613; -.
DR BindingDB; P08592; -.
DR ChEMBL; CHEMBL3638365; -.
DR MEROPS; I02.015; -.
DR TCDB; 1.C.50.1.1; the amyloid Beta-protein peptide (aBetapp) family.
DR GlyGen; P08592; 3 sites.
DR iPTMnet; P08592; -.
DR PhosphoSitePlus; P08592; -.
DR jPOST; P08592; -.
DR PaxDb; P08592; -.
DR PRIDE; P08592; -.
DR GeneID; 54226; -.
DR KEGG; rno:54226; -.
DR UCSC; RGD:2139; rat. [P08592-1]
DR CTD; 351; -.
DR RGD; 2139; App.
DR VEuPathDB; HostDB:ENSRNOG00000006997; -.
DR eggNOG; KOG3540; Eukaryota.
DR HOGENOM; CLU_014607_2_1_1; -.
DR InParanoid; P08592; -.
DR OMA; RERMSQX; -.
DR OrthoDB; 953529at2759; -.
DR PhylomeDB; P08592; -.
DR TreeFam; TF317274; -.
DR Reactome; R-RNO-114608; Platelet degranulation.
DR Reactome; R-RNO-3000178; ECM proteoglycans.
DR Reactome; R-RNO-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-RNO-416476; G alpha (q) signalling events.
DR Reactome; R-RNO-418594; G alpha (i) signalling events.
DR Reactome; R-RNO-432720; Lysosome Vesicle Biogenesis.
DR Reactome; R-RNO-444473; Formyl peptide receptors bind formyl peptides and many other ligands.
DR Reactome; R-RNO-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR Reactome; R-RNO-879415; Advanced glycosylation endproduct receptor signaling.
DR Reactome; R-RNO-8957275; Post-translational protein phosphorylation.
DR Reactome; R-RNO-933542; TRAF6 mediated NF-kB activation.
DR Reactome; R-RNO-9609523; Insertion of tail-anchored proteins into the endoplasmic reticulum membrane.
DR EvolutionaryTrace; P08592; -.
DR PRO; PR:P08592; -.
DR Proteomes; UP000002494; Chromosome 11.
DR Bgee; ENSRNOG00000006997; Expressed in frontal cortex and 19 other tissues.
DR ExpressionAtlas; P08592; baseline and differential.
DR Genevisible; P08592; RN.
DR GO; GO:0106003; C:amyloid-beta complex; IPI:ComplexPortal.
DR GO; GO:0045177; C:apical part of cell; ISO:RGD.
DR GO; GO:0097449; C:astrocyte projection; IDA:RGD.
DR GO; GO:0030424; C:axon; IDA:AgBase.
DR GO; GO:0009986; C:cell surface; IDA:AgBase.
DR GO; GO:0005911; C:cell-cell junction; ISO:RGD.
DR GO; GO:0035253; C:ciliary rootlet; ISO:RGD.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0030134; C:COPII-coated ER to Golgi transport vesicle; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISO:RGD.
DR GO; GO:0043198; C:dendritic shaft; ISO:RGD.
DR GO; GO:0043197; C:dendritic spine; ISO:RGD.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:RGD.
DR GO; GO:0005768; C:endosome; ISO:RGD.
DR GO; GO:0070381; C:endosome to plasma membrane transport vesicle; ISO:RGD.
DR GO; GO:0005615; C:extracellular space; IDA:RGD.
DR GO; GO:0005794; C:Golgi apparatus; IDA:RGD.
DR GO; GO:0005798; C:Golgi-associated vesicle; ISS:UniProtKB.
DR GO; GO:0030426; C:growth cone; IDA:RGD.
DR GO; GO:1990812; C:growth cone filopodium; IDA:RGD.
DR GO; GO:1990761; C:growth cone lamellipodium; IDA:RGD.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:1990777; C:lipoprotein particle; ISO:RGD.
DR GO; GO:0044304; C:main axon; IDA:RGD.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0045121; C:membrane raft; IDA:RGD.
DR GO; GO:0031594; C:neuromuscular junction; ISO:RGD.
DR GO; GO:0043005; C:neuron projection; IDA:RGD.
DR GO; GO:0005641; C:nuclear envelope lumen; ISO:RGD.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0048786; C:presynaptic active zone; ISO:RGD.
DR GO; GO:0043235; C:receptor complex; ISO:RGD.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:RGD.
DR GO; GO:0005790; C:smooth endoplasmic reticulum; IEA:GOC.
DR GO; GO:0051233; C:spindle midzone; ISO:RGD.
DR GO; GO:0045202; C:synapse; ISO:RGD.
DR GO; GO:0008021; C:synaptic vesicle; ISO:RGD.
DR GO; GO:0043195; C:terminal bouton; HDA:ParkinsonsUK-UCL.
DR GO; GO:0034185; F:apolipoprotein binding; ISO:RGD.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR GO; GO:0005109; F:frizzled binding; ISO:RGD.
DR GO; GO:0070851; F:growth factor receptor binding; IPI:RGD.
DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; ISO:RGD.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; ISO:RGD.
DR GO; GO:0016504; F:peptidase activator activity; IDA:RGD.
DR GO; GO:0046983; F:protein dimerization activity; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0051425; F:PTB domain binding; ISO:RGD.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; ISO:RGD.
DR GO; GO:0030546; F:signaling receptor activator activity; ISO:RGD.
DR GO; GO:0005102; F:signaling receptor binding; ISO:RGD.
DR GO; GO:0046914; F:transition metal ion binding; IEA:InterPro.
DR GO; GO:0008344; P:adult locomotory behavior; ISS:UniProtKB.
DR GO; GO:1990000; P:amyloid fibril formation; ISO:RGD.
DR GO; GO:0019731; P:antibacterial humoral response; IDA:UniProtKB.
DR GO; GO:0019732; P:antifungal humoral response; IDA:UniProtKB.
DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IDA:UniProtKB.
DR GO; GO:0048143; P:astrocyte activation; ISO:RGD.
DR GO; GO:0002265; P:astrocyte activation involved in immune response; ISO:RGD.
DR GO; GO:0008088; P:axo-dendritic transport; ISS:UniProtKB.
DR GO; GO:0016199; P:axon midline choice point recognition; ISS:UniProtKB.
DR GO; GO:0007409; P:axonogenesis; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0006878; P:cellular copper ion homeostasis; ISS:UniProtKB.
DR GO; GO:1904646; P:cellular response to amyloid-beta; ISO:RGD.
DR GO; GO:0071320; P:cellular response to cAMP; IEP:RGD.
DR GO; GO:0071280; P:cellular response to copper ion; IEP:RGD.
DR GO; GO:0071287; P:cellular response to manganese ion; IEP:RGD.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEP:RGD.
DR GO; GO:0071874; P:cellular response to norepinephrine stimulus; IMP:RGD.
DR GO; GO:0007417; P:central nervous system development; IBA:GO_Central.
DR GO; GO:0008203; P:cholesterol metabolic process; ISO:RGD.
DR GO; GO:0050890; P:cognition; ISS:UniProtKB.
DR GO; GO:0048669; P:collateral sprouting in absence of injury; ISS:UniProtKB.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IDA:UniProtKB.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB.
DR GO; GO:0016358; P:dendrite development; ISS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; ISS:UniProtKB.
DR GO; GO:0030198; P:extracellular matrix organization; ISS:UniProtKB.
DR GO; GO:0030900; P:forebrain development; ISO:RGD.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB.
DR GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007612; P:learning; ISO:RGD.
DR GO; GO:0007611; P:learning or memory; ISO:RGD.
DR GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB.
DR GO; GO:0007617; P:mating behavior; ISS:UniProtKB.
DR GO; GO:0014005; P:microglia development; ISO:RGD.
DR GO; GO:0001774; P:microglial cell activation; ISO:RGD.
DR GO; GO:0098815; P:modulation of excitatory postsynaptic potential; ISO:RGD.
DR GO; GO:0006378; P:mRNA polyadenylation; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:RGD.
DR GO; GO:1902951; P:negative regulation of dendritic spine maintenance; IDA:ComplexPortal.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD.
DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; ISO:RGD.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; ISO:RGD.
DR GO; GO:0050885; P:neuromuscular process controlling balance; ISO:RGD.
DR GO; GO:0051402; P:neuron apoptotic process; ISO:RGD.
DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl.
DR GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR GO; GO:1990535; P:neuron projection maintenance; ISO:RGD.
DR GO; GO:0016322; P:neuron remodeling; ISS:UniProtKB.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; ISO:RGD.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:RGD.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:1904472; P:positive regulation of endothelin production; ISO:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:ARUK-UCL.
DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; ISO:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0045821; P:positive regulation of glycolytic process; ISO:RGD.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISO:RGD.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISO:RGD.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISO:RGD.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:RGD.
DR GO; GO:1900454; P:positive regulation of long-term synaptic depression; ISO:RGD.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISO:RGD.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:ARUK-UCL.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:1901216; P:positive regulation of neuron death; ISO:RGD.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISO:RGD.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISO:RGD.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISO:RGD.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:RGD.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; ISO:RGD.
DR GO; GO:0042327; P:positive regulation of phosphorylation; ISO:RGD.
DR GO; GO:0032092; P:positive regulation of protein binding; ISO:RGD.
DR GO; GO:0051247; P:positive regulation of protein metabolic process; IDA:ARUK-UCL.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:2000406; P:positive regulation of T cell migration; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:RGD.
DR GO; GO:0051260; P:protein homooligomerization; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0051262; P:protein tetramerization; ISO:RGD.
DR GO; GO:0070206; P:protein trimerization; ISO:RGD.
DR GO; GO:1900221; P:regulation of amyloid-beta clearance; ISO:RGD.
DR GO; GO:0032268; P:regulation of cellular protein metabolic process; IEA:UniProt.
DR GO; GO:0007176; P:regulation of epidermal growth factor-activated receptor activity; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; ISO:RGD.
DR GO; GO:0043408; P:regulation of MAPK cascade; IDA:ComplexPortal.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISS:UniProtKB.
DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; ISO:RGD.
DR GO; GO:1905606; P:regulation of presynapse assembly; ISO:RGD.
DR GO; GO:0043393; P:regulation of protein binding; ISO:RGD.
DR GO; GO:0061097; P:regulation of protein tyrosine kinase activity; IDA:ComplexPortal.
DR GO; GO:1905945; P:regulation of response to calcium ion; IGI:ARUK-UCL.
DR GO; GO:0010469; P:regulation of signaling receptor activity; IDA:ComplexPortal.
DR GO; GO:0150003; P:regulation of spontaneous synaptic transmission; ISO:RGD.
DR GO; GO:0050803; P:regulation of synapse structure or activity; ISS:UniProtKB.
DR GO; GO:0006417; P:regulation of translation; ISS:UniProtKB.
DR GO; GO:0070555; P:response to interleukin-1; IDA:ARUK-UCL.
DR GO; GO:0010288; P:response to lead ion; IEP:RGD.
DR GO; GO:0006979; P:response to oxidative stress; ISO:RGD.
DR GO; GO:0009314; P:response to radiation; IEP:RGD.
DR GO; GO:0001878; P:response to yeast; IDA:UniProtKB.
DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; ISO:RGD.
DR GO; GO:0001967; P:suckling behavior; ISO:RGD.
DR GO; GO:0050808; P:synapse organization; ISO:RGD.
DR GO; GO:0051124; P:synaptic assembly at neuromuscular junction; ISO:RGD.
DR GO; GO:0008542; P:visual learning; ISS:UniProtKB.
DR CDD; cd00109; KU; 1.
DR DisProt; DP01887; -.
DR Gene3D; 1.20.120.770; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.1490.140; -; 1.
DR Gene3D; 3.90.570.10; -; 1.
DR Gene3D; 4.10.410.10; -; 1.
DR InterPro; IPR036669; Amyloid_Cu-bd_sf.
DR InterPro; IPR008155; Amyloid_glyco.
DR InterPro; IPR013803; Amyloid_glyco_Abeta.
DR InterPro; IPR011178; Amyloid_glyco_Cu-bd.
DR InterPro; IPR024329; Amyloid_glyco_E2_domain.
DR InterPro; IPR008154; Amyloid_glyco_extra.
DR InterPro; IPR015849; Amyloid_glyco_heparin-bd.
DR InterPro; IPR036454; Amyloid_glyco_heparin-bd_sf.
DR InterPro; IPR019745; Amyloid_glyco_intracell_CS.
DR InterPro; IPR028866; APP.
DR InterPro; IPR019543; APP_amyloid_C.
DR InterPro; IPR019744; APP_CUBD_CS.
DR InterPro; IPR036176; E2_sf.
DR InterPro; IPR002223; Kunitz_BPTI.
DR InterPro; IPR036880; Kunitz_BPTI_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR PANTHER; PTHR23103; PTHR23103; 1.
DR PANTHER; PTHR23103:SF7; PTHR23103:SF7; 1.
DR Pfam; PF10515; APP_amyloid; 1.
DR Pfam; PF12924; APP_Cu_bd; 1.
DR Pfam; PF12925; APP_E2; 1.
DR Pfam; PF02177; APP_N; 1.
DR Pfam; PF03494; Beta-APP; 1.
DR Pfam; PF00014; Kunitz_BPTI; 1.
DR PRINTS; PR00203; AMYLOIDA4.
DR PRINTS; PR00759; BASICPTASE.
DR PRINTS; PR00204; BETAAMYLOID.
DR SMART; SM00006; A4_EXTRA; 1.
DR SMART; SM00131; KU; 1.
DR SUPFAM; SSF109843; SSF109843; 1.
DR SUPFAM; SSF56491; SSF56491; 1.
DR SUPFAM; SSF57362; SSF57362; 1.
DR SUPFAM; SSF89811; SSF89811; 1.
DR PROSITE; PS00319; APP_CUBD; 1.
DR PROSITE; PS51869; APP_E1; 1.
DR PROSITE; PS51870; APP_E2; 1.
DR PROSITE; PS00320; APP_INTRA; 1.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 1.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amyloid; Apoptosis; Cell adhesion;
KW Cell membrane; Cell projection; Coated pit; Copper; Cytoplasm;
KW Cytoplasmic vesicle; Direct protein sequencing; Disulfide bond;
KW Endocytosis; Endoplasmic reticulum; Endosome; Glycoprotein;
KW Golgi apparatus; Heparin-binding; Iron; Isopeptide bond; Membrane;
KW Metal-binding; Notch signaling pathway; Nucleus; Phosphoprotein;
KW Protease inhibitor; Proteoglycan; Reference proteome; Secreted;
KW Serine protease inhibitor; Signal; Sulfation; Transmembrane;
KW Transmembrane helix; Ubl conjugation; Zinc.
FT SIGNAL 1..17
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT CHAIN 18..770
FT /note="Amyloid-beta precursor protein"
FT /id="PRO_0000000159"
FT CHAIN 18..687
FT /note="Soluble APP-alpha"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000160"
FT CHAIN 18..671
FT /note="Soluble APP-beta"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000161"
FT CHAIN 18..286
FT /note="N-APP"
FT /evidence="ECO:0000250"
FT /id="PRO_0000381971"
FT CHAIN 672..770
FT /note="C99"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000162"
FT CHAIN 672..713
FT /note="Amyloid-beta protein 42"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000163"
FT CHAIN 672..711
FT /note="Amyloid-beta protein 40"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000164"
FT CHAIN 688..770
FT /note="C83"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000165"
FT PEPTIDE 688..713
FT /note="P3(42)"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000166"
FT PEPTIDE 688..711
FT /note="P3(40)"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000167"
FT CHAIN 691..770
FT /note="C80"
FT /id="PRO_0000384579"
FT CHAIN 712..770
FT /note="Gamma-secretase C-terminal fragment 59"
FT /id="PRO_0000000168"
FT CHAIN 714..770
FT /note="Gamma-secretase C-terminal fragment 57"
FT /id="PRO_0000000169"
FT CHAIN 721..770
FT /note="Gamma-secretase C-terminal fragment 50"
FT /id="PRO_0000000170"
FT CHAIN 740..770
FT /note="C31"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000171"
FT TOPO_DOM 18..701
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 702..722
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT TOPO_DOM 723..770
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 28..189
FT /note="E1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT DOMAIN 291..341
FT /note="BPTI/Kunitz inhibitor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DOMAIN 374..565
FT /note="E2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01218"
FT REGION 28..123
FT /note="GFLD subdomain"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT REGION 131..189
FT /note="CuBD subdomain"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT REGION 135..155
FT /note="Copper-binding"
FT /evidence="ECO:0000250"
FT REGION 181..188
FT /note="Zinc-binding"
FT /evidence="ECO:0000250"
FT REGION 196..283
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 391..423
FT /note="Heparin-binding"
FT /evidence="ECO:0000250"
FT REGION 491..522
FT /note="Heparin-binding"
FT /evidence="ECO:0000250"
FT REGION 523..540
FT /note="Collagen-binding"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT REGION 695..722
FT /note="Interaction with PSEN1"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT REGION 732..751
FT /note="Interaction with G(o)-alpha"
FT REGION 756..770
FT /note="Required for the interaction with KIF5B and for
FT anterograde transport in axons"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT MOTIF 344..365
FT /note="OX-2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT MOTIF 724..734
FT /note="Basolateral sorting signal"
FT /evidence="ECO:0000250"
FT MOTIF 757..762
FT /note="YENPXY motif; contains endocytosis signal"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT COMPBIAS 196..210
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 225..263
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 267..283
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 96..110
FT /ligand="heparin"
FT /ligand_id="ChEBI:CHEBI:28304"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 147
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT BINDING 151
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT BINDING 168
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT BINDING 183
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 186
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 187
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 677
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 677
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 685
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 685
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 170
FT /note="Required for Cu(2+) reduction"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT SITE 197..198
FT /note="Cleavage; by caspases"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 219..220
FT /note="Cleavage; by caspases"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 301..302
FT /note="Reactive bond"
FT /evidence="ECO:0000250"
FT SITE 671..672
FT /note="Cleavage; by beta-secretase"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 678..679
FT /note="Cleavage; by ACE"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 687..688
FT /note="Cleavage; by alpha-secretase"
FT /evidence="ECO:0000269|PubMed:26479776"
FT SITE 690..691
FT /note="Cleavage; by theta-secretase"
FT /evidence="ECO:0000269|PubMed:26479776"
FT SITE 706
FT /note="Susceptible to oxidation"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 711..712
FT /note="Cleavage; by gamma-secretase; site 1"
FT /evidence="ECO:0000269|PubMed:26479776"
FT SITE 713..714
FT /note="Cleavage; by gamma-secretase; site 2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 720..721
FT /note="Cleavage; by gamma-secretase; site 3"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 739..740
FT /note="Cleavage; by a caspase"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT MOD_RES 198
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT MOD_RES 206
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT MOD_RES 217
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000255"
FT MOD_RES 262
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000255"
FT MOD_RES 336
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000255"
FT MOD_RES 441
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 497
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT MOD_RES 729
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:9085254"
FT MOD_RES 730
FT /note="Phosphoserine; by APP-kinase I"
FT /evidence="ECO:0000269|PubMed:10329382,
FT ECO:0000269|PubMed:9085254"
FT MOD_RES 743
FT /note="Phosphothreonine; by CDK5 and MAPK10"
FT /evidence="ECO:0000269|PubMed:10936190,
FT ECO:0000269|PubMed:9085254"
FT MOD_RES 757
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000250|UniProtKB:P12023"
FT CARBOHYD 542
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 571
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 656
FT /note="O-linked (Xyl...) (chondroitin sulfate) serine; in
FT L-APP isoforms"
FT DISULFID 38..62
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT DISULFID 73..117
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT DISULFID 98..105
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT DISULFID 133..187
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT DISULFID 144..174
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT DISULFID 158..186
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT DISULFID 291..341
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 300..324
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 316..337
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT CROSSLNK 763
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:22847417"
FT VAR_SEQ 289
FT /note="E -> V (in isoform APP695)"
FT /evidence="ECO:0000303|PubMed:2900758"
FT /id="VSP_000015"
FT VAR_SEQ 290..364
FT /note="Missing (in isoform APP695)"
FT /evidence="ECO:0000303|PubMed:2900758"
FT /id="VSP_000016"
FT MUTAGEN 656
FT /note="S->A: No chondroitin sulfate linkage to isoform L-
FT APP733."
FT /evidence="ECO:0000269|PubMed:7737970"
FT MUTAGEN 704
FT /note="G->V: Little oxidized neuronal proteins. Scarce
FT amyloid-beta protein 42 aggregation. No neurotoxicity."
FT /evidence="ECO:0000269|PubMed:11959460"
FT MUTAGEN 732..733
FT /note="HH->GL,GP: Almost complete loss of binding to GNAO1.
FT No inhibition of GTPase activity."
FT /evidence="ECO:0000269|PubMed:10024358"
FT MUTAGEN 743
FT /note="T->A: No effect on neurite growth and maturation."
FT /evidence="ECO:0000269|PubMed:10341243"
FT MUTAGEN 743
FT /note="T->E: Inhibits neurite growth and maturation."
FT /evidence="ECO:0000269|PubMed:10341243"
FT MUTAGEN 757
FT /note="Y->G: No DBB1 binding."
FT /evidence="ECO:0000269|PubMed:9930726"
FT MUTAGEN 759
FT /note="N->A: Some DBB1 binding."
FT /evidence="ECO:0000269|PubMed:9930726"
FT MUTAGEN 762
FT /note="Y->A: Some DBB1 binding."
FT /evidence="ECO:0000269|PubMed:9930726"
FT MUTAGEN 763
FT /note="K->R: Loss of ubiquitination."
FT /evidence="ECO:0000269|PubMed:22847417"
FT TURN 674..676
FT /evidence="ECO:0007829|PDB:2LI9"
FT TURN 679..686
FT /evidence="ECO:0007829|PDB:1NMJ"
FT HELIX 687..695
FT /evidence="ECO:0007829|PDB:1NMJ"
SQ SEQUENCE 770 AA; 86704 MW; C26C9D6BB2D929A7 CRC64;
MLPSLALLLL AAWTVRALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG KWESDPSGTK
TCIGTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHTH IVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDSIDSAD AEEDDSDVWW GGADTDYADG GEDKVVEVAE EEEVADVEEE
EAEDDEDVED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVSSQSLL KTTSEPLPQD
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPHHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHPFGVDSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
IKTEEISEVK MDAEFGHDSG FEVRHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL
VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
