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 27-MAR-2024, entry version 250. 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}, AD1 GN {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 synapses 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 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; 6. 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 GlyCosmos; P08592; 3 sites, No reported glycans. DR GlyGen; P08592; 3 sites. DR iPTMnet; P08592; -. DR PhosphoSitePlus; P08592; -. DR jPOST; P08592; -. DR PaxDb; 10116-ENSRNOP00000041613; -. DR Ensembl; ENSRNOT00055003610; ENSRNOP00055002711; ENSRNOG00055002269. [P08592-1] DR Ensembl; ENSRNOT00060028680; ENSRNOP00060023069; ENSRNOG00060016739. [P08592-1] DR Ensembl; ENSRNOT00065009663; ENSRNOP00065006970; ENSRNOG00065006297. [P08592-1] DR GeneID; 54226; -. DR KEGG; rno:54226; -. DR UCSC; RGD:2139; rat. [P08592-1] DR AGR; RGD:2139; -. 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 OrthoDB; 2907766at2759; -. 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 cell types or tissues. DR ExpressionAtlas; P08592; baseline and differential. DR GO; GO:0106003; C:amyloid-beta complex; ISO:RGD. 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; ISS:UniProtKB. 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; ISS:UniProtKB. 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:1990777; C:lipoprotein particle; ISO:RGD. DR GO; GO:0044304; C:main axon; IDA:RGD. DR GO; GO:0016020; C:membrane; ISS:UniProtKB. DR GO; GO:0045121; C:membrane raft; ISO:RGD. DR GO; GO:0031594; C:neuromuscular junction; ISO:RGD. DR GO; GO:0043005; C:neuron projection; ISO:RGD. DR GO; GO:0098992; C:neuronal dense core vesicle; IDA:SynGO. 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; ISO: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: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:0043167; F:ion binding; EXP:DisProt. 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:0051425; F:PTB domain binding; ISO:RGD. DR GO; GO:0048018; F:receptor ligand activity; 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:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; ISO:RGD. 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: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:0180011; P:cytoplasmic polyadenylation; ISO:RGD. 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; ISO:RGD. DR GO; GO:0045087; P:innate immune response; ISO:RGD. DR GO; GO:0006878; P:intracellular copper ion homeostasis; ISS: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:0000278; P:mitotic cell cycle; 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: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; ISO:RGD. DR GO; GO:0030182; P:neuron differentiation; ISO:RGD. 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:0050850; P:positive regulation of calcium-mediated signaling; ISO:RGD. DR GO; GO:0032722; P:positive regulation of chemokine production; 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; ISO:RGD. 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:1900273; P:positive regulation of long-term synaptic potentiation; ISO:RGD. DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISS:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:RGD. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; 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: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:0006468; P:protein phosphorylation; ISS:UniProtKB. DR GO; GO:1900221; P:regulation of amyloid-beta clearance; ISO:RGD. 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: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: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: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; cd22607; Kunitz_ABPP-like; 1. DR DisProt; DP01887; -. DR Gene3D; 6.10.250.1670; -; 1. DR Gene3D; 1.20.120.770; Amyloid precursor protein, E2 domain; 1. DR Gene3D; 3.30.1490.140; Amyloidogenic glycoprotein, copper-binding domain; 1. DR Gene3D; 3.90.570.10; Amyloidogenic glycoprotein, heparin-binding domain; 1. DR Gene3D; 4.10.410.10; Pancreatic trypsin inhibitor Kunitz domain; 1. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 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; 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; ALZHEIMER'S DISEASE BETA-AMYLOID RELATED; 1. DR PANTHER; PTHR23103:SF7; AMYLOID-BETA PRECURSOR PROTEIN; 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; SSF56491; A heparin-binding domain; 1. DR SUPFAM; SSF89811; Amyloid beta a4 protein copper binding domain (domain 2); 1. DR SUPFAM; SSF57362; BPTI-like; 1. DR SUPFAM; SSF109843; CAPPD, an extracellular domain of amyloid beta A4 protein; 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. DR Genevisible; P08592; RN. 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 FT L-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 //