A4_MOUSE
ID A4_MOUSE Reviewed; 770 AA.
AC P12023; P97487; P97942; Q99K32;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 09-MAY-2003, sequence version 3.
DT 03-AUG-2022, entry version 252.
DE RecName: Full=Amyloid-beta precursor protein {ECO:0000250|UniProtKB:P05067};
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|MGI:MGI:88059};
DE AltName: Full=Amyloid-beta A4 protein {ECO:0000250|UniProtKB:P08592};
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=APP-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=APP-C59;
DE AltName: Full=Amyloid intracellular domain 59;
DE Short=AID(59);
DE AltName: Full=Gamma-CTF(59);
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 57;
DE AltName: Full=APP-C57;
DE AltName: Full=Amyloid intracellular domain 57;
DE Short=AID(57);
DE AltName: Full=Gamma-CTF(57);
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 50;
DE AltName: Full=Amyloid intracellular domain 50;
DE Short=AID(50);
DE AltName: Full=Gamma-CTF(50);
DE Contains:
DE RecName: Full=C31;
DE Flags: Precursor;
GN Name=App {ECO:0000312|MGI:MGI:88059};
GN Synonyms=A4 {ECO:0000250|UniProtKB:P05067},
GN AD1 {ECO:0000250|UniProtKB:P05067};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC TISSUE=Brain;
RX PubMed=3322280; DOI=10.1016/0006-291x(87)90419-0;
RA Yamada T., Sasaki H., Furuya H., Miyata T., Goto I., Sakaki Y.;
RT "Complementary DNA for the mouse homolog of the human amyloid beta protein
RT precursor.";
RL Biochem. Biophys. Res. Commun. 149:665-671(1987).
RN [2]
RP SEQUENCE REVISION.
RA Yamada T.;
RL Submitted (MAR-1988) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC STRAIN=BALB/cJ; TISSUE=Brain;
RX PubMed=1756177; DOI=10.1016/0167-4781(91)90231-a;
RA de Strooper B., van Leuven F., van den Berghe H.;
RT "The amyloid beta protein precursor or proteinase nexin II from mouse is
RT closer related to its human homolog than previously reported.";
RL Biochim. Biophys. Acta 1129:141-143(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
RC STRAIN=SAMP8; TISSUE=Hippocampus;
RX PubMed=11235921; DOI=10.1139/o00-094;
RA Kumar V.B., Vyas K., Franko M., Choudhary V., Buddhiraju C., Alvarez J.,
RA Morley J.E.;
RT "Molecular cloning, expression, and regulation of hippocampal amyloid
RT precursor protein of senescence accelerated mouse (SAMP8).";
RL Biochem. Cell Biol. 79:57-67(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-19.
RX PubMed=1555768; DOI=10.1016/0378-1119(92)90375-y;
RA Izumi R., Yamada T., Yoshikai S., Sasaki H., Hattori M., Sakai Y.;
RT "Positive and negative regulatory elements for the expression of the
RT Alzheimer's disease amyloid precursor-encoding gene in mouse.";
RL Gene 112:189-195(1992).
RN [6]
RP PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM APP770).
RC TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 281-380, AND ALTERNATIVE SPLICING.
RC TISSUE=Brain, and Kidney;
RX PubMed=2493250; DOI=10.1016/0006-291x(89)92808-8;
RA Yamada T., Sasaki H., Dohura K., Goto I., Sakaki Y.;
RT "Structure and expression of the alternatively-spliced forms of mRNA for
RT the mouse homolog of Alzheimer's disease amyloid beta protein precursor.";
RL Biochem. Biophys. Res. Commun. 158:906-912(1989).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 289-364.
RC STRAIN=CD-1; TISSUE=Placenta;
RX PubMed=2569710; DOI=10.1093/nar/17.13.5396;
RA Fukuchi K., Martin G.M., Deeb S.S.;
RT "Sequence of the protease inhibitor domain of the A4 amyloid protein
RT precursor of Mus domesticus.";
RL Nucleic Acids Res. 17:5396-5396(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 656-737.
RC STRAIN=129/Sv;
RA Wragg M.A., Busfield F., Duff K., Korenblat K., Capecchi M., Loring J.F.,
RA Goate A.M.;
RT "Introduction of six mutations into the mouse genome using 'Hit and Run'
RT gene-targeting: introduction of familial Alzheimer's disease mutations into
RT the mouse amyloid precursor protein gene and humanization of the A-beta
RT fragment.";
RL Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP TISSUE SPECIFICITY OF ALTERNATIVE SPLICED FORMS.
RX PubMed=8510506; DOI=10.1016/0169-328x(93)90020-p;
RA Sola C., Mengod G., Ghetti B., Palacios J.M., Triarhou L.C.;
RT "Regional distribution of the alternatively spliced isoforms of beta APP
RT RNA transcript in the brain of normal, heterozygous and homozygous weaver
RT mutant mice as revealed by in situ hybridization histochemistry.";
RL Brain Res. Mol. Brain Res. 17:340-346(1993).
RN [11]
RP INTERACTION WITH KNS2.
RX PubMed=11144355; DOI=10.1016/s0896-6273(00)00124-0;
RA Kamal A., Stokin G.B., Yang Z., Xia C.-H., Goldstein L.S.;
RT "Axonal transport of amyloid precursor protein is mediated by direct
RT binding to the kinesin light chain subunit of kinesin-I.";
RL Neuron 28:449-459(2000).
RN [12]
RP PHOSPHORYLATION AT TYR-757.
RX PubMed=11279131; DOI=10.1074/jbc.m100792200;
RA Zambrano N., Bruni P., Minopoli G., Mosca R., Molino D., Russo C.,
RA Schettini G., Sudol M., Russo T.;
RT "The beta-amyloid precursor protein APP is tyrosine-phosphorylated in cells
RT expressing a constitutively active form of the Abl protoncogene.";
RL J. Biol. Chem. 276:19787-19792(2001).
RN [13]
RP PROTEOLYTIC PROCESSING BY GAMMA SECRETASE, AND INTERACTION WITH APBB1.
RX PubMed=11553691; DOI=10.1046/j.1471-4159.2001.00516.x;
RA Cupers P., Orlans I., Craessaerts K., Annaert W., De Strooper B.;
RT "The amyloid precursor protein (APP)-cytoplasmic fragment generated by
RT gamma-secretase is rapidly degraded but distributes partially in a nuclear
RT fraction of neurons in culture.";
RL J. Neurochem. 78:1168-1178(2001).
RN [14]
RP C-TERMINAL PROTEIN-PROTEIN INTERACTION, AND MUTAGENESIS OF TYR-728;
RP THR-743; TYR-757; ASN-759 AND TYR-762.
RX PubMed=11517249; DOI=10.1523/jneurosci.21-17-06597.2001;
RA Matsuda S., Yasukawa T., Homma Y., Ito Y., Niikura T., Hiraki T., Hirai S.,
RA Ohno S., Kita Y., Kawasumi M., Kouyama K., Yamamoto T., Kyriakis J.M.,
RA Nishimoto I.;
RT "C-jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1
RT scaffolds Alzheimer's amyloid precursor protein with JNK.";
RL J. Neurosci. 21:6597-6607(2001).
RN [15]
RP INTERACTION WITH DAB2, AND MUTAGENESIS OF GLY-756; TYR-757; ASN-759;
RP PRO-760 AND TYR-762.
RX PubMed=11247302; DOI=10.1034/j.1600-0854.2001.020206.x;
RA Morris S.M., Cooper J.A.;
RT "Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts
RT with AP-2.";
RL Traffic 2:111-123(2001).
RN [16]
RP INTERACTION WITH MAPK8IP1, AND PHOSPHORYLATION.
RX PubMed=11912189; DOI=10.1074/jbc.m108372200;
RA Taru H., Iijima K., Hase M., Kirino Y., Yagi Y., Suzuki T.;
RT "Interaction of Alzheimer's beta-amyloid precursor family proteins with
RT scaffold proteins of the JNK signaling cascade.";
RL J. Biol. Chem. 277:20070-20078(2002).
RN [17]
RP INTERACTION OF CTF PEPTIDES WITH NUMB.
RX PubMed=12011466; DOI=10.1073/pnas.102192599;
RA Roncarati R., Sestan N., Scheinfeld M.H., Berechid B.E., Lopez P.A.,
RA Meucci O., McGlade J.C., Rakic P., D'Adamio L.;
RT "The gamma-secretase-generated intracellular domain of beta-amyloid
RT precursor protein binds Numb and inhibits Notch signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:7102-7107(2002).
RN [18]
RP PROTEOLYTIC DEGRADATION BY IDE.
RX PubMed=12634421; DOI=10.1073/pnas.0230450100;
RA Farris W., Mansourian S., Chang Y., Lindsley L., Eckman E.A., Frosch M.P.,
RA Eckman C.B., Tanzi R.E., Selkoe D.J., Guenette S.;
RT "Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-
RT protein, and the beta-amyloid precursor protein intracellular domain in
RT vivo.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:4162-4167(2003).
RN [19]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=15677459; DOI=10.1074/jbc.m409179200;
RA Cappai R., Cheng F., Ciccotosto G.D., Needham B.E., Masters C.L.,
RA Multhaup G., Fransson L.A., Mani K.;
RT "The amyloid precursor protein (APP) of Alzheimer disease and its paralog,
RT APLP2, modulate the Cu/Zn-nitric oxide-catalyzed degradation of glypican-1
RT heparan sulfate in vivo.";
RL J. Biol. Chem. 280:13913-13920(2005).
RN [20]
RP INTERACTION WITH CPEB1.
RX PubMed=16314516; DOI=10.1128/mcb.25.24.10930-10939.2005;
RA Cao Q., Huang Y.-S., Kan M.-C., Richter J.D.;
RT "Amyloid precursor proteins anchor CPEB to membranes and promote
RT polyadenylation-induced translation.";
RL Mol. Cell. Biol. 25:10930-10939(2005).
RN [21]
RP INTERACTION WITH SORL1.
RX PubMed=16174740; DOI=10.1073/pnas.0503689102;
RA Andersen O.M., Reiche J., Schmidt V., Gotthardt M., Spoelgen R., Behlke J.,
RA von Arnim C.A., Breiderhoff T., Jansen P., Wu X., Bales K.R., Cappai R.,
RA Masters C.L., Gliemann J., Mufson E.J., Hyman B.T., Paul S.M., Nykjaer A.,
RA Willnow T.E.;
RT "Neuronal sorting protein-related receptor sorLA/LR11 regulates processing
RT of the amyloid precursor protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:13461-13466(2005).
RN [22]
RP INTERACTION WITH SORL1.
RX PubMed=16407538; DOI=10.1523/jneurosci.3882-05.2006;
RA Spoelgen R., von Arnim C.A., Thomas A.V., Peltan I.D., Koker M., Deng A.,
RA Irizarry M.C., Andersen O.M., Willnow T.E., Hyman B.T.;
RT "Interaction of the cytosolic domains of sorLA/LR11 with the amyloid
RT precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.";
RL J. Neurosci. 26:418-428(2006).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-441, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Kidney, Lung, Pancreas, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [24]
RP INTERACTION WITH NGS1.
RX PubMed=21084623; DOI=10.1523/jneurosci.4464-10.2010;
RA Norstrom E.M., Zhang C., Tanzi R., Sisodia S.S.;
RT "Identification of NEEP21 as a ss-amyloid precursor protein-interacting
RT protein in vivo that modulates amyloidogenic processing in vitro.";
RL J. Neurosci. 30:15677-15685(2010).
RN [25]
RP SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE.
RX PubMed=23931995; DOI=10.1016/j.neuron.2013.05.035;
RA Das U., Scott D.A., Ganguly A., Koo E.H., Tang Y., Roy S.;
RT "Activity-induced convergence of APP and BACE-1 in acidic microdomains via
RT an endocytosis-dependent pathway.";
RL Neuron 79:447-460(2013).
RN [26]
RP INTERACTION WITH VDAC1.
RX PubMed=25168729; DOI=10.1016/j.neuroscience.2014.07.079;
RA Fernandez-Echevarria C., Diaz M., Ferrer I., Canerina-Amaro A., Marin R.;
RT "Abeta promotes VDAC1 channel dephosphorylation in neuronal lipid rafts.
RT Relevance to the mechanisms of neurotoxicity in Alzheimer's disease.";
RL Neuroscience 278:354-366(2014).
RN [27]
RP SUBCELLULAR LOCATION.
RX PubMed=25592972; DOI=10.15252/emmm.201404438;
RA Kizuka Y., Kitazume S., Fujinawa R., Saito T., Iwata N., Saido T.C.,
RA Nakano M., Yamaguchi Y., Hashimoto Y., Staufenbiel M., Hatsuta H.,
RA Murayama S., Manya H., Endo T., Taniguchi N.;
RT "An aberrant sugar modification of BACE1 blocks its lysosomal targeting in
RT Alzheimer's disease.";
RL EMBO Mol. Med. 7:175-189(2015).
RN [28]
RP TISSUE SPECIFICITY.
RX PubMed=25757569; DOI=10.1096/fj.14-261453;
RA Suh J., Moncaster J.A., Wang L., Hafeez I., Herz J., Tanzi R.E.,
RA Goldstein L.E., Guenette S.Y.;
RT "FE65 and FE65L1 amyloid precursor protein-binding protein compound null
RT mice display adult-onset cataract and muscle weakness.";
RL FASEB J. 29:2628-2639(2015).
RN [29]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND
RP INDUCTION BY HIGH-FAT DIET.
RX PubMed=26260791; DOI=10.1074/jbc.m115.655076;
RA Satoh K., Abe-Dohmae S., Yokoyama S., St George-Hyslop P., Fraser P.E.;
RT "ATP-binding cassette transporter A7 (ABCA7) loss of function alters
RT Alzheimer amyloid processing.";
RL J. Biol. Chem. 290:24152-24165(2015).
RN [30]
RP INTERACTION WITH LRRK2, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP PHOSPHORYLATION AT THR-743.
RX PubMed=28720718; DOI=10.1126/scisignal.aam6790;
RA Chen Z.C., Zhang W., Chua L.L., Chai C., Li R., Lin L., Cao Z.,
RA Angeles D.C., Stanton L.W., Peng J.H., Zhou Z.D., Lim K.L., Zeng L.,
RA Tan E.K.;
RT "Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD
RT activity and neurotoxicity in Parkinson's disease.";
RL Sci. Signal. 10:0-0(2017).
RN [31]
RP INTERACTION WITH SYT7.
RX PubMed=30429473; DOI=10.1038/s41467-018-06813-x;
RA Barthet G., Jorda-Siquier T., Rumi-Masante J., Bernadou F., Mueller U.,
RA Mulle C.;
RT "Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and
RT presynaptic plasticity.";
RL Nat. Commun. 9:4780-4780(2018).
RN [32] {ECO:0007744|PDB:2ROZ}
RP STRUCTURE BY NMR OF 739-770, AND INTERACTION WITH APBB2.
RX PubMed=18650440; DOI=10.1074/jbc.m803892200;
RA Li H., Koshiba S., Hayashi F., Tochio N., Tomizawa T., Kasai T., Yabuki T.,
RA Motoda Y., Harada T., Watanabe S., Inoue M., Hayashizaki Y., Tanaka A.,
RA Kigawa T., Yokoyama S.;
RT "Structure of the C-terminal phosphotyrosine interaction domain of Fe65L1
RT complexed with the cytoplasmic tail of amyloid precursor protein reveals a
RT novel peptide binding mode.";
RL J. Biol. Chem. 283:27165-27178(2008).
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. Can promote transcription activation through binding to
CC APBB1-KAT5 and inhibit Notch signaling through interaction with Numb.
CC Couples to apoptosis-inducing pathways such as those mediated by G(o)
CC and JIP. Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a
CC kinesin I membrane receptor, mediating the axonal transport of beta-
CC secretase and presenilin 1 (By similarity). By acting as a kinesin I
CC membrane receptor, plays a role in axonal anterograde transport of
CC cargo towards synapes in axons (By similarity). May be involved in
CC copper homeostasis/oxidative stress through copper ion reduction. Can
CC regulate neurite outgrowth through binding to components of the
CC extracellular matrix such as heparin and collagen I and IV (By
CC similarity). The splice isoforms that contain the BPTI domain possess
CC protease inhibitor activity. Induces a AGER-dependent pathway that
CC involves activation of p38 MAPK, resulting in internalization of
CC amyloid-beta peptide and leading to mitochondrial dysfunction in
CC cultured cortical neurons (By similarity). Provides Cu(2+) ions for
CC GPC1 which are required for release of nitric oxide (NO) and subsequent
CC degradation of the heparan sulfate chains on GPC1. {ECO:0000250,
CC ECO:0000250|UniProtKB:P05067, ECO:0000269|PubMed:15677459}.
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 elicit 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: The gamma-CTF peptides as well as the caspase-cleaved
CC peptides, including C31, are potent enhancers of neuronal apoptosis.
CC {ECO:0000269|PubMed:15677459}.
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, NUMB and DAB1. Binding to DAB1 inhibits its serine
CC phosphorylation. Interacts (via NPXY motif) with DAB2 (via PID domain);
CC the interaction is impaired by tyrosine phosphorylation of the NPXY
CC motif. Also interacts with GPCR-like protein BPP, APPBP1, IB1, KNS2
CC (via its TPR domains), APPBP2 (via BaSS) and DDB1 (By similarity). In
CC vitro, it binds MAPT via the MT-binding domains (By similarity).
CC Associates with microtubules in the presence of ATP and in a kinesin-
CC dependent manner (By similarity). Interacts, through a C-terminal
CC domain, with GNAO1 (By similarity). Amyloid-beta protein 42 binds
CC CHRNA7 in hippocampal neurons (By similarity). Amyloid-beta associates
CC with HADH2 (By similarity). Interacts with ANKS1B, TNFRSF21 and AGER
CC (By similarity). Interacts with CPEB1. Interacts with ITM2B. Interacts
CC with ITM2C. Interacts with IDE. Can form homodimers; dimerization is
CC enhanced in the presence of Cu(2+) ions. Can form homodimers; this is
CC promoted by heparin binding (By similarity). Amyloid-beta protein 40
CC interacts with S100A9 (By similarity). CTF-alpha product of APP
CC interacts with GSAP (By similarity). Isoform APP695 interacts with
CC SORL1 (via N-terminal ectodomain); this interaction retains APP in the
CC trans-Golgi network and reduces processing into soluble APP-alpha and
CC amyloid-beta peptides (PubMed:16174740, PubMed:16407538). The C99
CC fragment also interacts with SORL1 (PubMed:16407538). Isoform APP751
CC interacts with SORL1 (PubMed:16174740). Isoform APP770 interacts with
CC SORL1 (PubMed:16174740). Interacts with PLD3 (By similarity). Interacts
CC with VDAC1 (PubMed:25168729). Interacts with NSG1; could regulate APP
CC processing (PubMed:21084623). Amyloid-beta protein 42 interacts with
CC FPR2 (By similarity). Interacts with SYT7 (PubMed:30429473). Interacts
CC (via transmembrane region) with PSEN1; the interaction is direct (By
CC similarity). Interacts with LRRK2 (PubMed:28720718). Interacts (via
CC cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-
CC terminus) with APBB2/FE65L1 (via C-terminus) (PubMed:18650440).
CC Interacts (via intracellular domain) with APBB3 (By similarity).
CC {ECO:0000250|UniProtKB:P05067, ECO:0000250|UniProtKB:P08592,
CC ECO:0000269|PubMed:16174740, ECO:0000269|PubMed:16407538,
CC ECO:0000269|PubMed:18650440, ECO:0000269|PubMed:21084623,
CC ECO:0000269|PubMed:25168729, ECO:0000269|PubMed:28720718,
CC ECO:0000269|PubMed:30429473}.
CC -!- INTERACTION:
CC P12023; P98084: Apba2; NbExp=2; IntAct=EBI-78814, EBI-81669;
CC P12023; Q9QXJ1: Apbb1; NbExp=2; IntAct=EBI-78814, EBI-81338;
CC P12023; Q03157: Aplp1; NbExp=4; IntAct=EBI-78814, EBI-399929;
CC P12023; Q06335: Aplp2; NbExp=3; IntAct=EBI-78814, EBI-446708;
CC P12023; P14211: Calr; NbExp=4; IntAct=EBI-78814, EBI-644340;
CC P12023; P97318: Dab1; NbExp=3; IntAct=EBI-78814, EBI-81680;
CC P12023; Q62108: Dlg4; NbExp=4; IntAct=EBI-78814, EBI-300895;
CC P12023; Q8BGT1: Flrt3; NbExp=2; IntAct=EBI-78814, EBI-16166902;
CC P12023; Q9D1T0: Lingo1; NbExp=2; IntAct=EBI-78814, EBI-2012981;
CC P12023; Q9WVI9-1: Mapk8ip1; NbExp=3; IntAct=EBI-78814, EBI-288461;
CC P12023; P27671: Rasgrf1; NbExp=2; IntAct=EBI-78814, EBI-645522;
CC P12023; Q61120: Shc3; NbExp=2; IntAct=EBI-78814, EBI-79107;
CC P12023; Q9JHI9: Slc40a1; NbExp=2; IntAct=EBI-78814, EBI-2931424;
CC P12023; O88307: Sorl1; NbExp=3; IntAct=EBI-78814, EBI-7540114;
CC P12023; Q6PHU5: Sort1; NbExp=3; IntAct=EBI-78814, EBI-6985663;
CC P12023; A0A1I9GFB9: Tiaf1; NbExp=2; IntAct=EBI-78814, EBI-21016230;
CC P12023; P15253: CALR; Xeno; NbExp=2; IntAct=EBI-78814, EBI-9005200;
CC P12023; Q9UQF2: MAPK8IP1; Xeno; NbExp=2; IntAct=EBI-78814, EBI-78404;
CC P12023-2; Q9WVI9-1: Mapk8ip1; NbExp=2; IntAct=EBI-286828, EBI-288461;
CC PRO_0000000118; P54763: Ephb2; NbExp=4; IntAct=EBI-14022231, EBI-537711;
CC PRO_0000000118; P04925: Prnp; NbExp=2; IntAct=EBI-14022231, EBI-768613;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26260791};
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:0000250|UniProtKB:P08592}. Cell projection, growth cone
CC {ECO:0000250|UniProtKB:P08592}. Membrane, clathrin-coated pit
CC {ECO:0000250|UniProtKB:P05067}. Early endosome
CC {ECO:0000269|PubMed:25592972, ECO:0000269|PubMed:26260791}. Cytoplasmic
CC vesicle {ECO:0000250|UniProtKB:P05067}. Golgi apparatus, trans-Golgi
CC network {ECO:0000269|PubMed:23931995}. Note=Cell surface protein that
CC rapidly becomes internalized via clathrin-coated pits. Only a minor
CC proportion is present at the cell membrane; most of the protein is
CC present in intracellular vesicles. During maturation, the immature APP
CC (N-glycosylated in the endoplasmic reticulum) moves to the Golgi
CC complex where complete maturation occurs (O-glycosylated and sulfated).
CC After 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. During neuronal
CC differentiation, the Thr-743 phosphorylated form is located mainly in
CC growth cones, moderately in neurites and sparingly in the cell body.
CC Casein kinase phosphorylation can occur either at the cell surface or
CC within a post-Golgi compartment (By similarity). Associates with GPC1
CC in perinuclear compartments (PubMed:15677459). Colocalizes with SORL1
CC in a vesicular pattern in cytoplasm and perinuclear regions (By
CC similarity). Upon neuronal activation, routed into BACE1-positive
CC recycling endosomes via a clathrin -dependent mechanism
CC (PubMed:23931995). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000269|PubMed:15677459, ECO:0000269|PubMed:23931995}.
CC -!- SUBCELLULAR LOCATION: [C99]: Early endosome
CC {ECO:0000250|UniProtKB:P05067}.
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: [Soluble APP-beta]: Secreted {ECO:0000305}.
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]: Nucleus
CC {ECO:0000269|PubMed:28720718}. Cytoplasm
CC {ECO:0000250|UniProtKB:P05067}. Note=Located to both the cytoplasm and
CC nuclei of neurons. It can be translocated to the nucleus through
CC association with APBB1 (Fe65) (By similarity). In dopaminergic neurons,
CC the phosphorylated Thr-743 form is localized to the nucleus
CC (PubMed:28720718). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000269|PubMed:28720718}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Comment=Additional isoforms seem to exist.;
CC Name=APP770;
CC IsoId=P12023-1; Sequence=Displayed;
CC Name=APP695;
CC IsoId=P12023-2; Sequence=VSP_000012, VSP_000013;
CC Name=APP751;
CC IsoId=P12023-3; Sequence=VSP_000014;
CC Name=APP714;
CC IsoId=P12023-4; Sequence=Not described;
CC -!- TISSUE SPECIFICITY: Expressed in the brain with expression in cortex,
CC cerebellum, hippocampus, olfactory bulb, neurons, astrocytes and
CC microglia (at protein level) (PubMed:25757569, PubMed:26260791,
CC PubMed:28720718). Expressed in the retinal lens (PubMed:25757569).
CC Expressed at a low level in muscle cells (at protein level)
CC (PubMed:25757569). {ECO:0000269|PubMed:25757569,
CC ECO:0000269|PubMed:26260791, ECO:0000269|PubMed:28720718}.
CC -!- TISSUE SPECIFICITY: [Isoform APP770]: Expressed in kidney.
CC {ECO:0000269|PubMed:8510506}.
CC -!- TISSUE SPECIFICITY: [Isoform APP751]: Widely expressed
CC (PubMed:8510506). Expressed in several different brain regions
CC including hippocampus, substantia nigra pars compacta and cerebellum
CC (PubMed:8510506). Within the cerebellum, abundantly expressed in
CC Purkinje cells (PubMed:8510506). {ECO:0000269|PubMed:8510506}.
CC -!- TISSUE SPECIFICITY: [Isoform APP695]: Expressed in the brain, kidney
CC and liver (PubMed:8510506). Expressed in several different brain
CC regions including hippocampus, substantia nigra pars compacta and
CC cerebellum (PubMed:8510506). Within the cerebellum, abundantly
CC expressed in Purkinje cells (PubMed:8510506).
CC {ECO:0000269|PubMed:8510506}.
CC -!- TISSUE SPECIFICITY: [Isoform APP714]: Expressed in several different
CC brain regions including hippocampus, substantia nigra pars compacta and
CC cerebellum (PubMed:8510506). Within the cerebellum, abundantly
CC expressed in Purkinje cells (PubMed:8510506).
CC {ECO:0000269|PubMed:8510506}.
CC -!- DEVELOPMENTAL STAGE: Expressed in 4 to 24 week old mice.
CC {ECO:0000269|PubMed:26260791}.
CC -!- INDUCTION: Up-regulated in animals on a high-fat diet compared to a
CC regular diet. {ECO:0000269|PubMed:26260791}.
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 (PubMed:11553691, PubMed:23931995). Cleavage either by alpha-secretase,
CC beta-secretase or theta-secretase leads to generation and extracellular
CC release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the
CC retention of corresponding membrane-anchored C-terminal fragments, C80,
CC C83 and C99 (PubMed:11553691, PubMed:23931995). Subsequent processing
CC of C80 and C83 by gamma-secretase yields P3 peptides. This is the major
CC 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 (By similarity). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000269|PubMed:11553691, ECO:0000269|PubMed:23931995}.
CC -!- PTM: Proteolytically cleaved by caspases during neuronal apoptosis.
CC Cleavage at Asp-739 by either CASP6, CASP8 or CASP9 results in the
CC production of the neurotoxic C31 peptide and the increased production
CC of amyloid-beta peptides. {ECO:0000250|UniProtKB:P05067}.
CC -!- PTM: N- and O-glycosylated. {ECO:0000250|UniProtKB:P05067}.
CC -!- PTM: Phosphorylation in the C-terminal on tyrosine, threonine and
CC serine residues is neuron-specific (By similarity). Phosphorylation can
CC affect APP processing, neuronal differentiation and interaction with
CC other proteins (By similarity). Phosphorylated on Thr-743 in neuronal
CC cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a
CC cell-cycle dependent manner with maximal levels at the G2/M phase and,
CC in vitro, by GSK-3-beta (By similarity). The Thr-743 phosphorylated
CC form causes a conformational change which reduces binding of Fe65
CC family members (By similarity). In dopaminergic (DA) neurons,
CC phosphorylation on Thr-743 by LRKK2 promotes the production and the
CC nuclear translocation of the APP intracellular domain (AICD) which
CC induces DA neuron apoptosis (PubMed:28720718). Phosphorylation on Tyr-
CC 757 is required for SHC binding (By similarity). Phosphorylated in the
CC extracellular domain by casein kinases on both soluble and membrane-
CC bound APP (By similarity). This phosphorylation is inhibited by heparin
CC (By similarity). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000269|PubMed:28720718}.
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:0000269|PubMed:12634421}.
CC -!- PTM: Sulfated on tyrosine residues. {ECO:0000250|UniProtKB:P05067}.
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 -!- 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; M18373; AAA37139.1; -; mRNA.
DR EMBL; X59379; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; U84012; AAB41502.1; -; mRNA.
DR EMBL; D10603; BAA01456.1; -; Genomic_DNA.
DR EMBL; BC005490; AAH05490.1; -; mRNA.
DR EMBL; M24397; AAA39929.1; -; mRNA.
DR EMBL; X15210; CAA33280.1; -; mRNA.
DR EMBL; U82624; AAB40919.1; -; Genomic_DNA.
DR CCDS; CCDS28285.1; -. [P12023-2]
DR CCDS; CCDS88958.1; -. [P12023-1]
DR PIR; A27485; A27485.
DR PIR; A32282; A32282.
DR PIR; S04855; S04855.
DR RefSeq; NP_001185752.1; NM_001198823.1. [P12023-1]
DR PDB; 2ROZ; NMR; -; A=739-770.
DR PDB; 2YSZ; NMR; -; A=739-770.
DR PDB; 2YT0; NMR; -; A=739-770.
DR PDB; 2YT1; NMR; -; A=739-770.
DR PDB; 4YN0; X-ray; 2.20 A; B=370-592.
DR PDB; 5MYK; X-ray; 1.60 A; C=674-689.
DR PDB; 7MRN; X-ray; 3.50 A; C/D=19-190.
DR PDBsum; 2ROZ; -.
DR PDBsum; 2YSZ; -.
DR PDBsum; 2YT0; -.
DR PDBsum; 2YT1; -.
DR PDBsum; 4YN0; -.
DR PDBsum; 5MYK; -.
DR PDBsum; 7MRN; -.
DR AlphaFoldDB; P12023; -.
DR BMRB; P12023; -.
DR SMR; P12023; -.
DR BioGRID; 198167; 137.
DR ComplexPortal; CPX-1105; Amyloid-beta protein 40/42 complex.
DR ComplexPortal; CPX-1106; Amyloid-beta protein 40 complex.
DR ComplexPortal; CPX-1107; Amyloid-beta protein 42 complex.
DR ComplexPortal; CPX-1121; Amyloid-beta protein 40/42 oligomeric complex.
DR ComplexPortal; CPX-1139; Amyloid-beta protein 42 oligomeric complex.
DR ComplexPortal; CPX-1181; Amyloid-beta protein 40 oligomeric complex.
DR CORUM; P12023; -.
DR ELM; P12023; -.
DR IntAct; P12023; 85.
DR MINT; P12023; -.
DR ChEMBL; CHEMBL4523942; -.
DR MEROPS; I02.015; -.
DR GlyGen; P12023; 2 sites.
DR iPTMnet; P12023; -.
DR PhosphoSitePlus; P12023; -.
DR MaxQB; P12023; -.
DR PaxDb; P12023; -.
DR PeptideAtlas; P12023; -.
DR PRIDE; P12023; -.
DR ProteomicsDB; 285696; -. [P12023-1]
DR ProteomicsDB; 285697; -. [P12023-2]
DR ProteomicsDB; 285698; -. [P12023-3]
DR ABCD; P12023; 1 sequenced antibody.
DR Antibodypedia; 668; 3991 antibodies from 52 providers.
DR DNASU; 11820; -.
DR Ensembl; ENSMUST00000005406; ENSMUSP00000005406; ENSMUSG00000022892. [P12023-2]
DR Ensembl; ENSMUST00000227723; ENSMUSP00000154061; ENSMUSG00000022892. [P12023-1]
DR GeneID; 11820; -.
DR KEGG; mmu:11820; -.
DR UCSC; uc007ztn.2; mouse. [P12023-1]
DR CTD; 351; -.
DR MGI; MGI:88059; App.
DR VEuPathDB; HostDB:ENSMUSG00000022892; -.
DR eggNOG; KOG3540; Eukaryota.
DR GeneTree; ENSGT00530000063252; -.
DR HOGENOM; CLU_014607_2_1_1; -.
DR InParanoid; P12023; -.
DR OMA; HEKFIPM; -.
DR PhylomeDB; P12023; -.
DR TreeFam; TF317274; -.
DR Reactome; R-MMU-114608; Platelet degranulation.
DR Reactome; R-MMU-3000178; ECM proteoglycans.
DR Reactome; R-MMU-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-MMU-416476; G alpha (q) signalling events.
DR Reactome; R-MMU-418594; G alpha (i) signalling events.
DR Reactome; R-MMU-432720; Lysosome Vesicle Biogenesis.
DR Reactome; R-MMU-444473; Formyl peptide receptors bind formyl peptides and many other ligands.
DR Reactome; R-MMU-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR Reactome; R-MMU-879415; Advanced glycosylation endproduct receptor signaling.
DR Reactome; R-MMU-8957275; Post-translational protein phosphorylation.
DR Reactome; R-MMU-933542; TRAF6 mediated NF-kB activation.
DR Reactome; R-MMU-9609523; Insertion of tail-anchored proteins into the endoplasmic reticulum membrane.
DR BioGRID-ORCS; 11820; 1 hit in 72 CRISPR screens.
DR ChiTaRS; App; mouse.
DR EvolutionaryTrace; P12023; -.
DR PRO; PR:P12023; -.
DR Proteomes; UP000000589; Chromosome 16.
DR RNAct; P12023; protein.
DR Bgee; ENSMUSG00000022892; Expressed in ciliary body and 284 other tissues.
DR ExpressionAtlas; P12023; baseline and differential.
DR Genevisible; P12023; MM.
DR GO; GO:0106003; C:amyloid-beta complex; ISO:MGI.
DR GO; GO:0045177; C:apical part of cell; IDA:MGI.
DR GO; GO:0097449; C:astrocyte projection; ISO:MGI.
DR GO; GO:0030424; C:axon; IDA:UniProtKB.
DR GO; GO:0044297; C:cell body; ISO:MGI.
DR GO; GO:0009986; C:cell surface; IDA:MGI.
DR GO; GO:0005911; C:cell-cell junction; IDA:MGI.
DR GO; GO:0035253; C:ciliary rootlet; IDA:MGI.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0030134; C:COPII-coated ER to Golgi transport vesicle; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
DR GO; GO:0043198; C:dendritic shaft; IEA:Ensembl.
DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl.
DR GO; GO:0005769; C:early endosome; IDA:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; ISO:MGI.
DR GO; GO:0070381; C:endosome to plasma membrane transport vesicle; ISO:MGI.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; IDA:MGI.
DR GO; GO:0005798; C:Golgi-associated vesicle; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; ISO:MGI.
DR GO; GO:1990812; C:growth cone filopodium; ISO:MGI.
DR GO; GO:1990761; C:growth cone lamellipodium; ISO:MGI.
DR GO; GO:0034364; C:high-density lipoprotein particle; ISO:MGI.
DR GO; GO:0016021; C:integral component of membrane; IDA:MGI.
DR GO; GO:0034363; C:intermediate-density lipoprotein particle; ISO:MGI.
DR GO; GO:1990777; C:lipoprotein particle; ISO:MGI.
DR GO; GO:0034362; C:low-density lipoprotein particle; ISO:MGI.
DR GO; GO:0005764; C:lysosome; ISO:MGI.
DR GO; GO:0044304; C:main axon; ISO:MGI.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0031594; C:neuromuscular junction; IDA:MGI.
DR GO; GO:0043005; C:neuron projection; IDA:MGI.
DR GO; GO:0005641; C:nuclear envelope lumen; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0098794; C:postsynapse; ISO:MGI.
DR GO; GO:0098793; C:presynapse; ISO:MGI.
DR GO; GO:0048786; C:presynaptic active zone; IDA:SynGO.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0043235; C:receptor complex; ISO:MGI.
DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
DR GO; GO:0005791; C:rough endoplasmic reticulum; ISO:MGI.
DR GO; GO:0005790; C:smooth endoplasmic reticulum; IEA:GOC.
DR GO; GO:0051233; C:spindle midzone; IDA:MGI.
DR GO; GO:0008021; C:synaptic vesicle; IDA:MGI.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; ISO:MGI.
DR GO; GO:0033130; F:acetylcholine receptor binding; ISO:MGI.
DR GO; GO:0034185; F:apolipoprotein binding; ISO:MGI.
DR GO; GO:0051087; F:chaperone binding; ISO:MGI.
DR GO; GO:0042056; F:chemoattractant activity; ISO:MGI.
DR GO; GO:0003682; F:chromatin binding; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0046875; F:ephrin receptor binding; ISO:MGI.
DR GO; GO:0005109; F:frizzled binding; ISO:MGI.
DR GO; GO:0001664; F:G protein-coupled receptor binding; ISO:MGI.
DR GO; GO:0070851; F:growth factor receptor binding; ISO:MGI.
DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; ISO:MGI.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0005158; F:insulin receptor binding; ISO:MGI.
DR GO; GO:0005178; F:integrin binding; ISO:MGI.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IPI:ARUK-UCL.
DR GO; GO:0016504; F:peptidase activator activity; ISO:MGI.
DR GO; GO:0046983; F:protein dimerization activity; ISO:MGI.
DR GO; GO:0046982; F:protein heterodimerization activity; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0051425; F:PTB domain binding; ISO:MGI.
DR GO; GO:0050786; F:RAGE receptor binding; ISO:MGI.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:MGI.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; ISO:MGI.
DR GO; GO:0030546; F:signaling receptor activator activity; IDA:ARUK-UCL.
DR GO; GO:0005102; F:signaling receptor binding; ISO:MGI.
DR GO; GO:0046914; F:transition metal ion binding; IEA:InterPro.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISO:MGI.
DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; ISO:MGI.
DR GO; GO:0008344; P:adult locomotory behavior; IMP:MGI.
DR GO; GO:1990000; P:amyloid fibril formation; ISO:MGI.
DR GO; GO:0019731; P:antibacterial humoral response; ISO:MGI.
DR GO; GO:0019732; P:antifungal humoral response; ISO:MGI.
DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; ISO:MGI.
DR GO; GO:0008306; P:associative learning; ISO:MGI.
DR GO; GO:0048143; P:astrocyte activation; ISO:MGI.
DR GO; GO:0002265; P:astrocyte activation involved in immune response; ISO:MGI.
DR GO; GO:0008088; P:axo-dendritic transport; IMP:MGI.
DR GO; GO:0016199; P:axon midline choice point recognition; IMP:MGI.
DR GO; GO:0007409; P:axonogenesis; IMP:MGI.
DR GO; GO:0019722; P:calcium-mediated signaling; ISO:MGI.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0006878; P:cellular copper ion homeostasis; IMP:MGI.
DR GO; GO:1904646; P:cellular response to amyloid-beta; ISO:MGI.
DR GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
DR GO; GO:0071280; P:cellular response to copper ion; IEA:Ensembl.
DR GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
DR GO; GO:0071874; P:cellular response to norepinephrine stimulus; ISO:MGI.
DR GO; GO:0007417; P:central nervous system development; IBA:GO_Central.
DR GO; GO:0008203; P:cholesterol metabolic process; IMP:MGI.
DR GO; GO:0050890; P:cognition; IDA:MGI.
DR GO; GO:0048669; P:collateral sprouting in absence of injury; IGI:MGI.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; ISO:MGI.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; ISO:MGI.
DR GO; GO:0016358; P:dendrite development; IMP:MGI.
DR GO; GO:0006897; P:endocytosis; IMP:MGI.
DR GO; GO:0030198; P:extracellular matrix organization; IGI:MGI.
DR GO; GO:0030900; P:forebrain development; IMP:MGI.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISO:MGI.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; IMP:MGI.
DR GO; GO:0045087; P:innate immune response; ISO:MGI.
DR GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; IMP:MGI.
DR GO; GO:0007612; P:learning; ISO:MGI.
DR GO; GO:0007611; P:learning or memory; ISO:MGI.
DR GO; GO:0007626; P:locomotory behavior; IGI:MGI.
DR GO; GO:0060291; P:long-term synaptic potentiation; TAS:ARUK-UCL.
DR GO; GO:0007617; P:mating behavior; IGI:MGI.
DR GO; GO:0007613; P:memory; ISO:MGI.
DR GO; GO:0014005; P:microglia development; ISO:MGI.
DR GO; GO:0001774; P:microglial cell activation; ISO:MGI.
DR GO; GO:0000278; P:mitotic cell cycle; IMP:MGI.
DR GO; GO:0098815; P:modulation of excitatory postsynaptic potential; ISO:MGI.
DR GO; GO:0006378; P:mRNA polyadenylation; IDA:MGI.
DR GO; GO:1903523; P:negative regulation of blood circulation; IGI:ARUK-UCL.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:MGI.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:MGI.
DR GO; GO:1902951; P:negative regulation of dendritic spine maintenance; ISO:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IDA:ComplexPortal.
DR GO; GO:1902894; P:negative regulation of miRNA transcription; ISO:MGI.
DR GO; GO:1901215; P:negative regulation of neuron death; ISO:MGI.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:MGI.
DR GO; GO:1900181; P:negative regulation of protein localization to nucleus; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; ISO:MGI.
DR GO; GO:0050885; P:neuromuscular process controlling balance; IGI:MGI.
DR GO; GO:0051402; P:neuron apoptotic process; IGI:MGI.
DR GO; GO:0070050; P:neuron cellular homeostasis; IGI:MGI.
DR GO; GO:0030182; P:neuron differentiation; IDA:MGI.
DR GO; GO:0031175; P:neuron projection development; IDA:MGI.
DR GO; GO:1990535; P:neuron projection maintenance; ISO:MGI.
DR GO; GO:0016322; P:neuron remodeling; IMP:MGI.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0061903; P:positive regulation of 1-phosphatidylinositol-3-kinase activity; ISO:MGI.
DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; ISO:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:1902961; P:positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process; ISO:MGI.
DR GO; GO:1905893; P:positive regulation of cellular response to thapsigargin; ISO:MGI.
DR GO; GO:1905896; P:positive regulation of cellular response to tunicamycin; ISO:MGI.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:MGI.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:MGI.
DR GO; GO:1904472; P:positive regulation of endothelin production; IGI:ARUK-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:MGI.
DR GO; GO:2000463; P:positive regulation of excitatory postsynaptic potential; ISO:MGI.
DR GO; GO:1904022; P:positive regulation of G protein-coupled receptor internalization; ISO:MGI.
DR GO; GO:0045745; P:positive regulation of G protein-coupled receptor signaling pathway; ISO:MGI.
DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IMP:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
DR GO; GO:0045821; P:positive regulation of glycolytic process; ISO:MGI.
DR GO; GO:0035066; P:positive regulation of histone acetylation; ISO:MGI.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISO:MGI.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; ISO:MGI.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISO:MGI.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISO:MGI.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:MGI.
DR GO; GO:1900454; P:positive regulation of long-term synaptic depression; ISO:MGI.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISO:MGI.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISO:MGI.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:MGI.
DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; ISO:MGI.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:MGI.
DR GO; GO:0090026; P:positive regulation of monocyte chemotaxis; ISO:MGI.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI.
DR GO; GO:1901216; P:positive regulation of neuron death; ISO:MGI.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IDA:ComplexPortal.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISO:MGI.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISO:MGI.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; ISO:MGI.
DR GO; GO:1903223; P:positive regulation of oxidative stress-induced neuron death; ISO:MGI.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:MGI.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; ISO:MGI.
DR GO; GO:0042327; P:positive regulation of phosphorylation; ISO:MGI.
DR GO; GO:0032092; P:positive regulation of protein binding; ISO:MGI.
DR GO; GO:1904591; P:positive regulation of protein import; ISO:MGI.
DR GO; GO:0051247; P:positive regulation of protein metabolic process; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; ISO:MGI.
DR GO; GO:1900122; P:positive regulation of receptor binding; ISO:MGI.
DR GO; GO:1905898; P:positive regulation of response to endoplasmic reticulum stress; ISO:MGI.
DR GO; GO:0032930; P:positive regulation of superoxide anion generation; ISO:MGI.
DR GO; GO:2000406; P:positive regulation of T cell migration; ISO:MGI.
DR GO; GO:1902949; P:positive regulation of tau-protein kinase activity; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL.
DR GO; GO:0051260; P:protein homooligomerization; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IMP:MGI.
DR GO; GO:0051262; P:protein tetramerization; ISO:MGI.
DR GO; GO:0070206; P:protein trimerization; ISO:MGI.
DR GO; GO:1903048; P:regulation of acetylcholine-gated cation channel activity; ISO:MGI.
DR GO; GO:1905906; P:regulation of amyloid fibril formation; ISO:MGI.
DR GO; GO:1900221; P:regulation of amyloid-beta clearance; ISO:MGI.
DR GO; GO:0032268; P:regulation of cellular protein metabolic process; IEA:UniProt.
DR GO; GO:1902950; P:regulation of dendritic spine maintenance; ISO:MGI.
DR GO; GO:0007176; P:regulation of epidermal growth factor-activated receptor activity; IGI:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IDA:MGI.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; ISO:MGI.
DR GO; GO:0043408; P:regulation of MAPK cascade; IDA:ComplexPortal.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IMP:MGI.
DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; ISO:MGI.
DR GO; GO:1905606; P:regulation of presynapse assembly; ISO:MGI.
DR GO; GO:0043393; P:regulation of protein binding; IMP:MGI.
DR GO; GO:0061097; P:regulation of protein tyrosine kinase activity; ISO:MGI.
DR GO; GO:1905945; P:regulation of response to calcium ion; ISO:MGI.
DR GO; GO:0010469; P:regulation of signaling receptor activity; ISO:MGI.
DR GO; GO:0150003; P:regulation of spontaneous synaptic transmission; ISO:MGI.
DR GO; GO:0050803; P:regulation of synapse structure or activity; IMP:MGI.
DR GO; GO:0034121; P:regulation of toll-like receptor signaling pathway; ISO:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0006417; P:regulation of translation; IDA:MGI.
DR GO; GO:0070555; P:response to interleukin-1; ISO:MGI.
DR GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IGI:MGI.
DR GO; GO:0001878; P:response to yeast; ISO:MGI.
DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IGI:MGI.
DR GO; GO:0001967; P:suckling behavior; IGI:MGI.
DR GO; GO:0050808; P:synapse organization; ISO:MGI.
DR GO; GO:0051124; P:synaptic assembly at neuromuscular junction; IGI:MGI.
DR GO; GO:0008542; P:visual learning; IMP:MGI.
DR CDD; cd00109; KU; 1.
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; Disulfide bond; Endocytosis; Endoplasmic reticulum;
KW Endosome; Glycoprotein; Golgi apparatus; Heparin-binding; Iron;
KW Isopeptide bond; Membrane; Metal-binding; Notch signaling pathway; Nucleus;
KW Phosphoprotein; Protease inhibitor; 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_0000000114"
FT CHAIN 18..687
FT /note="Soluble APP-alpha"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000115"
FT CHAIN 18..671
FT /note="Soluble APP-beta"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000116"
FT CHAIN 18..286
FT /note="N-APP"
FT /evidence="ECO:0000250"
FT /id="PRO_0000381968"
FT CHAIN 672..770
FT /note="C99"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000117"
FT CHAIN 672..713
FT /note="Amyloid-beta protein 42"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000118"
FT CHAIN 672..711
FT /note="Amyloid-beta protein 40"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000119"
FT CHAIN 688..770
FT /note="C83"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000120"
FT PEPTIDE 688..713
FT /note="P3(42)"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000121"
FT PEPTIDE 688..711
FT /note="P3(40)"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000122"
FT CHAIN 691..770
FT /note="C80"
FT /id="PRO_0000384576"
FT CHAIN 712..770
FT /note="Gamma-secretase C-terminal fragment 59"
FT /id="PRO_0000000123"
FT CHAIN 714..770
FT /note="Gamma-secretase C-terminal fragment 57"
FT /id="PRO_0000000124"
FT CHAIN 721..770
FT /note="Gamma-secretase C-terminal fragment 50"
FT /id="PRO_0000000125"
FT CHAIN 740..770
FT /note="C31"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000126"
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 181..188
FT /note="Zinc-binding"
FT /evidence="ECO:0000250"
FT REGION 193..284
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 /evidence="ECO:0000250"
FT REGION 756..770
FT /note="Interaction with DAB2"
FT /evidence="ECO:0000269|PubMed:11247302"
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 MOTIF 757..762
FT /note="YENPXY motif; contains endocytosis signal"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT COMPBIAS 195..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..284
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:0000250|UniProtKB:P08592"
FT SITE 690..691
FT /note="Cleavage; by theta-secretase"
FT /evidence="ECO:0000250|UniProtKB:P08592"
FT SITE 704
FT /note="Implicated in free radical propagation"
FT /evidence="ECO:0000250"
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:0000250|UniProtKB:P08592"
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:21183079"
FT MOD_RES 497
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT MOD_RES 729
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P08592"
FT MOD_RES 730
FT /note="Phosphoserine; by APP-kinase I"
FT /evidence="ECO:0000250|UniProtKB:P08592"
FT MOD_RES 743
FT /note="Phosphothreonine; by CDK5 and MAPK10 and LRRK2"
FT /evidence="ECO:0000269|PubMed:28720718"
FT MOD_RES 757
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000269|PubMed:11279131"
FT CARBOHYD 542
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0007744|PDB:4YN0"
FT CARBOHYD 571
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000305"
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:0000250|UniProtKB:P08592"
FT VAR_SEQ 289
FT /note="E -> V (in isoform APP695)"
FT /evidence="ECO:0000303|PubMed:11235921,
FT ECO:0000303|PubMed:1756177, ECO:0000303|PubMed:3322280"
FT /id="VSP_000012"
FT VAR_SEQ 290..364
FT /note="Missing (in isoform APP695)"
FT /evidence="ECO:0000303|PubMed:11235921,
FT ECO:0000303|PubMed:1756177, ECO:0000303|PubMed:3322280"
FT /id="VSP_000013"
FT VAR_SEQ 346..380
FT /note="Missing (in isoform APP751)"
FT /evidence="ECO:0000305"
FT /id="VSP_000014"
FT MUTAGEN 728
FT /note="Y->A: No effect on MAPK8IP1 binding."
FT /evidence="ECO:0000269|PubMed:11517249"
FT MUTAGEN 732..733
FT /note="HH->GL,GP: Almost complete loss of binding to G(o)
FT alpha subunit. No inhibition of GTPase activity."
FT MUTAGEN 743
FT /note="T->E: No effect on MAPK8IP1 binding."
FT /evidence="ECO:0000269|PubMed:11517249"
FT MUTAGEN 756
FT /note="G->F,H,N,S,W: Greatly impairs interaction with
FT DAB2."
FT /evidence="ECO:0000269|PubMed:11247302"
FT MUTAGEN 756
FT /note="G->Y: Impairs interaction with DAB2."
FT /evidence="ECO:0000269|PubMed:11247302"
FT MUTAGEN 757
FT /note="Y->F: Greatly promotes interaction with DAB2."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT MUTAGEN 757
FT /note="Y->G,H,V: Greatly impairs interaction with DAB2."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT MUTAGEN 757
FT /note="Y->G: No MAPK8IP1 nor APBA1 nor APBB1 nor DAB1
FT binding."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT MUTAGEN 757
FT /note="Y->I,W: Impairs interaction with DAB2."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT MUTAGEN 759
FT /note="N->A: No MAPK8IP1 nor APBA1 nor Dab1 binding. No
FT effect on APBB1 binding."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT MUTAGEN 759
FT /note="N->G,L,M,P: Greatly impairs interaction with DAB2."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT MUTAGEN 760
FT /note="P->E,F,I,K,L,Q,R,V,W,Y: Greatly impairs interaction
FT with DAB2."
FT /evidence="ECO:0000269|PubMed:11247302"
FT MUTAGEN 762
FT /note="Y->A: No MAPK8IP1 nor APBA1 nor Dab1 binding. No
FT effect on APBB1 binding."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT MUTAGEN 762
FT /note="Y->W: Greatly impairs interaction with DAB2."
FT /evidence="ECO:0000269|PubMed:11247302,
FT ECO:0000269|PubMed:11517249"
FT CONFLICT 211
FT /note="G -> V (in Ref. 1; AAA37139)"
FT /evidence="ECO:0000305"
FT CONFLICT 375
FT /note="V -> A (in Ref. 4; AAB41502)"
FT /evidence="ECO:0000305"
FT TURN 47..49
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 50..53
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 56..58
FT /evidence="ECO:0007829|PDB:7MRN"
FT HELIX 70..76
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 82..87
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 115..121
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 127..129
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 134..139
FT /evidence="ECO:0007829|PDB:7MRN"
FT HELIX 147..160
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 164..175
FT /evidence="ECO:0007829|PDB:7MRN"
FT STRAND 178..187
FT /evidence="ECO:0007829|PDB:7MRN"
FT HELIX 382..419
FT /evidence="ECO:0007829|PDB:4YN0"
FT TURN 420..422
FT /evidence="ECO:0007829|PDB:4YN0"
FT HELIX 425..481
FT /evidence="ECO:0007829|PDB:4YN0"
FT HELIX 487..518
FT /evidence="ECO:0007829|PDB:4YN0"
FT HELIX 520..550
FT /evidence="ECO:0007829|PDB:4YN0"
FT HELIX 552..581
FT /evidence="ECO:0007829|PDB:4YN0"
FT HELIX 744..753
FT /evidence="ECO:0007829|PDB:2ROZ"
SQ SEQUENCE 770 AA; 86722 MW; 988D89E089092A3E CRC64;
MLPSLALLLL AAWTVRALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG KWESDPSGTK
TCIGTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHTH IVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDSVDSAD AEEDDSDVWW GGADTDYADG GEDKVVEVAE EEEVADVEEE
EADDDEDVED GDEVEEEAEE PYEEATERTT STATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCVPFF YGGCGGNRNN FDTEEYCMAV CGSVSTQSLL KTTSEPLPQD
PDKLPTTAAS 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
