ID   E9PG40_HUMAN            Unreviewed;       714 AA.
AC   E9PG40;
DT   05-APR-2011, integrated into UniProtKB/TrEMBL.
DT   05-APR-2011, sequence version 1.
DT   27-MAR-2024, entry version 94.
DE   RecName: Full=Amyloid-beta A4 protein {ECO:0000256|RuleBase:RU367156};
GN   Name=APP {ECO:0000313|Ensembl:ENSP00000398879.2};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606 {ECO:0000313|Ensembl:ENSP00000398879.2, ECO:0000313|Proteomes:UP000005640};
RN   [1] {ECO:0000313|Ensembl:ENSP00000398879.2, ECO:0000313|Proteomes:UP000005640}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10830953; DOI=10.1038/35012518;
RG   Chromosome 21 mapping and sequencing consortium;
RA   Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA   Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA   Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA   Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA   Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA   Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA   Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA   Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA   Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA   Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA   Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT   "The DNA sequence of human chromosome 21.";
RL   Nature 405:311-319(2000).
RN   [2] {ECO:0007829|PubMed:21269460}
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Burckstummer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [3] {ECO:0007829|PubMed:24275569}
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [4] {ECO:0000313|Ensembl:ENSP00000398879.2}
RP   IDENTIFICATION.
RG   Ensembl;
RL   Submitted (NOV-2023) to UniProtKB.
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.
CC       {ECO:0000256|RuleBase:RU367156}.
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:0000256|ARBA:ARBA00003551}.
CC   -!- FUNCTION: The gamma-CTF peptides as well as the caspase-cleaved
CC       peptides, including C31, are potent enhancers of neuronal apoptosis.
CC       {ECO:0000256|ARBA:ARBA00002651}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000256|ARBA:ARBA00004251,
CC       ECO:0000256|RuleBase:RU367156}; Single-pass type I membrane protein
CC       {ECO:0000256|ARBA:ARBA00004251, ECO:0000256|RuleBase:RU367156}. Cell
CC       projection, growth cone {ECO:0000256|ARBA:ARBA00004624}. Cell surface
CC       {ECO:0000256|ARBA:ARBA00004241}. Cytoplasmic vesicle
CC       {ECO:0000256|ARBA:ARBA00004541}. Early endosome
CC       {ECO:0000256|ARBA:ARBA00004412}. Endoplasmic reticulum
CC       {ECO:0000256|ARBA:ARBA00004240}. Endosome
CC       {ECO:0000256|ARBA:ARBA00004177}. Golgi apparatus
CC       {ECO:0000256|ARBA:ARBA00004555}. Membrane, clathrin-coated pit
CC       {ECO:0000256|ARBA:ARBA00004600}. Membrane
CC       {ECO:0000256|ARBA:ARBA00004479}; Single-pass type I membrane protein
CC       {ECO:0000256|ARBA:ARBA00004479}. Nucleus
CC       {ECO:0000256|ARBA:ARBA00004123}. Perikaryon
CC       {ECO:0000256|ARBA:ARBA00004484}. Secreted
CC       {ECO:0000256|ARBA:ARBA00004613}. Vesicle
CC       {ECO:0000256|ARBA:ARBA00004373}.
CC   -!- SIMILARITY: Belongs to the APP family. {ECO:0000256|ARBA:ARBA00009449,
CC       ECO:0000256|PROSITE-ProRule:PRU01217, ECO:0000256|RuleBase:RU367156}.
CC   -!- CAUTION: Lacks conserved residue(s) required for the propagation of
CC       feature annotation. {ECO:0000256|PROSITE-ProRule:PRU01217}.
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DR   EMBL; AP001442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AP001443; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; KF457122; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; KF457123; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; KF457130; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; KF510514; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   RefSeq; NP_001129602.1; NM_001136130.2.
DR   AlphaFoldDB; E9PG40; -.
DR   SMR; E9PG40; -.
DR   MassIVE; E9PG40; -.
DR   MaxQB; E9PG40; -.
DR   PeptideAtlas; E9PG40; -.
DR   ProteomicsDB; 20239; -.
DR   Antibodypedia; 668; 4873 antibodies from 52 providers.
DR   DNASU; 351; -.
DR   Ensembl; ENST00000439274.6; ENSP00000398879.2; ENSG00000142192.22.
DR   GeneID; 351; -.
DR   UCSC; uc011ach.3; human.
DR   CTD; 351; -.
DR   HGNC; HGNC:620; APP.
DR   NIAGADS; ENSG00000142192; -.
DR   VEuPathDB; HostDB:ENSG00000142192; -.
DR   GeneTree; ENSGT00530000063252; -.
DR   OrthoDB; 2907766at2759; -.
DR   BioGRID-ORCS; 351; 12 hits in 1170 CRISPR screens.
DR   ChiTaRS; APP; human.
DR   GenomeRNAi; 351; -.
DR   Proteomes; UP000005640; Chromosome 21.
DR   Bgee; ENSG00000142192; Expressed in prefrontal cortex and 208 other cell types or tissues.
DR   ExpressionAtlas; E9PG40; baseline and differential.
DR   GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR   GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR   GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR   GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR   GO; GO:0005798; C:Golgi-associated vesicle; IEA:UniProtKB-UniRule.
DR   GO; GO:0030426; C:growth cone; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR   GO; GO:0008201; F:heparin binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR   GO; GO:0046914; F:transition metal ion binding; IEA:InterPro.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR   GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR   CDD; cd22607; Kunitz_ABPP-like; 1.
DR   Gene3D; 1.20.120.770; Amyloid precursor protein, E2 domain; 1.
DR   Gene3D; 4.10.230.10; Amyloidogenic glycoprotein, amyloid-beta peptide; 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; IPR037071; Amyloid_glyco_Abeta_sf.
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; E9PG40; HS.
PE   1: Evidence at protein level;
KW   Amyloid {ECO:0000256|ARBA:ARBA00023087, ECO:0000256|RuleBase:RU367156};
KW   Apoptosis {ECO:0000256|ARBA:ARBA00022703};
KW   Cell membrane {ECO:0000256|ARBA:ARBA00022475,
KW   ECO:0000256|RuleBase:RU367156};
KW   Cell projection {ECO:0000256|ARBA:ARBA00023273};
KW   Coated pit {ECO:0000256|ARBA:ARBA00023176};
KW   Coiled coil {ECO:0000256|SAM:Coils};
KW   Copper {ECO:0000256|ARBA:ARBA00023008};
KW   Cytoplasm {ECO:0000256|ARBA:ARBA00022490};
KW   Cytoplasmic vesicle {ECO:0000256|ARBA:ARBA00023329};
KW   Disulfide bond {ECO:0000256|ARBA:ARBA00023157, ECO:0000256|PROSITE-
KW   ProRule:PRU01217}; Endocytosis {ECO:0000256|ARBA:ARBA00022583};
KW   Endoplasmic reticulum {ECO:0000256|ARBA:ARBA00022824};
KW   Endosome {ECO:0000256|ARBA:ARBA00022753};
KW   Glycoprotein {ECO:0000256|ARBA:ARBA00023180};
KW   Golgi apparatus {ECO:0000256|ARBA:ARBA00023034};
KW   Heparin-binding {ECO:0000256|ARBA:ARBA00022674};
KW   Isopeptide bond {ECO:0000256|ARBA:ARBA00022499};
KW   Membrane {ECO:0000256|ARBA:ARBA00023136, ECO:0000256|RuleBase:RU367156};
KW   Metal-binding {ECO:0000256|ARBA:ARBA00022723};
KW   Notch signaling pathway {ECO:0000256|ARBA:ARBA00022976};
KW   Nucleus {ECO:0000256|ARBA:ARBA00023242};
KW   Phosphoprotein {ECO:0000256|ARBA:ARBA00022553};
KW   Protease inhibitor {ECO:0000256|ARBA:ARBA00022690};
KW   Proteoglycan {ECO:0000256|ARBA:ARBA00022974};
KW   Proteomics identification {ECO:0007829|EPD:E9PG40,
KW   ECO:0007829|MaxQB:E9PG40};
KW   Reference proteome {ECO:0000313|Proteomes:UP000005640};
KW   Secreted {ECO:0000256|ARBA:ARBA00022525};
KW   Serine protease inhibitor {ECO:0000256|ARBA:ARBA00022900};
KW   Signal {ECO:0000256|ARBA:ARBA00022729, ECO:0000256|SAM:SignalP};
KW   Sulfation {ECO:0000256|ARBA:ARBA00022641};
KW   Transmembrane {ECO:0000256|ARBA:ARBA00022692,
KW   ECO:0000256|RuleBase:RU367156};
KW   Transmembrane helix {ECO:0000256|ARBA:ARBA00022989,
KW   ECO:0000256|RuleBase:RU367156};
KW   Ubl conjugation {ECO:0000256|ARBA:ARBA00022843};
KW   Zinc {ECO:0000256|ARBA:ARBA00022833}.
FT   SIGNAL          1..17
FT                   /evidence="ECO:0000256|SAM:SignalP"
FT   CHAIN           18..714
FT                   /note="Amyloid-beta A4 protein"
FT                   /evidence="ECO:0000256|SAM:SignalP"
FT                   /id="PRO_5003242798"
FT   TRANSMEM        645..667
FT                   /note="Helical"
FT                   /evidence="ECO:0000256|RuleBase:RU367156"
FT   DOMAIN          1..133
FT                   /note="E1"
FT                   /evidence="ECO:0000259|PROSITE:PS51869"
FT   DOMAIN          235..285
FT                   /note="BPTI/Kunitz inhibitor"
FT                   /evidence="ECO:0000259|PROSITE:PS50279"
FT   DOMAIN          318..509
FT                   /note="E2"
FT                   /evidence="ECO:0000259|PROSITE:PS51870"
FT   REGION          1..67
FT                   /note="GFLD subdomain"
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU01217"
FT   REGION          75..133
FT                   /note="CuBD subdomain"
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU01217"
FT   REGION          138..228
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COILED          343..403
FT                   /evidence="ECO:0000256|SAM:Coils"
FT   COMPBIAS        139..154
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        169..207
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        211..228
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   DISULFID        42..49
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU01217"
FT   DISULFID        77..131
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU01217"
FT   DISULFID        88..118
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU01217"
FT   DISULFID        102..130
FT                   /evidence="ECO:0000256|PROSITE-ProRule:PRU01217"
SQ   SEQUENCE   714 AA;  80833 MW;  68CC52E6F29B777B CRC64;
     MLPGLALLLL AAWTARALEV YPELQITNVV EANQPVTIQN WCKRGRKQCK THPHFVIPYR
     CLVGEFVSDA LLVPDKCKFL HQERMDVCET HLHWHTVAKE TCSEKSTNLH DYGMLLPCGI
     DKFRGVEFVC CPLAEESDNV DSADAEEDDS DVWWGGADTD YADGSEDKVV EVAEEEEVAE
     VEEEEADDDE DDEDGDEVEE EAEEPYEEAT ERTTSIATTT TTTTESVEEV VREVCSEQAE
     TGPCRAMISR WYFDVTEGKC APFFYGGCGG NRNNFDTEEY CMAVCGSAMS QSLLKTTQEP
     LARDPVKLPT TAASTPDAVD KYLETPGDEN EHAHFQKAKE RLEAKHRERM SQVMREWEEA
     ERQAKNLPKA DKKAVIQHFQ EKVESLEQEA ANERQQLVET HMARVEAMLN DRRRLALENY
     ITALQAVPPR PRHVFNMLKK YVRAEQKDRQ HTLKHFEHVR MVDPKKAAQI RSQVMTHLRV
     IYERMNQSLS LLYNVPAVAE EIQDEVDELL QKEQNYSDDV LANMISEPRI SYGNDALMPS
     LTETKTTVEL LPVNGEFSLD DLQPWHSFGA DSVPANTENE VEPVDARPAA DRGLTTRPGS
     GLTNIKTEEI SEVKMDAEFR HDSGYEVHHQ KLVFFAEDVG SNKGAIIGLM VGGVVIATVI
     VITLVMLKKK QYTSIHHGVV EVDAAVTPEE RHLSKMQQNG YENPTYKFFE QMQN
//