A4_PANTR
ID A4_PANTR Reviewed; 770 AA.
AC Q5IS80;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 15-FEB-2005, sequence version 1.
DT 03-AUG-2022, entry version 142.
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:0000250|UniProtKB:P08592};
DE AltName: Full=Amyloid-beta A4 protein {ECO:0000250|UniProtKB:P08592};
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:0000250|UniProtKB:P05067};
GN Synonyms=A4 {ECO:0000250|UniProtKB:P05067},
GN AD1 {ECO:0000250|UniProtKB:P05067};
OS Pan troglodytes (Chimpanzee).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pan.
OX NCBI_TaxID=9598;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=15620360; DOI=10.1016/j.cell.2004.11.040;
RA Dorus S., Vallender E.J., Evans P.D., Anderson J.R., Gilbert S.L.,
RA Mahowald M., Wyckoff G.J., Malcom C.M., Lahn B.T.;
RT "Accelerated evolution of nervous system genes in the origin of Homo
RT sapiens.";
RL Cell 119:1027-1040(2004).
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 (By similarity).
CC Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin
CC I membrane receptor, mediating the axonal transport of beta-secretase
CC and presenilin 1 (By similarity). By acting as a kinesin I membrane
CC receptor, plays a role in axonal anterograde transport of cargo towards
CC synapes in axons (By similarity). May be involved in copper
CC homeostasis/oxidative stress through copper ion reduction (By
CC similarity). In vitro, copper-metallated APP induces neuronal death
CC directly or is potentiated through Cu(2+)-mediated low-density
CC lipoprotein oxidation (By similarity). Can regulate neurite outgrowth
CC through binding to components of the extracellular matrix such as
CC heparin and collagen I and IV. Induces a AGER-dependent pathway that
CC involves activation of p38 MAPK, resulting in internalization of
CC amyloid-beta peptide and 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 (By similarity). {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: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). Interacts with SORL1 (via N-terminal ectodomain); this
CC interaction retains APP in the trans-Golgi network and reduces
CC processing into soluble APP-alpha and amyloid-beta peptides (By
CC similarity). The C99 fragment also interacts with SORL1 (By
CC similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1
CC (By similarity). Interacts with NSG1; could regulate APP processing (By
CC similarity). Amyloid-beta protein 42 interacts with FPR2 (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 (By
CC similarity). Interacts (via C-terminus) with APBB2/FE65L1 (via C-
CC terminus) (By similarity). Interacts (via intracellular domain) with
CC APBB3 (By similarity). {ECO:0000250|UniProtKB:P05067,
CC ECO:0000250|UniProtKB:P08592, ECO:0000250|UniProtKB:P12023}.
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:0000250|UniProtKB:P05067}. Cell projection, growth cone
CC {ECO:0000250|UniProtKB:P05067}. 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. 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. Associates with GPC1 in perinuclear
CC compartments. Colocalizes with SORL1 in a vesicular pattern in
CC cytoplasm and perinuclear regions. {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: [C99]: Early endosome
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [Soluble APP-beta]: Secreted
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [Amyloid-beta protein 42]: Cell surface
CC {ECO:0000250|UniProtKB:P05067}. Note=Associates with FPR2 at the cell
CC surface and the complex is then rapidly internalized.
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [Gamma-secretase C-terminal fragment 59]: Nucleus
CC {ECO:0000250|UniProtKB:P05067}. 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). 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 -!- 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- and O-glycosylated. {ECO:0000250|UniProtKB:P05067}.
CC -!- PTM: Phosphorylation in the C-terminal on tyrosine, threonine and
CC serine residues is neuron-specific. Phosphorylation can affect APP
CC processing, neuronal differentiation and interaction with other
CC proteins. Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase
CC and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent
CC manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-
CC beta. The Thr-743 phosphorylated form causes a conformational change
CC which reduces binding of Fe65 family members. In dopaminergic (DA)
CC neurons, phosphorylation on Thr-743 by LRKK2 promotes the production
CC and the nuclear translocation of the APP intracellular domain (AICD)
CC which induces DA neuron apoptosis. Phosphorylation on Tyr-757 is
CC required for SHC binding. Phosphorylated in the extracellular domain by
CC casein kinases on both soluble and membrane-bound APP. This
CC phosphorylation is inhibited by heparin.
CC {ECO:0000250|UniProtKB:P05067}.
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 -!- 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. Extracellular zinc-binding increases
CC binding of heparin to APP and inhibits collagen-binding.
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SIMILARITY: Belongs to the APP family. {ECO:0000255|PROSITE-
CC ProRule:PRU01217}.
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DR EMBL; AY665248; AAV74286.1; -; mRNA.
DR RefSeq; NP_001013036.1; NM_001013018.1.
DR AlphaFoldDB; Q5IS80; -.
DR SMR; Q5IS80; -.
DR STRING; 9598.ENSPTRP00000023795; -.
DR MEROPS; I02.015; -.
DR PaxDb; Q5IS80; -.
DR PRIDE; Q5IS80; -.
DR GeneID; 473931; -.
DR KEGG; ptr:473931; -.
DR CTD; 351; -.
DR eggNOG; KOG3540; Eukaryota.
DR HOGENOM; CLU_014607_2_1_1; -.
DR InParanoid; Q5IS80; -.
DR OrthoDB; 953529at2759; -.
DR TreeFam; TF317274; -.
DR Proteomes; UP000002277; Unplaced.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0030546; F:signaling receptor activator activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0046914; F:transition metal ion binding; IEA:InterPro.
DR GO; GO:0008344; P:adult locomotory behavior; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0008088; P:axo-dendritic transport; ISS:UniProtKB.
DR GO; GO:0016199; P:axon midline choice point recognition; ISS:UniProtKB.
DR GO; GO:0007409; P:axonogenesis; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0006878; P:cellular copper ion homeostasis; ISS:UniProtKB.
DR GO; GO:0007417; P:central nervous system development; IBA:GO_Central.
DR GO; GO:0050890; P:cognition; ISS:UniProtKB.
DR GO; GO:0048669; P:collateral sprouting in absence of injury; ISS:UniProtKB.
DR GO; GO:0016358; P:dendrite development; ISS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; ISS:UniProtKB.
DR GO; GO:0030198; P:extracellular matrix organization; ISS:UniProtKB.
DR GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB.
DR GO; GO:0007617; P:mating behavior; ISS:UniProtKB.
DR GO; GO:0006378; P:mRNA polyadenylation; ISS:UniProtKB.
DR GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
DR GO; GO:0016322; P:neuron remodeling; ISS:UniProtKB.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0032268; P:regulation of cellular protein metabolic process; IEA:UniProt.
DR GO; GO:0007176; P:regulation of epidermal growth factor-activated receptor activity; ISS:UniProtKB.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISS:UniProtKB.
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:0008542; P:visual learning; ISS:UniProtKB.
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; 4.10.230.10; -; 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; 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; 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 2: Evidence at transcript level;
KW Amyloid; Apoptosis; Cell adhesion; Cell membrane; Cell projection;
KW Coated pit; Copper; Cytoplasm; Cytoplasmic vesicle; 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_0000000127"
FT CHAIN 18..687
FT /note="Soluble APP-alpha"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000128"
FT CHAIN 18..671
FT /note="Soluble APP-beta"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000129"
FT CHAIN 18..286
FT /note="N-APP"
FT /evidence="ECO:0000250"
FT /id="PRO_0000381969"
FT CHAIN 672..770
FT /note="C99"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000130"
FT CHAIN 672..713
FT /note="Amyloid-beta protein 42"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000131"
FT CHAIN 672..711
FT /note="Amyloid-beta protein 40"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000132"
FT CHAIN 688..770
FT /note="C83"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000133"
FT PEPTIDE 688..713
FT /note="P3(42)"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000134"
FT PEPTIDE 688..711
FT /note="P3(40)"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000135"
FT CHAIN 691..770
FT /note="C80"
FT /id="PRO_0000384577"
FT CHAIN 712..770
FT /note="Gamma-secretase C-terminal fragment 59"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000136"
FT CHAIN 714..770
FT /note="Gamma-secretase C-terminal fragment 57"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000137"
FT CHAIN 721..770
FT /note="Gamma-secretase C-terminal fragment 50"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000138"
FT CHAIN 740..770
FT /note="C31"
FT /evidence="ECO:0000255"
FT /id="PRO_0000000139"
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 194..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="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 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 681
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 681
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 684
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 684
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:0000250|UniProtKB:P05067"
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"
FT /evidence="ECO:0000250|UniProtKB:P05067"
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 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"
SQ SEQUENCE 770 AA; 86971 MW; 08EBAAFE7E4930A9 CRC64;
MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVMSQSLL KTTQEPLARD
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL
VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
