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A4_CAVPO
ID   A4_CAVPO                Reviewed;         770 AA.
AC   Q60495; Q60496;
DT   23-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT   23-APR-2003, sequence version 2.
DT   03-AUG-2022, entry version 166.
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     AltName: Full=CTF-beta;
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     AltName: Full=CTF-alpha;
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=Amyloid intracellular domain 50;
DE              Short=AICD-50;
DE              Short=AID(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   Cavia porcellus (Guinea pig).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Caviidae;
OC   Cavia.
OX   NCBI_TaxID=10141;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RC   TISSUE=Brain, and Liver;
RX   PubMed=9116031; DOI=10.1016/s0167-4781(96)00232-1;
RA   Beck M., Mueller D., Bigl V.;
RT   "Amyloid precursor protein in Guinea pigs -- complete cDNA sequence and
RT   alternative splicing.";
RL   Biochim. Biophys. Acta 1351:17-21(1997).
RN   [2]
RP   INTERACTION OF APP40-BETA WITH APOE.
RX   PubMed=9349544; DOI=10.1046/j.1471-4159.1997.69051995.x;
RA   Martel C.L., Mackic J.B., Matsubara E., Governale S., Miguel C., Miao W.,
RA   McComb J.G., Frangione B., Ghiso J., Zlokovic B.V.;
RT   "Isoform-specific effects of apolipoproteins E2, E3, and E4 on cerebral
RT   capillary sequestration and blood-brain barrier transport of circulating
RT   Alzheimer's amyloid beta.";
RL   J. Neurochem. 69:1995-2004(1997).
RN   [3]
RP   PROTEOLYTIC PROCESSING.
RX   PubMed=10619481; DOI=10.1016/s0306-4522(99)00390-5;
RA   Beck M., Brueckner M.K., Holzer M., Kaap S., Pannicke T., Arendt T.,
RA   Bigl V.;
RT   "Guinea-pig primary cell cultures provide a model to study expression and
RT   amyloidogenic processing of endogenous amyloid precursor protein.";
RL   Neuroscience 95:243-254(2000).
RN   [4]
RP   PROTEOLYTIC PROCESSING BY GAMMA-SECRETASE.
RX   PubMed=11035007; DOI=10.1074/jbc.m005968200;
RA   Pinnix I., Musunuru U., Tun H., Sridharan A., Golde T., Eckman C.,
RA   Ziani-Cherif C., Onstead L., Sambamurti K.;
RT   "A novel gamma-secretase assay based on detection of the putative C-
RT   terminal fragment-gamma of amyloid beta protein precursor.";
RL   J. Biol. Chem. 276:481-487(2001).
CC   -!- FUNCTION: Functions as a cell surface receptor and performs
CC       physiological functions on the surface of neurons relevant to neurite
CC       growth, neuronal adhesion and axonogenesis. Interaction between APP
CC       molecules on neighboring cells promotes synaptogenesis. Involved in
CC       cell mobility and transcription regulation through protein-protein
CC       interactions (By similarity). Can promote transcription activation
CC       through binding to APBB1-KAT5 and inhibit Notch signaling through
CC       interaction with Numb (By similarity). Couples to apoptosis-inducing
CC       pathways such as those mediated by G(o) and JIP (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. Amyloid-beta peptides bind to lipoproteins and
CC       apolipoproteins E and J in the CSF and to HDL particles in plasma,
CC       inhibiting metal-catalyzed oxidation of lipoproteins. Also bind GPC1 in
CC       lipid rafts (By similarity). {ECO:0000250}.
CC   -!- FUNCTION: Appicans elicit adhesion of neural cells to the extracellular
CC       matrix and may regulate neurite outgrowth in the brain. {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). Isoform APP695 interacts with SORL1 (via N-terminal
CC       ectodomain); this interaction retains APP in the trans-Golgi network
CC       and reduces processing into soluble APP-alpha and amyloid-beta peptides
CC       (By similarity). Isoform APP770 interacts with SORL1 (By similarity).
CC       The C99 fragment also interacts with SORL1 (By similarity). Interacts
CC       with PLD3 (By similarity). Interacts with VDAC1 (By similarity).
CC       Interacts with NSG1; could regulate APP processing (By similarity).
CC       Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts
CC       (via transmembrane region) with PSEN1; the interaction is direct (By
CC       similarity). Interacts with LRRK2 (By similarity). Interacts (via
CC       cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-
CC       terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts
CC       (via intracellular domain) with APBB3 (By similarity).
CC       {ECO:0000250|UniProtKB:P05067, ECO:0000250|UniProtKB:P08592,
CC       ECO:0000250|UniProtKB:P12023, ECO:0000269|PubMed:9349544}.
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) (By similarity). In dopaminergic neurons,
CC       the phosphorylated Thr-743 form is localized to the nucleus (By
CC       similarity). {ECO:0000250|UniProtKB:P05067,
CC       ECO:0000250|UniProtKB:P12023}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC         Comment=Additional isoforms, missing exons 7,8 and 15, seem to exist.
CC         The L-isoforms, missing exon 15, are referred to as appicans.;
CC       Name=APP770;
CC         IsoId=Q60495-1; Sequence=Displayed;
CC       Name=APP695;
CC         IsoId=Q60495-2; Sequence=VSP_007221, VSP_007222;
CC   -!- TISSUE SPECIFICITY: Isoform APP695 is the major isoform found in brain.
CC       The longer isoforms containing the BPTI domain are predominantly
CC       expressed in peripheral organs such as muscle and liver.
CC   -!- INDUCTION: Increased levels during neuronal differentiation.
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:10619481, PubMed:11035007). 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:10619481, PubMed:11035007). 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:10619481, ECO:0000269|PubMed:11035007}.
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 (PubMed:10619481, PubMed:11035007). Phosphorylated on
CC       Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells
CC       by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at
CC       the G2/M phase and, in vitro, by GSK-3-beta (By similarity). The Thr-
CC       743 phosphorylated form causes a conformational change which reduces
CC       binding of Fe65 family members (By similarity). 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 (By similarity). Phosphorylation on
CC       Tyr-757 is required for SHC binding. 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:10619481, ECO:0000269|PubMed:11035007}.
CC   -!- PTM: N- and O-glycosylated. O-linkage of chondroitin sulfate to the L-
CC       APP isoforms produces the APP proteoglycan core proteins, the appicans
CC       (By similarity). {ECO:0000250}.
CC   -!- PTM: Extracellular binding and reduction of copper, results in a
CC       corresponding oxidation of Cys-144 and Cys-158, and the formation of a
CC       disulfide bond. {ECO:0000250}.
CC   -!- PTM: Trophic-factor deprivation triggers the cleavage of surface APP by
CC       beta-secretase to release sAPP-beta which is further cleaved to release
CC       an N-terminal fragment of APP (N-APP). {ECO:0000250}.
CC   -!- PTM: Amyloid-beta peptides are degraded by IDE.
CC       {ECO:0000250|UniProtKB:P12023}.
CC   -!- PTM: Sulfated on tyrosine residues. {ECO:0000250|UniProtKB:P05067}.
CC   -!- 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; X97631; CAA66230.1; -; mRNA.
DR   EMBL; X99198; CAA67589.1; -; mRNA.
DR   AlphaFoldDB; Q60495; -.
DR   SMR; Q60495; -.
DR   STRING; 10141.ENSCPOP00000001291; -.
DR   MEROPS; I02.015; -.
DR   eggNOG; KOG3540; Eukaryota.
DR   InParanoid; Q60495; -.
DR   Proteomes; UP000005447; Unassembled WGS sequence.
DR   GO; GO:0030424; C:axon; ISS:UniProtKB.
DR   GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
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:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
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: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: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   1: Evidence at protein level;
KW   Alternative splicing; Amyloid; Apoptosis; Cell adhesion; Cell membrane;
KW   Cell projection; Coated pit; Copper; Cytoplasm; Cytoplasmic vesicle;
KW   Disulfide bond; 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_0000000076"
FT   CHAIN           18..687
FT                   /note="Soluble APP-alpha"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000077"
FT   CHAIN           18..671
FT                   /note="Soluble APP-beta"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000078"
FT   CHAIN           18..286
FT                   /note="N-APP"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000381965"
FT   CHAIN           672..770
FT                   /note="C99"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000079"
FT   CHAIN           672..713
FT                   /note="Amyloid-beta protein 42"
FT                   /evidence="ECO:0000250|UniProtKB:P05067"
FT                   /id="PRO_0000000080"
FT   CHAIN           672..711
FT                   /note="Amyloid-beta protein 40"
FT                   /evidence="ECO:0000250|UniProtKB:P05067"
FT                   /id="PRO_0000000081"
FT   CHAIN           688..770
FT                   /note="C83"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000082"
FT   PEPTIDE         688..713
FT                   /note="P3(42)"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000083"
FT   PEPTIDE         688..711
FT                   /note="P3(40)"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000084"
FT   CHAIN           691..770
FT                   /note="C80"
FT                   /id="PRO_0000384573"
FT   CHAIN           712..770
FT                   /note="Gamma-secretase C-terminal fragment 59"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000085"
FT   CHAIN           714..770
FT                   /note="Gamma-secretase C-terminal fragment 57"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000086"
FT   CHAIN           721..770
FT                   /note="Gamma-secretase C-terminal fragment 50"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000442140"
FT   CHAIN           740..770
FT                   /note="C31"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000000087"
FT   TOPO_DOM        18..701
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000305"
FT   TRANSMEM        702..722
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:P05067"
FT   TOPO_DOM        723..770
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000305"
FT   DOMAIN          28..189
FT                   /note="E1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT   DOMAIN          291..341
FT                   /note="BPTI/Kunitz inhibitor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT   DOMAIN          374..565
FT                   /note="E2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01218"
FT   REGION          28..123
FT                   /note="GFLD subdomain"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT   REGION          131..189
FT                   /note="CuBD subdomain"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01217"
FT   REGION          135..155
FT                   /note="Copper-binding"
FT                   /evidence="ECO:0000250"
FT   REGION          181..188
FT                   /note="Zinc-binding"
FT                   /evidence="ECO:0000250"
FT   REGION          196..281
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   MOTIF           757..762
FT                   /note="YENPXY motif; contains endocytosis signal"
FT                   /evidence="ECO:0000250|UniProtKB:P05067"
FT   COMPBIAS        196..210
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        225..263
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        267..281
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:P05067"
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         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   CARBOHYD        656
FT                   /note="O-linked (Xyl...) (chondroitin sulfate) serine"
FT                   /evidence="ECO:0000250"
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:0000305"
FT                   /id="VSP_007221"
FT   VAR_SEQ         290..364
FT                   /note="Missing (in isoform APP695)"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_007222"
SQ   SEQUENCE   770 AA;  86883 MW;  0AFD36C90F0D8B6C CRC64;
     MLPSLALLLL TTWTARALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG KWEPDPSGTK
     TCIGSKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR SRKQCKTHPH FVIPYRCLVG
     EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
     GVEFVCCPLA EESDNIDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVADVEEE
     EADDDEDVED GDEVEEEAEE PYEEATEKTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
     RSMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVMSQNLL KTSGEPVSQG
     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 WHPFGVDSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
     IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL
     VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
 
 
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