Gene/Proteome Database (LMPD)

LMPD ID
LMP012646
Gene ID
54226
Species
Rattus norvegicus (Rat)
Gene Name
amyloid beta (A4) precursor protein
Gene Symbol
App
Synonyms
Abeta;
Alternate Names
amyloid beta A4 protein; AG; ABPP; amyloid A4; amyloidogenic glycoprotein; alzheimer disease amyloid A4 protein homolog;
Chromosome
11
Map Location
11q11
Summary
activates voltage dependent calcium channels; may induce neuronal apoptosis [RGD, Feb 2006]
Orthologs
View orthologs and multiple alignments for App

Proteins

amyloid beta A4 protein precursor
Refseq ID NP_062161
Protein GI 27436861
UniProt ID P08592
mRNA ID NM_019288
Length 770
MLPSLALLLLAAWTVRALEVPTDGNAGLLAEPQIAMFCGKLNMHMNVQNGKWESDPSGTKTCIGTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHTHIVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDSIDSADAEEDDSDVWWGGADTDYADGGEDKVVEVAEEEEVADVEEEEAEDDEDVEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSVSSQSLLKTTSEPLPQDPVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPHHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHPFGVDSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN
sig_peptide: 1..17 inference: COORDINATES: ab initio prediction:SignalP:4.0 calculated_mol_wt: 1839 peptide sequence: MLPSLALLLLAAWTVRA mat_peptide: 18..770 product: Amyloid beta A4 protein experiment: experimental evidence, no additional details recorded note: propagated from UniProtKB/Swiss-Prot (P08592.2) calculated_mol_wt: 84883 peptide sequence: LEVPTDGNAGLLAEPQIAMFCGKLNMHMNVQNGKWESDPSGTKTCIGTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHTHIVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDSIDSADAEEDDSDVWWGGADTDYADGGEDKVVEVAEEEEVADVEEEEAEDDEDVEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSVSSQSLLKTTSEPLPQDPVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPHHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHPFGVDSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN

Gene Information

Entrez Gene ID
54226
Gene Name
amyloid beta (A4) precursor protein
Gene Symbol
App
Species
Rattus norvegicus

Gene Ontology (GO Annotations)

GO ID Source Type Description
GO:0030134 IEA:Ensembl C ER to Golgi transport vesicle
GO:0005794 ISS:UniProtKB C Golgi apparatus
GO:0045177 IEA:Ensembl C apical part of cell
GO:0030424 ISS:UniProtKB C axon
GO:0009986 IDA:AgBase C cell surface
GO:0005911 IEA:Ensembl C cell-cell junction
GO:0035253 IEA:Ensembl C ciliary rootlet
GO:0005905 IEA:UniProtKB-KW C coated pit
GO:0005737 ISS:UniProtKB C cytoplasm
GO:0043198 IEA:Ensembl C dendritic shaft
GO:0043197 IEA:Ensembl C dendritic spine
GO:0005615 IEA:Ensembl C extracellular space
GO:0070062 IEA:Ensembl C extracellular vesicular exosome
GO:0016021 ISS:UniProtKB C integral component of membrane
GO:0045121 IEA:Ensembl C membrane raft
GO:0031594 IEA:Ensembl C neuromuscular junction
GO:0043005 IDA:RGD C neuron projection
GO:0005641 IEA:Ensembl C nuclear envelope lumen
GO:0048471 IEA:Ensembl C perinuclear region of cytoplasm
GO:0005886 IEA:Ensembl C plasma membrane
GO:0043235 IEA:Ensembl C receptor complex
GO:0051233 IEA:Ensembl C spindle midzone
GO:0003677 ISS:UniProtKB F DNA binding
GO:0070851 IPI:RGD F growth factor receptor binding
GO:0008201 IEA:UniProtKB-KW F heparin binding
GO:0016504 IDA:RGD F peptidase activator activity
GO:0004867 IEA:UniProtKB-KW F serine-type endopeptidase inhibitor activity
GO:0046914 IEA:InterPro F transition metal ion binding
GO:0007219 IEA:UniProtKB-KW P Notch signaling pathway
GO:0008344 ISS:UniProtKB P adult locomotory behavior
GO:0008088 ISS:UniProtKB P axon cargo transport
GO:0016199 ISS:UniProtKB P axon midline choice point recognition
GO:0007409 ISS:UniProtKB P axonogenesis
GO:0007155 IEA:UniProtKB-KW P cell adhesion
GO:0006878 ISS:UniProtKB P cellular copper ion homeostasis
GO:0008203 IEA:Ensembl P cholesterol metabolic process
GO:0048669 ISS:UniProtKB P collateral sprouting in absence of injury
GO:0016358 ISS:UniProtKB P dendrite development
GO:0006897 ISS:UniProtKB P endocytosis
GO:0030198 ISS:UniProtKB P extracellular matrix organization
GO:0030900 IEA:Ensembl P forebrain development
GO:0035235 ISS:UniProtKB P ionotropic glutamate receptor signaling pathway
GO:0007626 ISS:UniProtKB P locomotory behavior
GO:0006378 ISS:UniProtKB P mRNA polyadenylation
GO:0007617 ISS:UniProtKB P mating behavior
GO:0045665 IEA:Ensembl P negative regulation of neuron differentiation
GO:0050885 IEA:Ensembl P neuromuscular process controlling balance
GO:0051402 IEA:Ensembl P neuron apoptotic process
GO:0031175 ISS:UniProtKB P neuron projection development
GO:0016322 ISS:UniProtKB P neuron remodeling
GO:0010971 IEA:Ensembl P positive regulation of G2/M transition of mitotic cell cycle
GO:0045931 ISS:UniProtKB P positive regulation of mitotic cell cycle
GO:0010952 IDA:GOC P positive regulation of peptidase activity
GO:0045944 IEA:Ensembl P positive regulation of transcription from RNA polymerase II promoter
GO:0006468 ISS:UniProtKB P protein phosphorylation
GO:0007176 ISS:UniProtKB P regulation of epidermal growth factor-activated receptor activity
GO:0040014 ISS:UniProtKB P regulation of multicellular organism growth
GO:0043393 IEA:Ensembl P regulation of protein binding
GO:0050803 ISS:UniProtKB P regulation of synapse structure and activity
GO:0006417 ISS:UniProtKB P regulation of translation
GO:0006979 IEA:Ensembl P response to oxidative stress
GO:0051563 IEA:Ensembl P smooth endoplasmic reticulum calcium ion homeostasis
GO:0001967 IEA:Ensembl P suckling behavior
GO:0051124 IEA:Ensembl P synaptic growth at neuromuscular junction
GO:0008542 ISS:UniProtKB P visual learning

KEGG Pathway Links

KEGG Pathway ID Description
ko05010 Alzheimer's disease
rno05010 Alzheimer's disease
rno04726 Serotonergic synapse

REACTOME Pathway Links

REACTOME Pathway ID Description
5953551 Activated TLR4 signalling
5954355 Advanced glycosylation endproduct receptor signaling
5954397 Amyloids
5954122 Class A/1 (Rhodopsin-like receptors)
5953792 Cytosolic sensors of pathogen-associated DNA
5953794 DEx/H-box helicases activate type I IFN and inflammatory cytokines production
5953253 Disease
5954200 Formyl peptide receptors bind formyl peptides and many other ligands
5954152 G alpha (i) signalling events
5953653 G alpha (q) signalling events
5953642 GPCR downstream signaling
5953758 GPCR ligand binding
5953537 Gastrin-CREB signalling pathway via PKC and MAPK
5953645 Hemostasis
5953410 Immune System
5953409 Innate Immune System
5953565 MyD88 cascade initiated on plasma membrane
5953562 MyD88 dependent cascade initiated on endosome
5953559 MyD88-independent cascade
5953550 MyD88:Mal cascade initiated on plasma membrane
5954121 Peptide ligand-binding receptors
5953644 Platelet activation, signaling and aggregation
5954102 Platelet degranulation
5953789 RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways
5953790 RIP-mediated NFkB activation via ZBP1
5953646 Response to elevated platelet cytosolic Ca2+
5953381 Signal Transduction
5953391 Signaling by GPCR
5953787 TAK1 activates NFkB by phosphorylation and activation of IKKs complex
5953788 TRAF6 mediated NF-kB activation
5953561 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
5953558 TRIF-mediated TLR3/TLR4 signaling
5953566 Toll Like Receptor 10 (TLR10) Cascade
5953555 Toll Like Receptor 2 (TLR2) Cascade
5953560 Toll Like Receptor 3 (TLR3) Cascade
5953552 Toll Like Receptor 4 (TLR4) Cascade
5953567 Toll Like Receptor 5 (TLR5) Cascade
5953564 Toll Like Receptor 7/8 (TLR7/8) Cascade
5953563 Toll Like Receptor 9 (TLR9) Cascade
5953554 Toll Like Receptor TLR1:TLR2 Cascade
5953556 Toll Like Receptor TLR6:TLR2 Cascade
5953553 Toll-Like Receptors Cascades
5953791 ZBP1(DAI) mediated induction of type I IFNs

Domain Information

InterPro Annotations

Accession Description
IPR028866 APP
IPR019543 APP_amyloid_C
IPR008155 Amyloid_glyco
IPR013803 Amyloid_glyco_Abeta
IPR011178 Amyloid_glyco_Cu-bd
IPR024329 Amyloid_glyco_E2_domain
IPR008154 Amyloid_glyco_extra
IPR019744 Amyloid_glyco_extracell_CS
IPR015849 Amyloid_glyco_heparin-bd
IPR019745 Amyloid_glyco_intracell_CS
IPR002223 Prot_inh_Kunz-m
IPR020901 Prtase_inh_Kunz-CS

UniProt Annotations

Entry Information

Gene Name
amyloid beta (A4) precursor protein
Protein Entry
A4_RAT
UniProt ID
P08592
Species
Rat

Comments

Comment Type Description
Alternative Products Event=Alternative splicing; Named isoforms=8; Name=APP770; IsoId=P08592-1; Sequence=Displayed; Name=APP695; IsoId=P08592-2; Sequence=VSP_000015, VSP_000016; Name=L-APP677; IsoId=P08592-3; Sequence=Not described; Note=L-isoforms are referred to as appicans.; Name=L-APP696; IsoId=P08592-4; Sequence=Not described; Note=L-isoforms are referred to as appicans.; Name=APP714; IsoId=P08592-5; Sequence=Not described; Name=L-APP733; IsoId=P08592-6; Sequence=Not described; Note=L-isoforms are referred to as appicans.; Name=APP751; IsoId=P08592-7; Sequence=Not described; Name=L-APP752; IsoId=P08592-8; Sequence=Not described; Note=L-isoforms are referred to as appicans.;
Developmental Stage From 6 days to 7 months, levels of KPI- containing isoforms increase in the brain cortex and hippocampus. Levels of L-APP increase in all brain regions during the same period, but levels are low compared to non-L-APP isoforms.
Domain The NPXY sequence motif found in many tyrosine- phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C- terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue. The NPXY site is also involved in clathrin-mediated endocytosis.
Domain The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.
Function Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.
Function Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicits inflammatory responses. Promotes both tau aggregation and TPK II- mediated phosphorylation. Also bind GPC1 in lipid rafts (By similarity)
Function Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis- inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid- beta peptide and leading to mitochondrial dysfunction in cultured mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity)
Function N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6)
Function The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis
Induction Phosphorylation of mature, glycosylated APP occurs 48- 72 hours after treatment of neuronal cells with nerve growth factor which correlates with the timing of neurite outgrowth
Mass Spectrometry Mass=5911.3; Method=MALDI; Range=721-770; Evidence= ;
Mass Spectrometry Mass=6024.4; Method=MALDI; Range=720-770; Evidence= ;
Miscellaneous Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. Rat and mouse beta- amyloid peptides have an arginine residue substituted for the bridging histidine residue and are thus less capable of forming amyloid aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding (By similarity)
Ptm Beta-amyloid peptides are degraded by IDE
Ptm Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond
Ptm N-glycosylated.
Ptm O-glycosylated. O-linkage of chondroitin sulfate to the L-APP isoforms produces the APP proteoglycan core proteins, the appicans. The chondroitin sulfate chain of appicans contains 4-O- sulfated galactose in the linkage region and chondroitin sulfate E in the repeated disaccharide region.
Ptm Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific. Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins. The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members. Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This phosphorylation is inhibited by heparin. {ECO:0000269|PubMed:10329382, ECO:0000269|PubMed:10341243, ECO:0000269|PubMed:10936190, ECO:0000269|PubMed:9085254}.
Ptm Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides
Ptm Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta- secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid beta proteins, amyloid-beta 40 (Abeta40) and amyloid-beta 42 (Abeta42), major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59) (By similarity)
Ptm Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP)
Similarity Belongs to the APP family
Similarity Contains 1 BPTI/Kunitz inhibitor domain
Subcellular Location Membrane ; Single-pass type I membrane protein . Membrane, clathrin-coated pit . Note=Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N- glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysosomes. Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. Gamma-CTF(59) peptide is located to both the cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65). Associates with GPC1 in perinuclear compartments (By similarity). Beta-APP42 associates with FPRL1 at the cell surface and the complex is then rapidly internalized (By similarity). APP sorts to the basolateral surface in epithelial cells (By similarity). During neuronal differentiation, the Thr-742 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body
Subunit Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine phosphorylation (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, FPRL1, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) (By similarity) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Interacts, through a C-terminal domain, with GNAO1. Amyloid beta-42 binds CHRNA7 in hippocampal neurons (By similarity). Beta-amyloid associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B, TNFRSF21 and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; this is promoted by heparin binding (By similarity). Beta-amyloid protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). Interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity)
Tissue Specificity In the brain, non-L-APP isoforms are expressed in neurons, isoform APP695 being the predominant form. In astrocytes and microglial cells, almost 50% is L-isoform (appican). {ECO:0000269|PubMed:7744833, ECO:0000269|PubMed:8996834}.

Identical and Related Proteins

Unique RefSeq proteins for LMP012646 (as displayed in Record Overview)

Protein GI Database Accession Length Protein Name
27436861 RefSeq NP_062161 770 amyloid beta A4 protein precursor

Identical Sequences to LMP012646 proteins

Reference Database Accession Length Protein Name
GI:27436861 EMBL CAL69794.1 770 unnamed protein product [Rattus norvegicus]
GI:27436861 EMBL CAL69798.1 770 unnamed protein product [Rattus norvegicus]
GI:27436861 GenBank AAM90259.1 770 APP770 [Rattus norvegicus]
GI:27436861 GenBank EDM10626.1 770 amyloid beta (A4) precursor protein, isoform CRA_a [Rattus norvegicus]

Related Sequences to LMP012646 proteins

Reference Database Accession Length Protein Name
GI:27436861 EMBL CAL69794.1 770 unnamed protein product [Rattus norvegicus]
GI:27436861 GenBank AAM90259.1 770 APP770 [Rattus norvegicus]
GI:27436861 GenBank EDM10626.1 770 amyloid beta (A4) precursor protein, isoform CRA_a [Rattus norvegicus]