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P08592

- A4_RAT

UniProt

P08592 - A4_RAT

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Protein

Amyloid beta A4 protein

Gene

App

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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 Cu2+ ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 (By similarity).By similarity
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).By similarity
Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.
The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.By similarity
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei144 – 1441Required for Cu(2+) reductionBy similarity
Metal bindingi147 – 1471Copper 1By similarity
Metal bindingi151 – 1511Copper 1By similarity
Metal bindingi168 – 1681Copper 1By similarity
Sitei301 – 3022Reactive bondBy similarity
Sitei671 – 6722Cleavage; by beta-secretaseBy similarity
Sitei672 – 6732Cleavage; by caspase-6
Metal bindingi677 – 6771Copper or zinc 2By similarity
Metal bindingi685 – 6851Copper or zinc 2By similarity
Sitei687 – 6882Cleavage; by alpha-secretaseBy similarity
Sitei690 – 6912Cleavage; by theta-secretaseBy similarity
Sitei711 – 7122Cleavage; by gamma-secretase; site 1By similarity
Sitei713 – 7142Cleavage; by gamma-secretase; site 2By similarity
Sitei720 – 7212Cleavage; by gamma-secretase; site 3By similarity
Sitei739 – 7402Cleavage; by caspase-6, caspase-8 or caspase-9By similarity

GO - Molecular functioni

  1. DNA binding Source: UniProtKB
  2. growth factor receptor binding Source: RGD
  3. heparin binding Source: UniProtKB-KW
  4. peptidase activator activity Source: RGD
  5. serine-type endopeptidase inhibitor activity Source: UniProtKB-KW
  6. transition metal ion binding Source: InterPro

GO - Biological processi

  1. adult locomotory behavior Source: UniProtKB
  2. axon cargo transport Source: UniProtKB
  3. axon midline choice point recognition Source: UniProtKB
  4. axonogenesis Source: UniProtKB
  5. cell adhesion Source: UniProtKB-KW
  6. cellular copper ion homeostasis Source: UniProtKB
  7. cholesterol metabolic process Source: Ensembl
  8. collateral sprouting in absence of injury Source: UniProtKB
  9. dendrite development Source: UniProtKB
  10. endocytosis Source: UniProtKB
  11. extracellular matrix organization Source: UniProtKB
  12. forebrain development Source: Ensembl
  13. ionotropic glutamate receptor signaling pathway Source: UniProtKB
  14. locomotory behavior Source: UniProtKB
  15. mating behavior Source: UniProtKB
  16. mRNA polyadenylation Source: UniProtKB
  17. negative regulation of neuron differentiation Source: Ensembl
  18. neuromuscular process controlling balance Source: Ensembl
  19. neuron apoptotic process Source: Ensembl
  20. neuron projection development Source: UniProtKB
  21. neuron remodeling Source: UniProtKB
  22. Notch signaling pathway Source: UniProtKB-KW
  23. positive regulation of G2/M transition of mitotic cell cycle Source: Ensembl
  24. positive regulation of mitotic cell cycle Source: UniProtKB
  25. positive regulation of peptidase activity Source: GOC
  26. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
  27. protein phosphorylation Source: UniProtKB
  28. regulation of epidermal growth factor-activated receptor activity Source: UniProtKB
  29. regulation of multicellular organism growth Source: UniProtKB
  30. regulation of protein binding Source: Ensembl
  31. regulation of synapse structure and activity Source: UniProtKB
  32. regulation of translation Source: UniProtKB
  33. response to oxidative stress Source: Ensembl
  34. smooth endoplasmic reticulum calcium ion homeostasis Source: Ensembl
  35. suckling behavior Source: Ensembl
  36. synaptic growth at neuromuscular junction Source: Ensembl
  37. visual learning Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Protease inhibitor, Serine protease inhibitor

Keywords - Biological processi

Apoptosis, Cell adhesion, Endocytosis, Notch signaling pathway

Keywords - Ligandi

Copper, Heparin-binding, Iron, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiREACT_194364. RIP-mediated NFkB activation via ZBP1.
REACT_196231. Advanced glycosylation endproduct receptor signaling.
REACT_198757. ECM proteoglycans.
REACT_199225. Amyloids.

Protein family/group databases

MEROPSiI02.015.
TCDBi1.C.50.1.1. the amyloid -protein peptide (app) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Amyloid beta A4 protein
Alternative name(s):
ABPP
Short name:
APP
Alzheimer disease amyloid A4 protein homolog
Amyloidogenic glycoprotein
Short name:
AG
Cleaved into the following 14 chains:
Soluble APP-alpha
Short name:
S-APP-alpha
Soluble APP-beta
Short name:
S-APP-beta
Alternative name(s):
Beta-APP42
Alternative name(s):
Beta-APP40
Alternative name(s):
Gamma-CTF(59)
Alternative name(s):
Gamma-CTF(57)
Alternative name(s):
Gamma-CTF(50)
Gene namesi
Name:App
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494: Chromosome 11

Organism-specific databases

RGDi2139. App.

Subcellular locationi

Membrane 1 Publication; Single-pass type I membrane protein 1 Publication. Membraneclathrin-coated pit 1 Publication
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.By similarity

GO - Cellular componenti

  1. apical part of cell Source: Ensembl
  2. axon Source: UniProtKB
  3. cell-cell junction Source: Ensembl
  4. cell surface Source: AgBase
  5. ciliary rootlet Source: Ensembl
  6. coated pit Source: UniProtKB-KW
  7. cytoplasm Source: UniProtKB
  8. dendritic shaft Source: Ensembl
  9. dendritic spine Source: Ensembl
  10. ER to Golgi transport vesicle Source: Ensembl
  11. extracellular space Source: Ensembl
  12. extracellular vesicular exosome Source: Ensembl
  13. Golgi apparatus Source: UniProtKB
  14. integral component of membrane Source: UniProtKB
  15. membrane raft Source: Ensembl
  16. neuromuscular junction Source: Ensembl
  17. neuron projection Source: RGD
  18. nuclear envelope lumen Source: Ensembl
  19. perinuclear region of cytoplasm Source: Ensembl
  20. plasma membrane Source: Ensembl
  21. receptor complex Source: Ensembl
  22. spindle midzone Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Amyloid, Coated pit, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi656 – 6561S → A: No chondroitin sulfate linkage to isoform L-APP733. 1 Publication
Mutagenesisi704 – 7041G → V: Little oxidized neuronal proteins. Scarce beta-APP42 peptide aggregation. No neurotoxicity. 1 Publication
Mutagenesisi732 – 7332HH → GL or GP: Almost complete loss of binding to GNAO1. No inhibition of GTPase activity. 1 Publication
Mutagenesisi743 – 7431T → A: No effect on neurite growth and maturation. 1 Publication
Mutagenesisi743 – 7431T → E: Inhibits neurite growth and maturation. 1 Publication
Mutagenesisi757 – 7571Y → G: No DBB1 binding. 1 Publication
Mutagenesisi759 – 7591N → A: Some DBB1 binding. 1 Publication
Mutagenesisi762 – 7621Y → A: Some DBB1 binding. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1717By similarityAdd
BLAST
Chaini18 – 770753Amyloid beta A4 proteinPRO_0000000159Add
BLAST
Chaini18 – 687670Soluble APP-alphaBy similarityPRO_0000000160Add
BLAST
Chaini18 – 671654Soluble APP-betaSequence AnalysisPRO_0000000161Add
BLAST
Chaini18 – 286269N-APPBy similarityPRO_0000381971Add
BLAST
Chaini672 – 77099C99Sequence AnalysisPRO_0000000162Add
BLAST
Chaini672 – 71342Beta-amyloid protein 42By similarityPRO_0000000163Add
BLAST
Chaini672 – 71140Beta-amyloid protein 40By similarityPRO_0000000164Add
BLAST
Chaini688 – 77083C83By similarityPRO_0000000165Add
BLAST
Peptidei688 – 71326P3(42)By similarityPRO_0000000166Add
BLAST
Peptidei688 – 71124P3(40)By similarityPRO_0000000167Add
BLAST
Chaini691 – 77080C80PRO_0000384579Add
BLAST
Chaini712 – 77059Gamma-secretase C-terminal fragment 59PRO_0000000168Add
BLAST
Chaini714 – 77057Gamma-secretase C-terminal fragment 57PRO_0000000169Add
BLAST
Chaini721 – 77050Gamma-secretase C-terminal fragment 50PRO_0000000170Add
BLAST
Chaini740 – 77031C31By similarityPRO_0000000171Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi38 ↔ 62PROSITE-ProRule annotation
Disulfide bondi73 ↔ 117PROSITE-ProRule annotation
Disulfide bondi98 ↔ 105PROSITE-ProRule annotation
Disulfide bondi133 ↔ 187PROSITE-ProRule annotation
Disulfide bondi144 ↔ 174PROSITE-ProRule annotation
Disulfide bondi158 ↔ 186PROSITE-ProRule annotation
Modified residuei198 – 1981Phosphoserine; by CK2By similarity
Modified residuei206 – 2061Phosphoserine; by CK1By similarity
Disulfide bondi291 ↔ 341PROSITE-ProRule annotation
Disulfide bondi300 ↔ 324PROSITE-ProRule annotation
Disulfide bondi316 ↔ 337PROSITE-ProRule annotation
Glycosylationi542 – 5421N-linked (GlcNAc...)Sequence Analysis
Glycosylationi571 – 5711N-linked (GlcNAc...)Sequence Analysis
Glycosylationi656 – 6561O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms
Modified residuei729 – 7291Phosphothreonine
Modified residuei730 – 7301Phosphoserine; by APP-kinase I1 Publication
Modified residuei743 – 7431Phosphothreonine; by CDK5 and MAPK101 Publication
Modified residuei757 – 7571Phosphotyrosine; by ABL1By similarity

Post-translational modificationi

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).By similarity
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.By similarity
N-glycosylated.
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.
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.4 Publications
Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond.By similarity
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).By similarity
Beta-amyloid peptides are degraded by IDE.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Proteoglycan

Proteomic databases

PaxDbiP08592.
PRIDEiP08592.

PTM databases

PhosphoSiteiP08592.

Expressioni

Tissue specificityi

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).2 Publications

Developmental stagei

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.

Inductioni

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.1 Publication

Gene expression databases

GenevestigatoriP08592.

Interactioni

Subunit structurei

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).By similarity

Protein-protein interaction databases

BioGridi248450. 2 interactions.
DIPiDIP-6114N.
DIP-618N.
DIP-685N.
IntActiP08592. 7 interactions.
MINTiMINT-1521802.

Structurei

Secondary structure

1
770
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Turni679 – 6868
Helixi687 – 6959

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1M7EX-ray2.45D/E/F755-763[»]
1NMJNMR-A672-699[»]
1OQNX-ray2.30C/D755-763[»]
ProteinModelPortaliP08592.
SMRiP08592. Positions 28-189, 287-342, 374-565, 672-699, 739-770.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP08592.

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini18 – 699682ExtracellularSequence AnalysisAdd
BLAST
Topological domaini724 – 77047CytoplasmicBy similarityAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei700 – 72324HelicalSequence AnalysisAdd
BLAST

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini291 – 34151BPTI/Kunitz inhibitorPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni96 – 11015Heparin-bindingBy similarityAdd
BLAST
Regioni135 – 15521Copper-bindingBy similarityAdd
BLAST
Regioni181 – 1888Zinc-bindingBy similarity
Regioni391 – 42333Heparin-bindingBy similarityAdd
BLAST
Regioni491 – 52232Heparin-bindingBy similarityAdd
BLAST
Regioni523 – 54018Collagen-bindingBy similarityAdd
BLAST
Regioni732 – 75120Interaction with G(o)-alphaAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi724 – 73411Basolateral sorting signalBy similarityAdd
BLAST
Motifi759 – 7624NPXY motif; contains endocytosis signal

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi230 – 26031Asp/Glu-rich (acidic)Add
BLAST
Compositional biasi274 – 2807Poly-Thr

Domaini

The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.
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.

Sequence similaritiesi

Belongs to the APP family.Curated
Contains 1 BPTI/Kunitz inhibitor domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG289770.
GeneTreeiENSGT00530000063252.
HOGENOMiHOG000232190.
HOVERGENiHBG000051.
InParanoidiP08592.
KOiK04520.
OMAiTHAHIVI.
OrthoDBiEOG7RNJZP.
PhylomeDBiP08592.
TreeFamiTF317274.

Family and domain databases

Gene3Di3.30.1490.140. 1 hit.
3.90.570.10. 1 hit.
4.10.230.10. 1 hit.
4.10.410.10. 1 hit.
InterProiIPR008155. 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.
IPR028866. APP.
IPR019543. APP_amyloid_C.
IPR002223. Prot_inh_Kunz-m.
IPR020901. Prtase_inh_Kunz-CS.
[Graphical view]
PANTHERiPTHR23103:SF7. PTHR23103:SF7. 1 hit.
PfamiPF10515. APP_amyloid. 1 hit.
PF12924. APP_Cu_bd. 1 hit.
PF12925. APP_E2. 1 hit.
PF02177. APP_N. 1 hit.
PF03494. Beta-APP. 1 hit.
PF00014. Kunitz_BPTI. 1 hit.
[Graphical view]
PRINTSiPR00203. AMYLOIDA4.
PR00759. BASICPTASE.
PR00204. BETAAMYLOID.
SMARTiSM00006. A4_EXTRA. 1 hit.
SM00131. KU. 1 hit.
[Graphical view]
SUPFAMiSSF109843. SSF109843. 1 hit.
SSF56491. SSF56491. 1 hit.
SSF57362. SSF57362. 1 hit.
SSF89811. SSF89811. 1 hit.
PROSITEiPS00319. A4_EXTRA. 1 hit.
PS00320. A4_INTRA. 1 hit.
PS00280. BPTI_KUNITZ_1. 1 hit.
PS50279. BPTI_KUNITZ_2. 1 hit.
[Graphical view]

Sequences (8)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 8 isoformsi produced by alternative splicing. Align

Isoform APP770 (identifier: P08592-1) [UniParc]FASTAAdd to Basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MLPSLALLLL AAWTVRALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG
60 70 80 90 100
KWESDPSGTK TCIGTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR
110 120 130 140 150
GRKQCKTHTH IVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW
160 170 180 190 200
HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDSIDSAD
210 220 230 240 250
AEEDDSDVWW GGADTDYADG GEDKVVEVAE EEEVADVEEE EAEDDEDVED
260 270 280 290 300
GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
310 320 330 340 350
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVSSQSLL
360 370 380 390 400
KTTSEPLPQD PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA
410 420 430 440 450
KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER
460 470 480 490 500
QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPHHV FNMLKKYVRA
510 520 530 540 550
EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN
560 570 580 590 600
VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
610 620 630 640 650
KTTVELLPVN GEFSLDDLQP WHPFGVDSVP ANTENEVEPV DARPAADRGL
660 670 680 690 700
TTRPGSGLTN IKTEEISEVK MDAEFGHDSG FEVRHQKLVF FAEDVGSNKG
710 720 730 740 750
AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS
760 770
KMQQNGYENP TYKFFEQMQN
Length:770
Mass (Da):86,704
Last modified:December 1, 1992 - v2
Checksum:iC26C9D6BB2D929A7
GO
Isoform APP695 (identifier: P08592-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-364: Missing.

Show »
Length:695
Mass (Da):78,483
Checksum:i61D21E1E941972DC
GO
Isoform L-APP677 (identifier: P08592-3)

Sequence is not available

Note: L-isoforms are referred to as appicans.

Length:
Mass (Da):
Isoform L-APP696 (identifier: P08592-4)

Sequence is not available

Note: L-isoforms are referred to as appicans.

Length:
Mass (Da):
Isoform APP714 (identifier: P08592-5)

Sequence is not available
Length:
Mass (Da):
Isoform L-APP733 (identifier: P08592-6)

Sequence is not available

Note: L-isoforms are referred to as appicans.

Length:
Mass (Da):
Isoform APP751 (identifier: P08592-7)

Sequence is not available
Length:
Mass (Da):
Isoform L-APP752 (identifier: P08592-8)

Sequence is not available

Note: L-isoforms are referred to as appicans.

Length:
Mass (Da):

Mass spectrometryi

Molecular mass is 5911.3 Da from positions 721 - 770. Determined by MALDI. 1 Publication
Molecular mass is 6024.4 Da from positions 720 - 770. Determined by MALDI. 1 Publication

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei289 – 2891E → V in isoform APP695. 1 PublicationVSP_000015
Alternative sequencei290 – 36475Missing in isoform APP695. 1 PublicationVSP_000016Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X07648 mRNA. Translation: CAA30488.1.
AF513015 mRNA. Translation: AAM90259.1.
X14066 mRNA. Translation: CAA32229.1.
PIRiS00550.
S03607.
S23094.
RefSeqiNP_062161.1. NM_019288.2. [P08592-1]
XP_006248073.1. XM_006248011.2. [P08592-2]
UniGeneiRn.2104.

Genome annotation databases

EnsembliENSRNOT00000044081; ENSRNOP00000040243; ENSRNOG00000006997. [P08592-2]
ENSRNOT00000048854; ENSRNOP00000041613; ENSRNOG00000006997. [P08592-1]
GeneIDi54226.
KEGGirno:54226.
UCSCiRGD:2139. rat. [P08592-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X07648 mRNA. Translation: CAA30488.1 .
AF513015 mRNA. Translation: AAM90259.1 .
X14066 mRNA. Translation: CAA32229.1 .
PIRi S00550.
S03607.
S23094.
RefSeqi NP_062161.1. NM_019288.2. [P08592-1 ]
XP_006248073.1. XM_006248011.2. [P08592-2 ]
UniGenei Rn.2104.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1M7E X-ray 2.45 D/E/F 755-763 [» ]
1NMJ NMR - A 672-699 [» ]
1OQN X-ray 2.30 C/D 755-763 [» ]
ProteinModelPortali P08592.
SMRi P08592. Positions 28-189, 287-342, 374-565, 672-699, 739-770.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 248450. 2 interactions.
DIPi DIP-6114N.
DIP-618N.
DIP-685N.
IntActi P08592. 7 interactions.
MINTi MINT-1521802.

Protein family/group databases

MEROPSi I02.015.
TCDBi 1.C.50.1.1. the amyloid -protein peptide (app) family.

PTM databases

PhosphoSitei P08592.

Proteomic databases

PaxDbi P08592.
PRIDEi P08592.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSRNOT00000044081 ; ENSRNOP00000040243 ; ENSRNOG00000006997 . [P08592-2 ]
ENSRNOT00000048854 ; ENSRNOP00000041613 ; ENSRNOG00000006997 . [P08592-1 ]
GeneIDi 54226.
KEGGi rno:54226.
UCSCi RGD:2139. rat. [P08592-1 ]

Organism-specific databases

CTDi 351.
RGDi 2139. App.

Phylogenomic databases

eggNOGi NOG289770.
GeneTreei ENSGT00530000063252.
HOGENOMi HOG000232190.
HOVERGENi HBG000051.
InParanoidi P08592.
KOi K04520.
OMAi THAHIVI.
OrthoDBi EOG7RNJZP.
PhylomeDBi P08592.
TreeFami TF317274.

Enzyme and pathway databases

Reactomei REACT_194364. RIP-mediated NFkB activation via ZBP1.
REACT_196231. Advanced glycosylation endproduct receptor signaling.
REACT_198757. ECM proteoglycans.
REACT_199225. Amyloids.

Miscellaneous databases

EvolutionaryTracei P08592.
NextBioi 610648.
PROi P08592.

Gene expression databases

Genevestigatori P08592.

Family and domain databases

Gene3Di 3.30.1490.140. 1 hit.
3.90.570.10. 1 hit.
4.10.230.10. 1 hit.
4.10.410.10. 1 hit.
InterProi 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.
IPR028866. APP.
IPR019543. APP_amyloid_C.
IPR002223. Prot_inh_Kunz-m.
IPR020901. Prtase_inh_Kunz-CS.
[Graphical view ]
PANTHERi PTHR23103:SF7. PTHR23103:SF7. 1 hit.
Pfami PF10515. APP_amyloid. 1 hit.
PF12924. APP_Cu_bd. 1 hit.
PF12925. APP_E2. 1 hit.
PF02177. APP_N. 1 hit.
PF03494. Beta-APP. 1 hit.
PF00014. Kunitz_BPTI. 1 hit.
[Graphical view ]
PRINTSi PR00203. AMYLOIDA4.
PR00759. BASICPTASE.
PR00204. BETAAMYLOID.
SMARTi SM00006. A4_EXTRA. 1 hit.
SM00131. KU. 1 hit.
[Graphical view ]
SUPFAMi SSF109843. SSF109843. 1 hit.
SSF56491. SSF56491. 1 hit.
SSF57362. SSF57362. 1 hit.
SSF89811. SSF89811. 1 hit.
PROSITEi PS00319. A4_EXTRA. 1 hit.
PS00320. A4_INTRA. 1 hit.
PS00280. BPTI_KUNITZ_1. 1 hit.
PS50279. BPTI_KUNITZ_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact."
    Shivers B.D., Hilbich C., Multhaup G., Salbaum J.M., Beyreuther K., Seeburg P.H.
    EMBO J. 7:1365-1370(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
    Tissue: Brain.
  2. "A new beta amyloid precursor protein cDNA found in Rat6 embryo fibroblasts."
    Feng J., Song S., Zheng J.
    Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP770).
  3. "Amyloid beta protein precursor is possibly a heparan sulfate proteoglycan core protein."
    Schubert D., Schroeder R., LaCorbiere M., Saitoh T., Cole G.
    Science 241:223-226(1988) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 18-44.
  4. "Purification and tissue level of the beta-amyloid peptide precursor of rat brain."
    Potempska A., Styles J., Mehta P., Kim K.S., Miller D.L.
    J. Biol. Chem. 266:8464-8469(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 18-32.
  5. "The sequence of the two extra exons in rat preA4."
    Kang J., Mueller-Hill B.
    Nucleic Acids Res. 17:2130-2130(1989) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 289-364.
    Tissue: Liver.
  6. "Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch."
    Gu Y., Misonou H., Sato T., Dohmae N., Takio K., Ihara Y.
    J. Biol. Chem. 276:35235-35238(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF 720-730, MASS SPECTROMETRY.
  7. "APP gene family. Alternative splicing generates functionally related isoforms."
    Sandbrink R., Masters C.L., Beyreuther K.
    Ann. N. Y. Acad. Sci. 777:281-287(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: ALTERNATIVE SPLICING.
  8. "The Alzheimer amyloid precursor proteoglycan (appican) is present in brain and is produced by astrocytes but not by neurons in primary neural cultures."
    Shioi J., Pangalos M.N., Ripellino J.A., Vassilacopoulou D., Mytilineou C., Margolis R.U., Robakis N.K.
    J. Biol. Chem. 270:11839-11844(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY OF APPICAN.
  9. "Expression of the APP gene family in brain cells, brain development and aging."
    Sandbrink R., Monning U., Masters C.L., Beyreuther K.
    Gerontology 43:119-131(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY OF ISOFORMS.
  10. "A 127-kDa protein (UV-DDB) binds to the cytoplasmic domain of the Alzheimer's amyloid precursor protein."
    Watanabe T., Sukegawa J., Tomita S., Iijima K., Oguchi S., Suzuki T., Nairn A.C., Greengard P.
    J. Neurochem. 72:549-556(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH DDB1, MUTAGENESIS OF TYR-757; ASN-759 AND TYR-762.
  11. "The amyloid precursor protein interacts with Go heterotrimeric protein within a cell compartment specialized in signal transduction."
    Brouillet E., Trembleau A., Galanaud D., Volovitch M., Bouillot C., Valenza C., Prochiantz A., Allinquant B.
    J. Neurosci. 19:1717-1727(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH GNAO1, MUTAGENESIS OF 732-HIS-HIS-733.
  12. "The beta A4 amyloid precursor protein binding to copper."
    Hesse L., Beher D., Masters C.L., Multhaup G.
    FEBS Lett. 349:109-116(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: COPPER-BINDING.
  13. "The chondroitin sulfate attachment site of appican is formed by splicing out exon 15 of the amyloid precursor gene."
    Pangalos M.N., Efthimiopoulos S., Shioi J., Robakis N.K.
    J. Biol. Chem. 270:10388-10391(1995) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERISTICS OF APPICAN, MUTAGENESIS OF SER-656.
  14. "The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction."
    Huang X., Atwood C.S., Hartshorn M.A., Multhaup G., Goldstein L.E., Scarpa R.C., Cuajungco M.P., Gray D.N., Lim J., Moir R.D., Tanzi R.E., Bush A.I.
    Biochemistry 38:7609-7616(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: BETA-AMYLOID METAL-BINDING.
  15. "Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease."
    Liu S.T., Howlett G., Barrow C.J.
    Biochemistry 38:9373-9378(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: BETA-AMYLOID ZINC-BINDING.
  16. "Role of glycine-33 and methionine-35 in Alzheimer's amyloid beta-peptide 1-42-associated oxidative stress and neurotoxicity."
    Kanski J., Varadarajan S., Aksenova M., Butterfield D.A.
    Biochim. Biophys. Acta 1586:190-198(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: IMPORTANCE OF GLY-704 IN FREE RADICAL PROPAGATION, MUTAGENESIS OF GLY-704.
  17. "The cytoplasmic domain of Alzheimer's amyloid precursor protein is phosphorylated at Thr654, Ser655, and Thr668 in adult rat brain and cultured cells."
    Oishi M., Nairn A.C., Czernik A.J., Lim G.S., Isohara T., Gandy S.E., Greengard P., Suzuki T.
    Mol. Med. 3:111-123(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION.
  18. "Phosphorylation of the cytoplasmic domain of Alzheimer's beta-amyloid precursor protein at Ser655 by a novel protein kinase."
    Isohara T., Horiuchi A., Watanabe T., Ando K., Czernik A.J., Uno I., Greengard P., Nairn A.C., Suzuki T.
    Biochem. Biophys. Res. Commun. 258:300-305(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT SER-730.
  19. "Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation."
    Ando K., Oishi M., Takeda S., Iijima K., Isohara T., Nairn A.C., Kirino Y., Greengard P., Suzuki T.
    J. Neurosci. 19:4421-4427(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION, INDUCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF THR-743.
  20. "Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5."
    Iijima K., Ando K., Takeda S., Satoh Y., Seki T., Itohara S., Greengard P., Kirino Y., Nairn A.C., Suzuki T.
    J. Neurochem. 75:1085-1091(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT THR-743.
  21. "Appican, the proteoglycan form of the amyloid precursor protein, contains chondroitin sulfate E in the repeating disaccharide region and 4-O-sulfated galactose in the linkage region."
    Tsuchida K., Shioi J., Yamada S., Boghosian G., Wu A., Cai H., Sugahara K., Robakis N.K.
    J. Biol. Chem. 276:37155-37160(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE OF CARBOHYDRATE IN APPICAN.

Entry informationi

Entry nameiA4_RAT
AccessioniPrimary (citable) accession number: P08592
Secondary accession number(s): Q547B7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: December 1, 1992
Last modified: October 29, 2014
This is version 177 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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).By similarity

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3