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Protein

Amyloid beta A4 protein

Gene

App

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: 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 binds 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)DescriptionActionsGraphical viewLength
Sitei144Required for Cu(2+) reductionBy similarity1
Metal bindingi147Copper 1By similarity1
Metal bindingi151Copper 1By similarity1
Metal bindingi168Copper 1By similarity1
Sitei301 – 302Reactive bondBy similarity2
Metal bindingi677Copper or zinc 2By similarity1
Metal bindingi685Copper or zinc 2By similarity1

GO - Molecular functioni

  • DNA binding Source: UniProtKB
  • growth factor receptor binding Source: RGD
  • heparin binding Source: UniProtKB-KW
  • peptidase activator activity Source: RGD
  • serine-type endopeptidase inhibitor activity Source: UniProtKB-KW
  • transition metal ion binding Source: InterPro

GO - Biological processi

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

ReactomeiR-RNO-114608. Platelet degranulation.
R-RNO-1810476. RIP-mediated NFkB activation via ZBP1.
R-RNO-3000178. ECM proteoglycans.
R-RNO-3134963. DEx/H-box helicases activate type I IFN and inflammatory cytokines production.
R-RNO-416476. G alpha (q) signalling events.
R-RNO-418594. G alpha (i) signalling events.
R-RNO-432720. Lysosome Vesicle Biogenesis.
R-RNO-444473. Formyl peptide receptors bind formyl peptides and many other ligands.
R-RNO-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-RNO-879415. Advanced glycosylation endproduct receptor signaling.
R-RNO-933542. TRAF6 mediated NF-kB activation.

Protein family/group databases

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

Names & Taxonomyi

Protein namesi
Recommended name:
Amyloid beta A4 protein
Alternative name(s):
ABPP
Short name:
APP
Alzheimer disease amyloid A4 protein homolog
Amyloid precursor proteinCurated
Amyloidogenic glycoprotein
Short name:
AG
Beta-amyloid precursor proteinCurated
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
Proteomesi
  • UP000002494 Componenti: 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

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini18 – 699ExtracellularSequence analysisAdd BLAST682
Transmembranei700 – 723HelicalSequence analysisAdd BLAST24
Topological domaini724 – 770CytoplasmicBy similarityAdd BLAST47

GO - Cellular componenti

  • apical part of cell Source: Ensembl
  • astrocyte projection Source: RGD
  • axon Source: UniProtKB
  • cell-cell junction Source: Ensembl
  • cell surface Source: AgBase
  • ciliary rootlet Source: Ensembl
  • clathrin-coated pit Source: UniProtKB-SubCell
  • cytoplasm Source: UniProtKB
  • dendritic shaft Source: Ensembl
  • dendritic spine Source: Ensembl
  • endosome Source: Ensembl
  • ER to Golgi transport vesicle Source: Ensembl
  • extracellular exosome Source: Ensembl
  • extracellular space Source: RGD
  • Golgi apparatus Source: UniProtKB
  • growth cone Source: RGD
  • growth cone filopodium Source: RGD
  • growth cone lamellipodium Source: RGD
  • integral component of membrane Source: UniProtKB
  • main axon Source: RGD
  • membrane raft Source: Ensembl
  • neuromuscular junction Source: Ensembl
  • neuron projection Source: RGD
  • nuclear envelope lumen Source: Ensembl
  • perinuclear region of cytoplasm Source: Ensembl
  • plasma membrane Source: RGD
  • receptor complex Source: Ensembl
  • rough endoplasmic reticulum Source: RGD
  • smooth endoplasmic reticulum Source: GOC
  • spindle midzone Source: Ensembl
  • terminal bouton Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Cellular componenti

Amyloid, Coated pit, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi656S → A: No chondroitin sulfate linkage to isoform L-APP733. 1 Publication1
Mutagenesisi704G → V: Little oxidized neuronal proteins. Scarce beta-APP42 peptide aggregation. No neurotoxicity. 1 Publication1
Mutagenesisi732 – 733HH → GL or GP: Almost complete loss of binding to GNAO1. No inhibition of GTPase activity. 1 Publication2
Mutagenesisi743T → A: No effect on neurite growth and maturation. 1 Publication1
Mutagenesisi743T → E: Inhibits neurite growth and maturation. 1 Publication1
Mutagenesisi757Y → G: No DBB1 binding. 1 Publication1
Mutagenesisi759N → A: Some DBB1 binding. 1 Publication1
Mutagenesisi762Y → A: Some DBB1 binding. 1 Publication1
Mutagenesisi763K → R: Loss of ubiquitination. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL3638365.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 17By similarityAdd BLAST17
ChainiPRO_000000015918 – 770Amyloid beta A4 proteinAdd BLAST753
ChainiPRO_000000016018 – 687Soluble APP-alphaBy similarityAdd BLAST670
ChainiPRO_000000016118 – 671Soluble APP-betaSequence analysisAdd BLAST654
ChainiPRO_000038197118 – 286N-APPBy similarityAdd BLAST269
ChainiPRO_0000000162672 – 770C99Sequence analysisAdd BLAST99
ChainiPRO_0000000163672 – 713Beta-amyloid protein 42By similarityAdd BLAST42
ChainiPRO_0000000164672 – 711Beta-amyloid protein 40By similarityAdd BLAST40
ChainiPRO_0000000165688 – 770C83By similarityAdd BLAST83
PeptideiPRO_0000000166688 – 713P3(42)By similarityAdd BLAST26
PeptideiPRO_0000000167688 – 711P3(40)By similarityAdd BLAST24
ChainiPRO_0000384579691 – 770C80Add BLAST80
ChainiPRO_0000000168712 – 770Gamma-secretase C-terminal fragment 59Add BLAST59
ChainiPRO_0000000169714 – 770Gamma-secretase C-terminal fragment 57Add BLAST57
ChainiPRO_0000000170721 – 770Gamma-secretase C-terminal fragment 50Add BLAST50
ChainiPRO_0000000171740 – 770C31By similarityAdd BLAST31

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
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 residuei198Phosphoserine; by CK2By similarity1
Modified residuei206Phosphoserine; by CK1By similarity1
Disulfide bondi291 ↔ 341PROSITE-ProRule annotation
Disulfide bondi300 ↔ 324PROSITE-ProRule annotation
Disulfide bondi316 ↔ 337PROSITE-ProRule annotation
Modified residuei441PhosphoserineCombined sources1
Modified residuei497PhosphotyrosineBy similarity1
Glycosylationi542N-linked (GlcNAc...)Sequence analysis1
Glycosylationi571N-linked (GlcNAc...)Sequence analysis1
Glycosylationi656O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms1
Modified residuei729Phosphothreonine1 Publication1
Modified residuei730Phosphoserine; by APP-kinase I2 Publications1
Modified residuei743Phosphothreonine; by CDK5 and MAPK102 Publications1
Modified residuei757Phosphotyrosine; by ABL1By similarity1
Cross-linki763Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication

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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei671 – 672Cleavage; by beta-secretaseBy similarity2
Sitei672 – 673Cleavage; by caspase-62
Sitei687 – 688Cleavage; by alpha-secretase1 Publication2
Sitei690 – 691Cleavage; by theta-secretase1 Publication2
Sitei711 – 712Cleavage; by gamma-secretase; site 11 Publication2
Sitei713 – 714Cleavage; by gamma-secretase; site 2By similarity2
Sitei720 – 721Cleavage; by gamma-secretase; site 3By similarity2
Sitei739 – 740Cleavage; by caspase-6, caspase-8 or caspase-9By similarity2

Keywords - PTMi

Disulfide bond, Glycoprotein, Isopeptide bond, Phosphoprotein, Proteoglycan, Ubl conjugation

Proteomic databases

PaxDbiP08592.
PRIDEiP08592.

PTM databases

iPTMnetiP08592.
PhosphoSitePlusiP08592.

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

BgeeiENSRNOG00000006997.
ExpressionAtlasiP08592. baseline and differential.
GenevisibleiP08592. RN.

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). Interacts with VDAC1 (By similarity).By similarity

GO - Molecular functioni

  • growth factor receptor binding Source: RGD

Protein-protein interaction databases

BioGridi248450. 3 interactors.
DIPiDIP-6114N.
DIP-618N.
DIP-685N.
IntActiP08592. 8 interactors.
MINTiMINT-1521802.
STRINGi10116.ENSRNOP00000041613.

Chemistry databases

BindingDBiP08592.

Structurei

Secondary structure

1770
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni674 – 676Combined sources3
Turni679 – 686Combined sources8
Helixi687 – 695Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1M7EX-ray2.45D/E/F755-763[»]
1NMJNMR-A672-699[»]
1OQNX-ray2.30C/D755-763[»]
2LI9NMR-A/B672-687[»]
ProteinModelPortaliP08592.
SMRiP08592.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP08592.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini291 – 341BPTI/Kunitz inhibitorPROSITE-ProRule annotationAdd BLAST51

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni96 – 110Heparin-bindingBy similarityAdd BLAST15
Regioni135 – 155Copper-bindingBy similarityAdd BLAST21
Regioni181 – 188Zinc-bindingBy similarity8
Regioni391 – 423Heparin-bindingBy similarityAdd BLAST33
Regioni491 – 522Heparin-bindingBy similarityAdd BLAST32
Regioni523 – 540Collagen-bindingBy similarityAdd BLAST18
Regioni732 – 751Interaction with G(o)-alphaAdd BLAST20

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi724 – 734Basolateral sorting signalBy similarityAdd BLAST11
Motifi759 – 762NPXY motif; contains endocytosis signal4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi230 – 260Asp/Glu-rich (acidic)Add BLAST31
Compositional biasi274 – 280Poly-Thr7

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

eggNOGiKOG3540. Eukaryota.
ENOG410ZTKC. LUCA.
GeneTreeiENSGT00530000063252.
HOGENOMiHOG000232190.
HOVERGENiHBG000051.
InParanoidiP08592.
KOiK04520.
OMAiCKTHAHI.
OrthoDBiEOG091G0UW4.
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. Kunitz_BPTI.
IPR020901. Prtase_inh_Kunz-CS.
[Graphical view]
PANTHERiPTHR23103:SF7. PTHR23103:SF7. 2 hits.
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. AlignAdd to basket

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)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_000015289E → V in isoform APP695. 1 Publication1
Alternative sequenceiVSP_000016290 – 364Missing in isoform APP695. 1 PublicationAdd BLAST75

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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_006248011.3. [P08592-2]
UniGeneiRn.2104.

Genome annotation databases

EnsembliENSRNOT00000048854; 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:
EMBLi
GenBanki
DDBJi
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_006248011.3. [P08592-2]
UniGeneiRn.2104.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1M7EX-ray2.45D/E/F755-763[»]
1NMJNMR-A672-699[»]
1OQNX-ray2.30C/D755-763[»]
2LI9NMR-A/B672-687[»]
ProteinModelPortaliP08592.
SMRiP08592.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi248450. 3 interactors.
DIPiDIP-6114N.
DIP-618N.
DIP-685N.
IntActiP08592. 8 interactors.
MINTiMINT-1521802.
STRINGi10116.ENSRNOP00000041613.

Chemistry databases

BindingDBiP08592.
ChEMBLiCHEMBL3638365.

Protein family/group databases

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

PTM databases

iPTMnetiP08592.
PhosphoSitePlusiP08592.

Proteomic databases

PaxDbiP08592.
PRIDEiP08592.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000048854; ENSRNOP00000041613; ENSRNOG00000006997. [P08592-1]
GeneIDi54226.
KEGGirno:54226.
UCSCiRGD:2139. rat. [P08592-1]

Organism-specific databases

CTDi351.
RGDi2139. App.

Phylogenomic databases

eggNOGiKOG3540. Eukaryota.
ENOG410ZTKC. LUCA.
GeneTreeiENSGT00530000063252.
HOGENOMiHOG000232190.
HOVERGENiHBG000051.
InParanoidiP08592.
KOiK04520.
OMAiCKTHAHI.
OrthoDBiEOG091G0UW4.
PhylomeDBiP08592.
TreeFamiTF317274.

Enzyme and pathway databases

ReactomeiR-RNO-114608. Platelet degranulation.
R-RNO-1810476. RIP-mediated NFkB activation via ZBP1.
R-RNO-3000178. ECM proteoglycans.
R-RNO-3134963. DEx/H-box helicases activate type I IFN and inflammatory cytokines production.
R-RNO-416476. G alpha (q) signalling events.
R-RNO-418594. G alpha (i) signalling events.
R-RNO-432720. Lysosome Vesicle Biogenesis.
R-RNO-444473. Formyl peptide receptors bind formyl peptides and many other ligands.
R-RNO-445989. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
R-RNO-879415. Advanced glycosylation endproduct receptor signaling.
R-RNO-933542. TRAF6 mediated NF-kB activation.

Miscellaneous databases

EvolutionaryTraceiP08592.
PROiP08592.

Gene expression databases

BgeeiENSRNOG00000006997.
ExpressionAtlasiP08592. baseline and differential.
GenevisibleiP08592. RN.

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. Kunitz_BPTI.
IPR020901. Prtase_inh_Kunz-CS.
[Graphical view]
PANTHERiPTHR23103:SF7. PTHR23103:SF7. 2 hits.
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]
ProtoNetiSearch...

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: November 30, 2016
This is version 199 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.