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P12023

- A4_MOUSE

UniProt

P12023 - A4_MOUSE

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Protein
Amyloid beta A4 protein
Gene
App
Organism
Mus musculus (Mouse)
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. Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity By similarity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. 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 cortical neurons By similarity. Provides Cu2+ ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.1 Publication
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 elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also bind GPC1 in lipid rafts By similarity.1 Publication
The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.1 Publication
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6) By similarity.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei144 – 1441Required for Cu(2+) reduction By similarity
Metal bindingi147 – 1471Copper 1 By similarity
Metal bindingi151 – 1511Copper 1 By similarity
Metal bindingi168 – 1681Copper 1 By similarity
Sitei301 – 3022Reactive bond By similarity
Sitei671 – 6722Cleavage; by beta-secretase By similarity
Sitei672 – 6732Cleavage; by caspase-6 By similarity
Metal bindingi677 – 6771Copper or zinc 2 By similarity
Metal bindingi685 – 6851Copper or zinc 2 By similarity
Sitei687 – 6882Cleavage; by alpha-secretase By similarity
Sitei690 – 6912Cleavage; by theta-secretase By similarity
Sitei704 – 7041Implicated in free radical propagation By similarity
Sitei706 – 7061Susceptible to oxidation By similarity
Sitei711 – 7122Cleavage; by gamma-secretase; site 1 By similarity
Sitei713 – 7142Cleavage; by gamma-secretase; site 2 By similarity
Sitei720 – 7212Cleavage; by gamma-secretase; site 3 By similarity
Sitei739 – 7402Cleavage; by caspase-6, caspase-8 or caspase-9 By similarity

GO - Molecular functioni

  1. DNA binding Source: MGI
  2. heparin binding Source: UniProtKB-KW
  3. peptidase activator activity Source: Ensembl
  4. protein binding Source: IntAct
  5. serine-type endopeptidase inhibitor activity Source: UniProtKB-KW
  6. transition metal ion binding Source: InterPro
Complete GO annotation...

GO - Biological processi

  1. Notch signaling pathway Source: UniProtKB-KW
  2. adult locomotory behavior Source: MGI
  3. axon cargo transport Source: MGI
  4. axon midline choice point recognition Source: MGI
  5. axonogenesis Source: MGI
  6. cell adhesion Source: UniProtKB-KW
  7. cellular copper ion homeostasis Source: MGI
  8. cholesterol metabolic process Source: MGI
  9. collateral sprouting in absence of injury Source: MGI
  10. dendrite development Source: MGI
  11. endocytosis Source: MGI
  12. extracellular matrix organization Source: MGI
  13. forebrain development Source: MGI
  14. ionotropic glutamate receptor signaling pathway Source: MGI
  15. locomotory behavior Source: MGI
  16. mRNA polyadenylation Source: MGI
  17. mating behavior Source: MGI
  18. negative regulation of neuron differentiation Source: MGI
  19. neuromuscular process controlling balance Source: MGI
  20. neuron apoptotic process Source: MGI
  21. neuron projection development Source: MGI
  22. neuron remodeling Source: MGI
  23. positive regulation of G2/M transition of mitotic cell cycle Source: MGI
  24. positive regulation of mitotic cell cycle Source: MGI
  25. positive regulation of transcription from RNA polymerase II promoter Source: MGI
  26. protein homooligomerization Source: MGI
  27. protein phosphorylation Source: MGI
  28. regulation of epidermal growth factor-activated receptor activity Source: MGI
  29. regulation of gene expression Source: MGI
  30. regulation of multicellular organism growth Source: MGI
  31. regulation of protein binding Source: MGI
  32. regulation of synapse structure and activity Source: MGI
  33. regulation of translation Source: MGI
  34. response to oxidative stress Source: MGI
  35. smooth endoplasmic reticulum calcium ion homeostasis Source: MGI
  36. suckling behavior Source: MGI
  37. synaptic growth at neuromuscular junction Source: MGI
  38. visual learning Source: MGI
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_196606. ECM proteoglycans.
REACT_198563. Amyloids.
REACT_198647. Advanced glycosylation endproduct receptor signaling.
REACT_202898. TRAF6 mediated NF-kB activation.
REACT_207651. G alpha (q) signalling events.
REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_222971. RIP-mediated NFkB activation via ZBP1.

Protein family/group databases

MEROPSiI02.015.

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):
APP-C99
Alternative name(s):
Beta-APP42
Alternative name(s):
Beta-APP40
Alternative name(s):
APP-C59
Amyloid intracellular domain 59
Short name:
AID(59)
Gamma-CTF(59)
Alternative name(s):
APP-C57
Amyloid intracellular domain 57
Short name:
AID(57)
Gamma-CTF(57)
Alternative name(s):
Amyloid intracellular domain 50
Short name:
AID(50)
Gamma-CTF(50)
Gene namesi
Name:App
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 16

Organism-specific databases

MGIiMGI:88059. App.

Subcellular locationi

Membrane; Single-pass type I membrane protein. Membraneclathrin-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). 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-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body. Casein kinase phosphorylation can occur either at the cell surface or within a post-Golgi compartment. Associates with GPC1 in perinuclear compartments.1 Publication

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini18 – 699682Extracellular Reviewed prediction
Add
BLAST
Transmembranei700 – 72324Helical; Reviewed prediction
Add
BLAST
Topological domaini724 – 77047Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. ER to Golgi transport vesicle Source: MGI
  2. Golgi apparatus Source: MGI
  3. apical part of cell Source: MGI
  4. axon Source: MGI
  5. cell surface Source: Ensembl
  6. cell-cell junction Source: MGI
  7. ciliary rootlet Source: MGI
  8. coated pit Source: UniProtKB-SubCell
  9. cytoplasm Source: MGI
  10. cytoplasmic vesicle Source: MGI
  11. dendritic shaft Source: Ensembl
  12. dendritic spine Source: Ensembl
  13. integral component of membrane Source: MGI
  14. membrane Source: MGI
  15. neuromuscular junction Source: MGI
  16. neuron projection Source: MGI
  17. perinuclear region of cytoplasm Source: MGI
  18. plasma membrane Source: MGI
  19. receptor complex Source: MGI
  20. spindle midzone Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Amyloid, Coated pit, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi728 – 7281Y → A: No effect on MAPK8IP1 binding. 1 Publication
Mutagenesisi732 – 7332HH → GL or GP: Almost complete loss of binding to G(o) alpha subunit. No inhibition of GTPase activity.
Mutagenesisi743 – 7431T → E: No effect on MAPK8IP1 binding. 1 Publication
Mutagenesisi756 – 7561G → F, H, N, S or W: Greatly impairs interaction with DAB2. 1 Publication
Mutagenesisi756 – 7561G → Y: Impairs interaction with DAB2. 1 Publication
Mutagenesisi757 – 7571Y → F: Greatly promotes interaction with DAB2. 2 Publications
Mutagenesisi757 – 7571Y → G, H or V: Greatly impairs interaction with DAB2. 2 Publications
Mutagenesisi757 – 7571Y → G: No MAPK8IP1 nor APBA1 nor APBB1 nor DAB1 binding. 2 Publications
Mutagenesisi757 – 7571Y → I or W: Impairs interaction with DAB2. 2 Publications
Mutagenesisi759 – 7591N → A: No MAPK8IP1 nor APBA1 nor Dab1 binding. No effect on APBB1 binding. 2 Publications
Mutagenesisi759 – 7591N → G, L, M or P: Greatly impairs interaction with DAB2. 2 Publications
Mutagenesisi760 – 7601P → E, F, I, K, L, Q, R, V, W or Y: Greatly impairs interaction with DAB2. 1 Publication
Mutagenesisi762 – 7621Y → A: No MAPK8IP1 nor APBA1 nor Dab1 binding. No effect on APBB1 binding. 2 Publications
Mutagenesisi762 – 7621Y → W: Greatly impairs interaction with DAB2. 2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1717 By similarity
Add
BLAST
Chaini18 – 770753Amyloid beta A4 protein
PRO_0000000114Add
BLAST
Chaini18 – 687670Soluble APP-alpha Reviewed prediction
PRO_0000000115Add
BLAST
Chaini18 – 671654Soluble APP-beta Reviewed prediction
PRO_0000000116Add
BLAST
Chaini18 – 286269N-APP By similarity
PRO_0000381968Add
BLAST
Chaini672 – 77099C99 By similarity
PRO_0000000117Add
BLAST
Chaini672 – 71342Beta-amyloid protein 42 By similarity
PRO_0000000118Add
BLAST
Chaini672 – 71140Beta-amyloid protein 40 By similarity
PRO_0000000119Add
BLAST
Chaini688 – 77083C83 By similarity
PRO_0000000120Add
BLAST
Peptidei688 – 71326P3(42) By similarity
PRO_0000000121Add
BLAST
Peptidei688 – 71124P3(40) By similarity
PRO_0000000122Add
BLAST
Chaini691 – 77080C80
PRO_0000384576Add
BLAST
Chaini712 – 77059Gamma-secretase C-terminal fragment 59
PRO_0000000123Add
BLAST
Chaini714 – 77057Gamma-secretase C-terminal fragment 57
PRO_0000000124Add
BLAST
Chaini721 – 77050Gamma-secretase C-terminal fragment 50
PRO_0000000125Add
BLAST
Chaini740 – 77031C31 By similarity
PRO_0000000126Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi38 ↔ 62 By similarity
Disulfide bondi73 ↔ 117 By similarity
Disulfide bondi98 ↔ 105 By similarity
Disulfide bondi133 ↔ 187 By similarity
Disulfide bondi144 ↔ 174 By similarity
Disulfide bondi158 ↔ 186 By similarity
Modified residuei198 – 1981Phosphoserine; by CK2 By similarity
Modified residuei206 – 2061Phosphoserine; by CK1 By similarity
Disulfide bondi291 ↔ 341 By similarity
Disulfide bondi300 ↔ 324 By similarity
Disulfide bondi316 ↔ 337 By similarity
Glycosylationi542 – 5421N-linked (GlcNAc...) Inferred
Glycosylationi571 – 5711N-linked (GlcNAc...) Inferred
Modified residuei729 – 7291Phosphothreonine By similarity
Modified residuei730 – 7301Phosphoserine; by APP-kinase I By similarity
Modified residuei743 – 7431Phosphothreonine; by CDK5 and MAPK10
Modified residuei757 – 7571Phosphotyrosine; by ABL11 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.
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.1 Publication
N- and O-glycosylated By similarity.
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 By similarity. Phosphorylation on Tyr-757 is required for SHC binding By similarity.2 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.1 Publication
Beta-amyloid peptides are degraded by IDE By similarity.

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiP12023.
PaxDbiP12023.
PRIDEiP12023.

PTM databases

PhosphoSiteiP12023.

Expressioni

Tissue specificityi

Isoform APP770 is expressed in kidney. Isoform APP751 is widely expressed. Isoform APP695 is expressed in brain, kidney and liver. Isoform APP695, isoform APP714 and isoform APP751 are expressed in several different brain regions including hippocampus, substania nigra pars compacta and cerebellum. In the cerebellum, these isoforms are abundantly expressed in Purkinje cells.1 Publication

Gene expression databases

ArrayExpressiP12023.
BgeeiP12023.
CleanExiMM_APP.
GenevestigatoriP12023.

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, NUMB and DAB1. Binding to DAB1 inhibits its serine phosphorylation. 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) and DDB1 By similarity. 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 By similarity. Amyloid beta-42 binds CHRNA7 in hippocampal neurons By similarity. Beta-amyloid associates with HADH2 By similarity. Interacts with ANKS1B, TNFRSF21 and AGER By similarity. Interacts with CPEB1. 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 SORL1.8 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Apba2P980842EBI-78814,EBI-81669
Apbb1Q9QXJ12EBI-78814,EBI-81338
Aplp1Q031574EBI-78814,EBI-399929
Aplp2Q063353EBI-78814,EBI-446708
CALRP152532EBI-78814,EBI-9005200From a different organism.
CalrP142114EBI-78814,EBI-644340
Dab1P973183EBI-78814,EBI-81680
Dlg4Q621084EBI-78814,EBI-300895
Lingo1Q9D1T02EBI-78814,EBI-2012981
MAPK8IP1Q9UQF22EBI-78814,EBI-78404From a different organism.
Mapk8ip1Q9WVI9-13EBI-78814,EBI-288461
Shc3Q611202EBI-78814,EBI-79107
Slc40a1Q9JHI92EBI-78814,EBI-2931424

Protein-protein interaction databases

BioGridi198167. 9 interactions.
IntActiP12023. 77 interactions.
MINTiMINT-208509.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi744 – 75310

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2ROZNMR-A739-770[»]
2YSZNMR-A739-770[»]
2YT0NMR-A739-770[»]
2YT1NMR-A739-770[»]
ProteinModelPortaliP12023.
SMRiP12023. Positions 26-192, 287-342, 371-566, 686-726, 741-768.

Miscellaneous databases

EvolutionaryTraceiP12023.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini291 – 34151BPTI/Kunitz inhibitor
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni96 – 11015Heparin-binding By similarity
Add
BLAST
Regioni181 – 1888Zinc-binding By similarity
Regioni391 – 42333Heparin-binding By similarity
Add
BLAST
Regioni491 – 52232Heparin-binding By similarity
Add
BLAST
Regioni523 – 54018Collagen-binding By similarity
Add
BLAST
Regioni732 – 75120Interaction with G(o)-alpha By similarity
Add
BLAST
Regioni756 – 77015Interaction with DAB2
Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi724 – 73411Basolateral sorting signal
Add
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 By similarity.

Sequence similaritiesi

Belongs to the APP family.

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG289770.
HOGENOMiHOG000232190.
HOVERGENiHBG000051.
InParanoidiP12023.
KOiK04520.
OMAiTHAHIVI.
OrthoDBiEOG7RNJZP.
PhylomeDBiP12023.
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 (4)i

Sequence statusi: Complete.

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

This entry describes 4 isoformsi produced by alternative splicing. Align

Note: Additional isoforms seem to exist.

Isoform APP770 (identifier: P12023-1) [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

MLPSLALLLL AAWTVRALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG    50
KWESDPSGTK TCIGTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR 100
GRKQCKTHTH IVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW 150
HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDSVDSAD 200
AEEDDSDVWW GGADTDYADG GEDKVVEVAE EEEVADVEEE EADDDEDVED 250
GDEVEEEAEE PYEEATERTT STATTTTTTT ESVEEVVREV CSEQAETGPC 300
RAMISRWYFD VTEGKCVPFF YGGCGGNRNN FDTEEYCMAV CGSVSTQSLL 350
KTTSEPLPQD PDKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA 400
KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER 450
QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPHHV FNMLKKYVRA 500
EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN 550
VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET 600
KTTVELLPVN GEFSLDDLQP WHPFGVDSVP ANTENEVEPV DARPAADRGL 650
TTRPGSGLTN IKTEEISEVK MDAEFGHDSG FEVRHQKLVF FAEDVGSNKG 700
AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS 750
KMQQNGYENP TYKFFEQMQN 770
Length:770
Mass (Da):86,722
Last modified:May 9, 2003 - v3
Checksum:i988D89E089092A3E
GO
Isoform APP695 (identifier: P12023-2) [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):78,443
Checksum:i0DE93FA56FB20F3A
GO
Isoform APP751 (identifier: P12023-3) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     346-380: Missing.

Show »
Length:735
Mass (Da):82,968
Checksum:iBE4D5EC285943E89
GO
Isoform APP714 (identifier: P12023-4)

Sequence is not available
Length:
Mass (Da):

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei289 – 2891E → V in isoform APP695.
VSP_000012
Alternative sequencei290 – 36475Missing in isoform APP695.
VSP_000013Add
BLAST
Alternative sequencei346 – 38035Missing in isoform APP751.
VSP_000014Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti211 – 2111G → V in AAA37139. 1 Publication
Sequence conflicti375 – 3751V → A in AAB41502. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
M18373 mRNA. Translation: AAA37139.1.
X59379 mRNA. No translation available.
U84012 mRNA. Translation: AAB41502.1.
D10603 Genomic DNA. Translation: BAA01456.1.
BC005490 mRNA. Translation: AAH05490.1.
M24397 mRNA. Translation: AAA39929.1.
X15210 mRNA. Translation: CAA33280.1.
U82624 Genomic DNA. Translation: AAB40919.1.
CCDSiCCDS28285.1. [P12023-2]
PIRiA27485.
A32282.
S04855.
RefSeqiNP_001185752.1. NM_001198823.1. [P12023-1]
UniGeneiMm.277585.
Mm.489029.
Mm.490986.

Genome annotation databases

EnsembliENSMUST00000005406; ENSMUSP00000005406; ENSMUSG00000022892. [P12023-2]
GeneIDi11820.
KEGGimmu:11820.
UCSCiuc007ztn.2. mouse. [P12023-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
M18373 mRNA. Translation: AAA37139.1 .
X59379 mRNA. No translation available.
U84012 mRNA. Translation: AAB41502.1 .
D10603 Genomic DNA. Translation: BAA01456.1 .
BC005490 mRNA. Translation: AAH05490.1 .
M24397 mRNA. Translation: AAA39929.1 .
X15210 mRNA. Translation: CAA33280.1 .
U82624 Genomic DNA. Translation: AAB40919.1 .
CCDSi CCDS28285.1. [P12023-2 ]
PIRi A27485.
A32282.
S04855.
RefSeqi NP_001185752.1. NM_001198823.1. [P12023-1 ]
UniGenei Mm.277585.
Mm.489029.
Mm.490986.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2ROZ NMR - A 739-770 [» ]
2YSZ NMR - A 739-770 [» ]
2YT0 NMR - A 739-770 [» ]
2YT1 NMR - A 739-770 [» ]
ProteinModelPortali P12023.
SMRi P12023. Positions 26-192, 287-342, 371-566, 686-726, 741-768.
ModBasei Search...

Protein-protein interaction databases

BioGridi 198167. 9 interactions.
IntActi P12023. 77 interactions.
MINTi MINT-208509.

Protein family/group databases

MEROPSi I02.015.

PTM databases

PhosphoSitei P12023.

Proteomic databases

MaxQBi P12023.
PaxDbi P12023.
PRIDEi P12023.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000005406 ; ENSMUSP00000005406 ; ENSMUSG00000022892 . [P12023-2 ]
GeneIDi 11820.
KEGGi mmu:11820.
UCSCi uc007ztn.2. mouse. [P12023-1 ]

Organism-specific databases

CTDi 351.
MGIi MGI:88059. App.

Phylogenomic databases

eggNOGi NOG289770.
HOGENOMi HOG000232190.
HOVERGENi HBG000051.
InParanoidi P12023.
KOi K04520.
OMAi THAHIVI.
OrthoDBi EOG7RNJZP.
PhylomeDBi P12023.
TreeFami TF317274.

Enzyme and pathway databases

Reactomei REACT_196606. ECM proteoglycans.
REACT_198563. Amyloids.
REACT_198647. Advanced glycosylation endproduct receptor signaling.
REACT_202898. TRAF6 mediated NF-kB activation.
REACT_207651. G alpha (q) signalling events.
REACT_219800. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_222971. RIP-mediated NFkB activation via ZBP1.

Miscellaneous databases

ChiTaRSi app. mouse.
EvolutionaryTracei P12023.
NextBioi 279717.
PROi P12023.
SOURCEi Search...

Gene expression databases

ArrayExpressi P12023.
Bgeei P12023.
CleanExi MM_APP.
Genevestigatori P12023.

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

« Hide 'large scale' publications
  1. "Complementary DNA for the mouse homolog of the human amyloid beta protein precursor."
    Yamada T., Sasaki H., Furuya H., Miyata T., Goto I., Sakaki Y.
    Biochem. Biophys. Res. Commun. 149:665-671(1987) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
    Tissue: Brain.
  2. Yamada T.
    Submitted (MAR-1988) to the EMBL/GenBank/DDBJ databases
    Cited for: SEQUENCE REVISION.
  3. "The amyloid beta protein precursor or proteinase nexin II from mouse is closer related to its human homolog than previously reported."
    de Strooper B., van Leuven F., van den Berghe H.
    Biochim. Biophys. Acta 1129:141-143(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
    Strain: BALB/c.
    Tissue: Brain.
  4. "Molecular cloning, expression, and regulation of hippocampal amyloid precursor protein of senescence accelerated mouse (SAMP8)."
    Kumar V.B., Vyas K., Franko M., Choudhary V., Buddhiraju C., Alvarez J., Morley J.E.
    Biochem. Cell Biol. 79:57-67(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
    Strain: SAMP8.
    Tissue: Hippocampus.
  5. "Positive and negative regulatory elements for the expression of the Alzheimer's disease amyloid precursor-encoding gene in mouse."
    Izumi R., Yamada T., Yoshikai S., Sasaki H., Hattori M., Sakai Y.
    Gene 112:189-195(1992) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-19.
  6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM APP770).
    Tissue: Mammary tumor.
  7. "Structure and expression of the alternatively-spliced forms of mRNA for the mouse homolog of Alzheimer's disease amyloid beta protein precursor."
    Yamada T., Sasaki H., Dohura K., Goto I., Sakaki Y.
    Biochem. Biophys. Res. Commun. 158:906-912(1989) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 281-380, ALTERNATIVE SPLICING.
    Tissue: Brain and Kidney.
  8. "Sequence of the protease inhibitor domain of the A4 amyloid protein precursor of Mus domesticus."
    Fukuchi K., Martin G.M., Deeb S.S.
    Nucleic Acids Res. 17:5396-5396(1989) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 289-364.
    Strain: CD-1.
    Tissue: Placenta.
  9. "Introduction of six mutations into the mouse genome using 'Hit and Run' gene-targeting: introduction of familial Alzheimer's disease mutations into the mouse amyloid precursor protein gene and humanization of the A-beta fragment."
    Wragg M.A., Busfield F., Duff K., Korenblat K., Capecchi M., Loring J.F., Goate A.M.
    Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 656-737.
    Strain: 129/Sv.
  10. "Regional distribution of the alternatively spliced isoforms of beta APP RNA transcript in the brain of normal, heterozygous and homozygous weaver mutant mice as revealed by in situ hybridization histochemistry."
    Sola C., Mengod G., Ghetti B., Palacios J.M., Triarhou L.C.
    Brain Res. Mol. Brain Res. 17:340-346(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY OF ALTERNATIVE SPLICED FORMS.
  11. "Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I."
    Kamal A., Stokin G.B., Yang Z., Xia C.-H., Goldstein L.S.
    Neuron 28:449-459(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH KNS2.
  12. "The beta-amyloid precursor protein APP is tyrosine-phosphorylated in cells expressing a constitutively active form of the Abl protoncogene."
    Zambrano N., Bruni P., Minopoli G., Mosca R., Molino D., Russo C., Schettini G., Sudol M., Russo T.
    J. Biol. Chem. 276:19787-19792(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT TYR-757.
  13. "C-jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK."
    Matsuda S., Yasukawa T., Homma Y., Ito Y., Niikura T., Hiraki T., Hirai S., Ohno S., Kita Y., Kawasumi M., Kouyama K., Yamamoto T., Kyriakis J.M., Nishimoto I.
    J. Neurosci. 21:6597-6607(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: C-TERMINAL PROTEIN-PROTEIN INTERACTION, MUTAGENESIS OF TYR-728; THR-743; TYR-757; ASN-759 AND TYR-762.
  14. "Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2."
    Morris S.M., Cooper J.A.
    Traffic 2:111-123(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH DAB2, MUTAGENESIS OF GLY-756; TYR-757; ASN-759; PRO-760 AND TYR-762.
  15. "Interaction of Alzheimer's beta-amyloid precursor family proteins with scaffold proteins of the JNK signaling cascade."
    Taru H., Iijima K., Hase M., Kirino Y., Yagi Y., Suzuki T.
    J. Biol. Chem. 277:20070-20078(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH MAPK8IP1, PHOSPHORYLATION.
  16. "The gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds Numb and inhibits Notch signaling."
    Roncarati R., Sestan N., Scheinfeld M.H., Berechid B.E., Lopez P.A., Meucci O., McGlade J.C., Rakic P., D'Adamio L.
    Proc. Natl. Acad. Sci. U.S.A. 99:7102-7107(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION OF CTF PEPTIDES WITH NUMB.
  17. "The amyloid precursor protein (APP)-cytoplasmic fragment generated by gamma-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurons in culture."
    Cupers P., Orlans I., Craessaerts K., Annaert W., De Strooper B.
    J. Neurochem. 78:1168-1178(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEOLYTIC PROCESSING BY GAMMA SECRETASE, INTERACTION WITH APBB1.
  18. "The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo."
    Cappai R., Cheng F., Ciccotosto G.D., Needham B.E., Masters C.L., Multhaup G., Fransson L.A., Mani K.
    J. Biol. Chem. 280:13913-13920(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, FUNCTION.
  19. "Amyloid precursor proteins anchor CPEB to membranes and promote polyadenylation-induced translation."
    Cao Q., Huang Y.-S., Kan M.-C., Richter J.D.
    Mol. Cell. Biol. 25:10930-10939(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CPEB1.
  20. Cited for: INTERACTION WITH APP.

Entry informationi

Entry nameiA4_MOUSE
AccessioniPrimary (citable) accession number: P12023
Secondary accession number(s): P97487, P97942, Q99K32
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: May 9, 2003
Last modified: September 3, 2014
This is version 183 of the entry and version 3 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.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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