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P05067

- A4_HUMAN

UniProt

P05067 - A4_HUMAN

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Protein
Amyloid beta A4 protein
Gene
APP, A4, AD1
Organism
Homo sapiens (Human)
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 inhibits 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. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu2+-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. 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. Provides Cu2+ ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.5 Publications
Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu2+ and Fe3+ to Cu+ and Fe2+, respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.5 Publications
Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain By similarity.5 Publications
The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.5 Publications
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).5 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei144 – 1441Required for Cu(2+) reduction
Metal bindingi147 – 1471Copper 1
Metal bindingi151 – 1511Copper 1
Metal bindingi168 – 1681Copper 1
Sitei301 – 3022Reactive bond
Sitei671 – 6722Cleavage; by beta-secretase
Sitei672 – 6732Cleavage; by caspase-6; when associated with variant 670-N-L-671
Metal bindingi677 – 6771Copper or zinc 2
Metal bindingi681 – 6811Copper or zinc 2 Inferred
Metal bindingi684 – 6841Copper or zinc 2
Metal bindingi685 – 6851Copper or zinc 2
Sitei687 – 6882Cleavage; by alpha-secretase
Sitei690 – 6912Cleavage; by theta-secretase
Sitei704 – 7041Implicated in free radical propagation By similarity
Sitei706 – 7061Susceptible to oxidation
Sitei711 – 7122Cleavage; by gamma-secretase; site 1
Sitei713 – 7142Cleavage; by gamma-secretase; site 2
Sitei720 – 7212Cleavage; by gamma-secretase; site 3
Sitei739 – 7402Cleavage; by caspase-6, caspase-8 or caspase-9

GO - Molecular functioni

  1. DNA binding Source: UniProtKB
  2. PTB domain binding Source: BHF-UCL
  3. acetylcholine receptor binding Source: UniProtKB
  4. enzyme binding Source: ParkinsonsUK-UCL
  5. heparin binding Source: UniProtKB-KW
  6. identical protein binding Source: IntAct
  7. peptidase activator activity Source: Ensembl
  8. protein binding Source: IntAct
  9. receptor binding Source: BHF-UCL
  10. serine-type endopeptidase inhibitor activity Source: UniProtKB
  11. transition metal ion binding Source: InterPro
Complete GO annotation...

GO - Biological processi

  1. Notch signaling pathway Source: UniProtKB-KW
  2. adult locomotory behavior Source: UniProtKB
  3. axon cargo transport Source: UniProtKB
  4. axon midline choice point recognition Source: UniProtKB
  5. axonogenesis Source: UniProtKB
  6. blood coagulation Source: Reactome
  7. cell adhesion Source: UniProtKB-KW
  8. cellular copper ion homeostasis Source: UniProtKB
  9. cholesterol metabolic process Source: Ensembl
  10. collateral sprouting in absence of injury Source: UniProtKB
  11. dendrite development Source: UniProtKB
  12. endocytosis Source: UniProtKB
  13. extracellular matrix organization Source: UniProtKB
  14. forebrain development Source: Ensembl
  15. innate immune response Source: Reactome
  16. ionotropic glutamate receptor signaling pathway Source: UniProtKB
  17. locomotory behavior Source: UniProtKB
  18. mRNA polyadenylation Source: UniProtKB
  19. mating behavior Source: UniProtKB
  20. mitotic G2 phase Source: UniProtKB
  21. negative regulation of endopeptidase activity Source: GOC
  22. negative regulation of neuron differentiation Source: Ensembl
  23. neuromuscular process controlling balance Source: Ensembl
  24. neuron apoptotic process Source: UniProtKB
  25. neuron projection development Source: UniProtKB
  26. neuron remodeling Source: UniProtKB
  27. nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway Source: Reactome
  28. platelet activation Source: Reactome
  29. platelet degranulation Source: Reactome
  30. positive regulation of G2/M transition of mitotic cell cycle Source: Ensembl
  31. positive regulation of mitotic cell cycle Source: UniProtKB
  32. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
  33. protein phosphorylation Source: UniProtKB
  34. regulation of epidermal growth factor-activated receptor activity Source: UniProtKB
  35. regulation of multicellular organism growth Source: UniProtKB
  36. regulation of protein binding Source: Ensembl
  37. regulation of synapse structure and activity Source: UniProtKB
  38. regulation of translation Source: UniProtKB
  39. response to oxidative stress Source: Ensembl
  40. smooth endoplasmic reticulum calcium ion homeostasis Source: Ensembl
  41. suckling behavior Source: Ensembl
  42. synaptic growth at neuromuscular junction Source: Ensembl
  43. 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

BioCyciMetaCyc:ENSG00000142192-MONOMER.
ReactomeiREACT_118563. RIP-mediated NFkB activation via ZBP1.
REACT_163906. ECM proteoglycans.
REACT_18283. G alpha (q) signalling events.
REACT_19231. G alpha (i) signalling events.
REACT_21264. Formyl peptide receptors bind formyl peptides and many other ligands.
REACT_21281. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_24969. TRAF6 mediated NF-kB activation.
REACT_25195. Advanced glycosylation endproduct receptor signaling.
REACT_75808. The NLRP3 inflammasome.
REACT_75925. Amyloids.
SABIO-RKP05067.

Protein family/group databases

MEROPSiI02.015.
TCDBi1.C.50.1.2. the amyloid -protein peptide (app) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Amyloid beta A4 protein
Alternative name(s):
ABPP
APPI
Short name:
APP
Alzheimer disease amyloid protein
Cerebral vascular amyloid peptide
Short name:
CVAP
PreA4
Protease nexin-II
Short name:
PN-II
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):
Amyloid intracellular domain 59
Short name:
AICD-59
Short name:
AID(59)
Gamma-CTF(59)
Alternative name(s):
Amyloid intracellular domain 57
Short name:
AICD-57
Short name:
AID(57)
Gamma-CTF(57)
Alternative name(s):
Amyloid intracellular domain 50
Short name:
AICD-50
Short name:
AID(50)
Gamma-CTF(50)
Gene namesi
Name:APP
Synonyms:A4, AD1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 21

Organism-specific databases

HGNCiHGNC:620. 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 FRPL1 at the cell surface and the complex is then rapidly internalized. APP sorts to the basolateral surface in epithelial cells. 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. Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions.3 Publications

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. Golgi apparatus Source: UniProtKB
  2. apical part of cell Source: Ensembl
  3. axon Source: UniProtKB
  4. cell surface Source: UniProtKB
  5. ciliary rootlet Source: Ensembl
  6. coated pit Source: UniProtKB-SubCell
  7. cytoplasm Source: UniProtKB
  8. cytosol Source: Reactome
  9. dendritic shaft Source: MGI
  10. dendritic spine Source: MGI
  11. extracellular region Source: Reactome
  12. extracellular space Source: UniProt
  13. extracellular vesicular exosome Source: UniProt
  14. integral component of membrane Source: UniProtKB
  15. integral component of plasma membrane Source: ProtInc
  16. intracellular membrane-bounded organelle Source: HPA
  17. membrane raft Source: ParkinsonsUK-UCL
  18. neuromuscular junction Source: Ensembl
  19. nuclear envelope lumen Source: Alzheimers_University_of_Toronto
  20. perinuclear region of cytoplasm Source: UniProt
  21. plasma membrane Source: UniProtKB
  22. platelet alpha granule lumen Source: Reactome
  23. receptor complex Source: MGI
  24. spindle midzone Source: Ensembl
  25. synapse Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Amyloid, Coated pit, Membrane

Pathology & Biotechi

Involvement in diseasei

Alzheimer disease 1 (AD1) [MIM:104300]: A familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.
Note: The disease is caused by mutations affecting the gene represented in this entry.26 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti670 – 6712KM → NL in AD1.
VAR_000015
Natural varianti678 – 6781D → N in AD1. 1 Publication
VAR_044424
Natural varianti692 – 6921A → G in AD1; Flemish mutation; increases the solubility of processed beta-amyloid peptides and increases the stability of peptide oligomers. 3 Publications
VAR_000016
Natural varianti693 – 6931E → G in AD1. 2 Publications
VAR_014215
Natural varianti713 – 7131A → T in AD1. 2 Publications
VAR_000019
Natural varianti714 – 7141T → A in AD1. 1 Publication
VAR_032277
Natural varianti714 – 7141T → I in AD1; increased beta-APP42/beta-APP40 ratio. 2 Publications
VAR_014218
Natural varianti715 – 7151V → M in AD1; decreased beta-APP40/total APP-beta. 1 Publication
VAR_010108
Natural varianti716 – 7161I → V in AD1. 1 Publication
VAR_000020
Natural varianti717 – 7171V → F in AD1. 4 Publications
VAR_000023
Natural varianti717 – 7171V → G in AD1. 2 Publications
VAR_000022
Natural varianti717 – 7171V → I in AD1. 7 Publications
VAR_000021
Natural varianti717 – 7171V → L in AD1. 1 Publication
VAR_014219
Natural varianti723 – 7231L → P in AD1. 1 Publication
VAR_010109
Cerebral amyloid angiopathy, APP-related (CAA-APP) [MIM:605714]: A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.
Note: The disease is caused by mutations affecting the gene represented in this entry.5 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti693 – 6931E → K in CAA-APP; Italian type.
VAR_014216
Natural varianti693 – 6931E → Q in CAA-APP; Dutch type. 1 Publication
VAR_000017
Natural varianti694 – 6941D → N in CAA-APP; Iowa type. 2 Publications
VAR_014217
Natural varianti705 – 7051L → V in CAA-APP; Italian type. 1 Publication
VAR_032276

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi99 – 1024KRGR → NQGG: Reduced heparin-binding. 1 Publication
Mutagenesisi137 – 1371H → N: Binds copper. Forms dimer. 1 Publication
Mutagenesisi141 – 1411M → T: Binds copper. Forms dimer. 1 Publication
Mutagenesisi144 – 1441C → S: Binds copper. No dimer formation. No copper reducing activity. 2 Publications
Mutagenesisi147 – 1493HLH → ALA: 50% decrease in copper reducing activity. 3 Publications
Mutagenesisi147 – 1471H → A: Some decrease in copper reducing activity. 2 Publications
Mutagenesisi147 – 1471H → N: Binds copper. Forms dimer. 2 Publications
Mutagenesisi147 – 1471H → Y: Greatly reduced copper-mediated low-density lipoprotein oxidation. 2 Publications
Mutagenesisi151 – 1511H → K: Greatly reduced copper-mediated low-density lipoprotein oxidation. 2 Publications
Mutagenesisi151 – 1511H → N: Binds copper. Forms dimer. 2 Publications
Mutagenesisi198 – 1981S → A: Greatly reduced casein kinase phosphorylation. 2 Publications
Mutagenesisi206 – 2061S → A: Reduced casein kinase phosphorylation. 2 Publications
Mutagenesisi499 – 4991R → A: Reduced affinity for heparin; when associated with A-503. 1 Publication
Mutagenesisi503 – 5031K → A: Reduced affinity for heparin; when associated with A-499. 1 Publication
Mutagenesisi656 – 6561S → A: Abolishes chondroitin sulfate binding in L-APP733 isoform. 1 Publication
Mutagenesisi676 – 6761R → G: 60-70% zinc-induced beta-APP (28) peptide aggregation. 1 Publication
Mutagenesisi681 – 6811Y → F: 60-70% zinc-induced beta-APP (28) peptide aggregation. 1 Publication
Mutagenesisi684 – 6841H → R: Only 23% zinc-induced beta-APP (28) peptide aggregation. 1 Publication
Mutagenesisi704 – 7041G → V: Reduced protein oxidation. No hippocampal neuron toxicity.
Mutagenesisi706 – 7061M → L: Reduced lipid peroxidation inhibition. 2 Publications
Mutagenesisi706 – 7061M → V: No free radical production. No hippocampal neuron toxicity. 2 Publications
Mutagenesisi717 – 7171V → C or S: Unchanged beta-APP42/total APP-beta ratio. 2 Publications
Mutagenesisi717 – 7171V → F, G or I: Increased beta-APP42/beta-APP40 ratio. 2 Publications
Mutagenesisi717 – 7171V → K: Decreased beta-APP42/total APP-beta ratio. 2 Publications
Mutagenesisi717 – 7171V → M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage. 2 Publications
Mutagenesisi728 – 7281Y → A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion. 3 Publications
Mutagenesisi739 – 7391D → A: No cleavage by caspases during apoptosis. 3 Publications
Mutagenesisi739 – 7391D → N: No effect on FADD-induced apoptosis. 3 Publications
Mutagenesisi743 – 7431T → A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension. 4 Publications
Mutagenesisi743 – 7431T → E: Reduced NGF-stimulated neurite extension. No effect on APP maturation. 4 Publications
Mutagenesisi756 – 7561G → A: APP internalization unchanged. No change in beta-APP42 secretion. 1 Publication
Mutagenesisi757 – 7571Y → A: Little APP internalization. Reduced beta-APP42 secretion. 4 Publications
Mutagenesisi757 – 7571Y → G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1. 4 Publications
Mutagenesisi759 – 7591N → A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion. 2 Publications
Mutagenesisi760 – 7601P → A: Little APP internalization. Reduced beta-APP42 secretion. 1 Publication
Mutagenesisi762 – 7621Y → A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion. 2 Publications

Keywords - Diseasei

Alzheimer disease, Amyloidosis, Disease mutation, Neurodegeneration

Organism-specific databases

MIMi104300. phenotype.
605714. phenotype.
Orphaneti1020. Early-onset autosomal dominant Alzheimer disease.
324723. Hereditary cerebral hemorrhage with amyloidosis, Arctic type.
100006. Hereditary cerebral hemorrhage with amyloidosis, Dutch type.
324718. Hereditary cerebral hemorrhage with amyloidosis, Flemish type.
324708. Hereditary cerebral hemorrhage with amyloidosis, Iowa type.
324713. Hereditary cerebral hemorrhage with amyloidosis, Italian type.
324703. Hereditary cerebral hemorrhage with amyloidosis, Piedmont type.
PharmGKBiPA24910.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 17172 Publications
Add
BLAST
Chaini18 – 770753Amyloid beta A4 protein
PRO_0000000088Add
BLAST
Chaini18 – 687670Soluble APP-alpha
PRO_0000000089Add
BLAST
Chaini18 – 671654Soluble APP-beta
PRO_0000000090Add
BLAST
Chaini18 – 286269N-APP
PRO_0000381966Add
BLAST
Chaini672 – 77099C99
PRO_0000000091Add
BLAST
Chaini672 – 71342Beta-amyloid protein 42
PRO_0000000092Add
BLAST
Chaini672 – 71140Beta-amyloid protein 40
PRO_0000000093Add
BLAST
Chaini688 – 77083C83
PRO_0000000094Add
BLAST
Peptidei688 – 71326P3(42)
PRO_0000000095Add
BLAST
Peptidei688 – 71124P3(40)
PRO_0000000096Add
BLAST
Chaini691 – 77080C80
PRO_0000384574Add
BLAST
Chaini712 – 77059Gamma-secretase C-terminal fragment 59
PRO_0000000097Add
BLAST
Chaini714 – 77057Gamma-secretase C-terminal fragment 57
PRO_0000000098Add
BLAST
Chaini721 – 77050Gamma-secretase C-terminal fragment 50 By similarity
PRO_0000000099Add
BLAST
Chaini740 – 77031C31
PRO_0000000100Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi38 ↔ 624 Publications
Disulfide bondi73 ↔ 1174 Publications
Disulfide bondi98 ↔ 1054 Publications
Disulfide bondi133 ↔ 1874 Publications
Disulfide bondi144 ↔ 1744 Publications
Disulfide bondi158 ↔ 1864 Publications
Modified residuei198 – 1981Phosphoserine; by CK21 Publication
Modified residuei206 – 2061Phosphoserine; by CK11 Publication
Disulfide bondi291 ↔ 3414 Publications
Disulfide bondi300 ↔ 3244 Publications
Disulfide bondi316 ↔ 3374 Publications
Glycosylationi542 – 5421N-linked (GlcNAc...)1 Publication
Glycosylationi571 – 5711N-linked (GlcNAc...) Inferred
Glycosylationi614 – 6141O-linked (GalNAc...)1 Publication
Glycosylationi623 – 6231O-linked (GalNAc...)1 Publication
Glycosylationi628 – 6281O-linked (GalNAc...)1 Publication
Glycosylationi633 – 6331O-linked (GalNAc...)1 Publication
Glycosylationi651 – 6511O-linked (GalNAc...)1 Publication
Glycosylationi652 – 6521O-linked (GalNAc...)1 Publication
Glycosylationi656 – 6561O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms1 Publication
Glycosylationi659 – 6591O-linked (GalNAc...)
Glycosylationi663 – 6631O-linked (GalNAc...) Inferred
Glycosylationi667 – 6671O-linked (GalNAc...) Inferred
Glycosylationi679 – 6791O-linked (GalNAc...)1 Publication
Glycosylationi697 – 6971O-linked (GalNAc...)1 Publication
Modified residuei729 – 7291Phosphothreonine By similarity
Modified residuei730 – 7301Phosphoserine; by APP-kinase I By similarity
Modified residuei743 – 7431Phosphothreonine; by CDK5 and MAPK101 Publication
Modified residuei757 – 7571Phosphotyrosine1 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). Many other minor beta-amyloid peptides, beta-amyloid 1-X peptides, are found in cerebral spinal fluid (CSF) including the beta-amyloid X-15 peptides, produced from the cleavage by alpha-secretase and all terminatiing at Gln-686.
Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-6, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides.7 Publications
N- and O-glycosylated. O-glycosylation on Ser and Thr residues with core 1 or possibly core 8 glycans. Partial tyrosine glycosylation (Tyr-681) is found on some minor, short beta-amyloid peptides (beta-amyloid 1-15, 1-16, 1-17, 1-18, 1-19 and 1-20) but not found on beta-amyloid 38, beta-amyloid 40 nor on beta-amyloid 42. Modification on a tyrosine is unusual and is more prevelant in AD patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr, Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O-AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is O-acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac 2,8Neu5Ac linked. O-glycosylations in the vicinity of the cleavage sites may influence the proteolytic processing. Appicans are L-APP isoforms with O-linked chondroitin sulfate.2 Publications
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. Phosphorylated on Thr-743 in neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. 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.7 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. In vitro, the APP-Cu+ complex in the presence of hydrogen peroxide results in an increased production of beta-amyloid-containing peptides.
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).7 Publications
Beta-amyloid peptides are degraded by IDE.

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Proteoglycan

Proteomic databases

MaxQBiP05067.
PaxDbiP05067.
PRIDEiP05067.

2D gel databases

SWISS-2DPAGEP05067.

PTM databases

PhosphoSiteiP05067.
UniCarbKBiP05067.

Miscellaneous databases

PMAP-CutDBP05067.

Expressioni

Tissue specificityi

Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex-opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra-striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells. Isoform APP751 is the most abundant form in T-lymphocytes. Appican is expressed in astrocytes.2 Publications

Inductioni

Increased levels during neuronal differentiation.

Gene expression databases

ArrayExpressiP05067.
BgeeiP05067.
GenevestigatoriP05067.

Organism-specific databases

HPAiCAB000157.
HPA001462.

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) By similarity, APPBP2 (via BaSS) 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. Beta-amyloid associates with HADH2. Soluble APP binds, via its N-terminal head, to FBLN1. Interacts with CPEB1 and AGER By similarity. Interacts with ANKS1B and TNFRSF21. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; this is promoted by heparin binding. Beta-amyloid protein 40 interacts with S100A9. CTF-alpha product of APP interacts with GSAP. Interacts with SORL1.27 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself94EBI-77613,EBI-77613
Q306T33EBI-77613,EBI-8294101From a different organism.
AGRNP316963EBI-2431589,EBI-457650From a different organism.
APBA1Q024103EBI-77613,EBI-368690
APBB1O002135EBI-77613,EBI-81694
APBB2Q928702EBI-77613,EBI-79277
APLP1P516932EBI-302641,EBI-74648
APLP2Q064812EBI-302641,EBI-79306
APOA1P026475EBI-77613,EBI-701692
BLMHQ138672EBI-302641,EBI-718504
CALRP152533EBI-77613,EBI-9005200From a different organism.
CALRQ8K3H72EBI-3894543,EBI-9005068From a different organism.
COL18A1P390602EBI-821758,EBI-2566375
CTSDP073392EBI-77613,EBI-2115097
FLOT1O759555EBI-77613,EBI-603643
FOSP011003EBI-77613,EBI-852851
GPR3P460892EBI-302641,EBI-3909653
HOMER3Q9NSC53EBI-302661,EBI-748420
HSD17B10Q997144EBI-77613,EBI-79964
ITM2AO437363EBI-302641,EBI-2431769
JUNP054122EBI-77613,EBI-852823
MAPTP106369EBI-77613,EBI-366182
MED12Q930742EBI-77613,EBI-394357
MT-ND3P038972EBI-821758,EBI-1246249
NF1P213593EBI-77613,EBI-1172917
NGFRP081382EBI-77613,EBI-1387782
NgfrP071742EBI-2431589,EBI-1038810From a different organism.
PCBD1P614572EBI-77613,EBI-740475
PCOLCEQ151133EBI-821758,EBI-8869614
PDIA3P301013EBI-77613,EBI-979862
PIN1Q135262EBI-302641,EBI-714158
PRNPP041563EBI-77613,EBI-977302
PSEN1P497686EBI-77613,EBI-297277
SHC1P293535EBI-77613,EBI-78835
SHC3Q925292EBI-77613,EBI-79084
SLC40A1Q9NP594EBI-77613,EBI-725153
Slc5a7Q8BGY92EBI-77613,EBI-2010752From a different organism.
SPON1Q9HCB63EBI-302641,EBI-2431846
TGFB1P011372EBI-77613,EBI-779636
TGFB2P618126EBI-77613,EBI-779581
TNFRSF21O755093EBI-77613,EBI-2313231
TP53BP2Q136253EBI-77613,EBI-77642

Protein-protein interaction databases

BioGridi106848. 1971 interactions.
DIPiDIP-574N.
IntActiP05067. 113 interactions.
MINTiMINT-150767.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi33 – 353
Beta strandi43 – 453
Turni47 – 493
Beta strandi52 – 543
Helixi66 – 7611
Beta strandi82 – 876
Beta strandi92 – 943
Beta strandi97 – 993
Helixi100 – 1023
Beta strandi103 – 1064
Beta strandi110 – 1123
Beta strandi115 – 1195
Beta strandi134 – 1396
Helixi147 – 16014
Beta strandi163 – 17412
Turni175 – 1773
Beta strandi178 – 18811
Helixi288 – 2925
Beta strandi299 – 3013
Beta strandi304 – 3107
Turni311 – 3144
Beta strandi315 – 3217
Beta strandi323 – 3253
Beta strandi331 – 3333
Helixi334 – 3418
Helixi374 – 3807
Helixi389 – 41830
Beta strandi421 – 4233
Helixi425 – 48056
Beta strandi482 – 4843
Helixi487 – 51832
Helixi520 – 54627
Helixi547 – 5504
Helixi552 – 56615
Helixi673 – 6753
Beta strandi679 – 6824
Beta strandi683 – 6853
Beta strandi688 – 6914
Helixi695 – 6973
Beta strandi698 – 7003
Beta strandi702 – 7054
Beta strandi707 – 7126
Helixi744 – 75411
Beta strandi755 – 7584
Beta strandi763 – 7653

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1AAPX-ray1.50A/B287-344[»]
1AMBNMR-A672-699[»]
1AMCNMR-A672-699[»]
1AMLNMR-A672-711[»]
1BA4NMR-A672-711[»]
1BA6NMR-A672-711[»]
1BJBNMR-A672-699[»]
1BJCNMR-A672-699[»]
1BRCX-ray2.50I287-342[»]
1CA0X-ray2.10D/I289-342[»]
1HZ3NMR-A681-706[»]
1IYTNMR-A672-713[»]
1MWPX-ray1.80A28-123[»]
1OWTNMR-A124-189[»]
1QCMNMR-A696-706[»]
1QWPNMR-A696-706[»]
1QXCNMR-A696-706[»]
1QYTNMR-A696-706[»]
1TAWX-ray1.80B287-344[»]
1TKNNMR-A460-569[»]
1UO7model-A672-713[»]
1UO8model-A672-713[»]
1UOAmodel-A672-713[»]
1UOImodel-A672-713[»]
1X11X-ray2.50C/D754-766[»]
1Z0QNMR-A672-713[»]
1ZE7NMR-A672-687[»]
1ZE9NMR-A672-687[»]
1ZJDX-ray2.60B289-344[»]
2BEGNMR-A/B/C/D/E672-713[»]
2BOMmodel-A/B681-713[»]
2BP4NMR-A672-687[»]
2FJZX-ray1.61A133-189[»]
2FK1X-ray1.60A133-189[»]
2FK2X-ray1.65A133-189[»]
2FK3X-ray2.40A/B/C/D/E/F/G/H133-189[»]
2FKLX-ray2.50A/B124-189[»]
2FMAX-ray0.85A133-189[»]
2G47X-ray2.10C/D672-711[»]
2IPUX-ray1.65P/Q672-679[»]
2LFMNMR-A672-711[»]
2LLMNMR-A686-726[»]
2LMNNMR-A/B/C/D/E/F/G/H/I/J/K/L672-711[»]
2LMONMR-A/B/C/D/E/F/G/H/I/J/K/L672-711[»]
2LMPNMR-A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R672-711[»]
2LMQNMR-A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R672-711[»]
2LNQNMR-A/B/C/D/E/F/G/H672-711[»]
2LOHNMR-A/B686-726[»]
2LP1NMR-A671-770[»]
2LZ3NMR-A/B699-726[»]
2LZ4NMR-A/B699-726[»]
2M4JNMR-A/B/C/D/E/F/G/H/I672-711[»]
2M9RNMR-A672-711[»]
2M9SNMR-A672-711[»]
2OTKNMR-C672-711[»]
2R0WX-ray2.50Q672-679[»]
2WK3X-ray2.59C/D672-713[»]
2Y29X-ray2.30A687-692[»]
2Y2AX-ray1.91A687-692[»]
2Y3JX-ray1.99A/B/C/D/E/F/G/H701-706[»]
2Y3KX-ray1.90A/B/C/D/E/F/G/H706-713[»]
2Y3LX-ray2.10A/B/C/G706-713[»]
3AYUX-ray2.00B586-595[»]
3BAEX-ray1.59A672-699[»]
3BKJX-ray1.59A672-687[»]
3DXCX-ray2.10B/D739-770[»]
3DXDX-ray2.20B/D739-770[»]
3DXEX-ray2.00B/D739-770[»]
3GCIX-ray2.04P707-713[»]
3IFLX-ray1.50P672-678[»]
3IFNX-ray1.50P672-711[»]
3IFOX-ray2.15P/Q672-678[»]
3IFPX-ray2.95P/Q/R/S672-678[»]
3JQ5X-ray2.03B672-679[»]
3JQLX-ray1.20B687-692[»]
3JTIX-ray1.80B699-706[»]
3KTMX-ray2.70A/B/C/D/E/F/G/H18-190[»]
3L33X-ray2.48E/F/G/H290-341[»]
3L81X-ray1.60B761-767[»]
3MOQX-ray2.05A/B/C/D689-712[»]
3MXCX-ray2.00L754-762[»]
3MXYX-ray2.30L754-762[»]
3NYJX-ray3.20A365-567[»]
3NYLX-ray2.80A365-570[»]
3OVJX-ray1.80A/B/C/D687-692[»]
3OW9X-ray1.80A/B687-692[»]
3SV1X-ray3.30D/E/F754-767[»]
3U0TX-ray2.50E/F701-711[»]
3UMHX-ray2.00A370-575[»]
3UMIX-ray2.40A370-575[»]
3UMKX-ray2.60A370-575[»]
4HIXX-ray2.20A672-699[»]
4MDRX-ray1.85B758-767[»]
4NGEX-ray2.70B/E672-711[»]
4ONFX-ray2.00P672-678[»]
4ONGX-ray2.20P672-711[»]
ProteinModelPortaliP05067.
SMRiP05067. Positions 26-192, 287-342, 385-567, 683-728, 741-768.

Miscellaneous databases

EvolutionaryTraceiP05067.

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
Add
BLAST
Regioni181 – 1888Zinc-binding
Regioni391 – 42333Heparin-binding
Add
BLAST
Regioni491 – 52232Heparin-binding
Add
BLAST
Regioni523 – 54018Collagen-binding
Add
BLAST
Regioni732 – 75120Interaction with G(o)-alpha
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.7 Publications
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.7 Publications

Sequence similaritiesi

Belongs to the APP family.

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG289770.
HOVERGENiHBG000051.
InParanoidiP05067.
KOiK04520.
OMAiTHAHIVI.
OrthoDBiEOG7RNJZP.
PhylomeDBiP05067.
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 (11)i

Sequence statusi: Complete.

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

This entry describes 11 isoformsi produced by alternative splicing. Align

Note: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.

Isoform APP770 (identifier: P05067-1) [UniParc]FASTAAdd to Basket

Also known as: PreA4 770

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

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG    50
KWDSDPSGTK TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR 100
GRKQCKTHPH FVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW 150
HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDNVDSAD 200
AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE EADDDEDDED 250
GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC 300
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL 350
KTTQEPLARD PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA 400
KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER 450
QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPRHV FNMLKKYVRA 500
EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN 550
VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET 600
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL 650
TTRPGSGLTN IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG 700
AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS 750
KMQQNGYENP TYKFFEQMQN 770

Note: A major isoform.

Length:770
Mass (Da):86,943
Last modified:November 1, 1991 - v3
Checksum:iA12EE761403740F5
GO
Isoform APP305 (identifier: P05067-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     290-305: VCSEQAETGPCRAMIS → KWYKEVHSGQARWLML
     306-770: Missing.

Show »
Length:305
Mass (Da):34,358
Checksum:iD1CCD7237262687A
GO
Isoform L-APP677 (identifier: P05067-3) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-364: Missing.
     637-654: Missing.

Note: The L-isoforms are referred to as appicans.

Show »
Length:677
Mass (Da):76,760
Checksum:i48334D3EEF26990E
GO
Isoform APP695 (identifier: P05067-4) [UniParc]FASTAAdd to Basket

Also known as: PreA4 695

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

Note: A major isoform.

Show »
Length:695
Mass (Da):78,663
Checksum:i4F6EA0139F969D56
GO
Isoform L-APP696 (identifier: P05067-5) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-345: Missing.
     637-654: Missing.

Note: The L-isoforms are referred to as appicans.

Show »
Length:696
Mass (Da):78,866
Checksum:i66DFDFFCFDB75A72
GO
Isoform APP714 (identifier: P05067-6) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-345: Missing.

Show »
Length:714
Mass (Da):80,769
Checksum:i124EA691773DC13B
GO
Isoform L-APP733 (identifier: P05067-7) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     345-345: M → I
     346-364: Missing.
     637-654: Missing.

Note: The L-isoforms are referred to as appicans.

Show »
Length:733
Mass (Da):82,916
Checksum:i44528239D68A53EE
GO
Isoform APP751 (identifier: P05067-8) [UniParc]FASTAAdd to Basket

Also known as: PreA4 751

The sequence of this isoform differs from the canonical sequence as follows:
     345-345: M → I
     346-364: Missing.

Note: A major isoform.

Show »
Length:751
Mass (Da):84,819
Checksum:iC987C557C5A3714E
GO
Isoform L-APP752 (identifier: P05067-9) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     637-654: Missing.

Show »
Length:752
Mass (Da):85,040
Checksum:i074CFF767CBED2E0
GO
Isoform APP639 (identifier: P05067-10) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     19-74: Missing.
     289-363: Missing.
     364-364: L → V

Show »
Length:639
Mass (Da):72,553
Checksum:iC4120DEC51A59A95
GO
Isoform 11 (identifier: P05067-11) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-19: MLPGLALLLLAAWTARALE → MDQLEDLLVLFINY
     345-364: MSQSLLKTTQEPLARDPVKL → I

Show »
Length:746
Mass (Da):84,521
Checksum:i843411EFBDEFACE3
GO

Sequence cautioni

The sequence AAA58727.1 differs from that shown. Reason: Contamination by an Alu repeat.

Mass spectrometryi

Molecular mass is 6461.6 Da from positions 712 - 767. Determined by MALDI. 1 Publication
Molecular mass is 6451.6 Da from positions 714 - 770. Determined by MALDI. 1 Publication
Molecular mass is 6436.8 Da from positions 715 - 769. Determined by MALDI. 1 Publication
Molecular mass is 5752.5 Da from positions 719 - 767. Determined by MALDI. 1 Publication

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti501 – 5011E → K.1 Publication
Corresponds to variant rs45588932 [ dbSNP | Ensembl ].
VAR_022315
Natural varianti665 – 6651E → D in a patient with late onset Alzheimer disease. 1 Publication
VAR_010107
Natural varianti670 – 6712KM → NL in AD1.
VAR_000015
Natural varianti678 – 6781D → N in AD1. 1 Publication
VAR_044424
Natural varianti692 – 6921A → G in AD1; Flemish mutation; increases the solubility of processed beta-amyloid peptides and increases the stability of peptide oligomers. 3 Publications
VAR_000016
Natural varianti693 – 6931E → G in AD1. 2 Publications
VAR_014215
Natural varianti693 – 6931E → K in CAA-APP; Italian type.
VAR_014216
Natural varianti693 – 6931E → Q in CAA-APP; Dutch type. 1 Publication
VAR_000017
Natural varianti694 – 6941D → N in CAA-APP; Iowa type. 2 Publications
VAR_014217
Natural varianti705 – 7051L → V in CAA-APP; Italian type. 1 Publication
VAR_032276
Natural varianti713 – 7131A → T in AD1. 2 Publications
VAR_000019
Natural varianti713 – 7131A → V in one chronic schizophrenia patient; unknown pathological significance. 1 Publication
Corresponds to variant rs1800557 [ dbSNP | Ensembl ].
VAR_000018
Natural varianti714 – 7141T → A in AD1. 1 Publication
VAR_032277
Natural varianti714 – 7141T → I in AD1; increased beta-APP42/beta-APP40 ratio. 2 Publications
VAR_014218
Natural varianti715 – 7151V → M in AD1; decreased beta-APP40/total APP-beta. 1 Publication
VAR_010108
Natural varianti716 – 7161I → V in AD1. 1 Publication
VAR_000020
Natural varianti717 – 7171V → F in AD1. 4 Publications
VAR_000023
Natural varianti717 – 7171V → G in AD1. 2 Publications
VAR_000022
Natural varianti717 – 7171V → I in AD1. 7 Publications
VAR_000021
Natural varianti717 – 7171V → L in AD1. 1 Publication
VAR_014219
Natural varianti723 – 7231L → P in AD1. 1 Publication
VAR_010109

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 1919MLPGL…ARALE → MDQLEDLLVLFINY in isoform 11.
VSP_045446Add
BLAST
Alternative sequencei19 – 7456Missing in isoform APP639.
VSP_009116Add
BLAST
Alternative sequencei289 – 36375Missing in isoform APP639.
VSP_009117Add
BLAST
Alternative sequencei289 – 2891E → V in isoform APP695, isoform L-APP696, isoform L-APP677 and isoform APP714.
VSP_000002
Alternative sequencei290 – 36475Missing in isoform APP695 and isoform L-APP677.
VSP_000004Add
BLAST
Alternative sequencei290 – 34556Missing in isoform L-APP696 and isoform APP714.
VSP_000003Add
BLAST
Alternative sequencei290 – 30516VCSEQ…RAMIS → KWYKEVHSGQARWLML in isoform APP305.
VSP_000005Add
BLAST
Alternative sequencei306 – 770465Missing in isoform APP305.
VSP_000006Add
BLAST
Alternative sequencei345 – 36420MSQSL…DPVKL → I in isoform 11.
VSP_045447Add
BLAST
Alternative sequencei345 – 3451M → I in isoform L-APP733 and isoform APP751.
VSP_000007
Alternative sequencei346 – 36419Missing in isoform L-APP733 and isoform APP751.
VSP_000008Add
BLAST
Alternative sequencei364 – 3641L → V in isoform APP639.
VSP_009118
Alternative sequencei637 – 65418Missing in isoform L-APP677, isoform L-APP696, isoform L-APP733 and isoform L-APP752.
VSP_000009Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti15 – 162AR → VW in CAA31830. 1 Publication
Sequence conflicti647 – 6471D → E in AAA51722. 1 Publication
Sequence conflicti724 – 7241Missing in AAB26263. 1 Publication
Sequence conflicti724 – 7241Missing in AAB26264. 1 Publication
Sequence conflicti731 – 7311I → N in AAB26263. 1 Publication
Sequence conflicti731 – 7311I → N in AAB26264. 1 Publication
Sequence conflicti731 – 7311I → N in AAB26265. 1 Publication
Sequence conflicti757 – 7571Y → S in AAA35540. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
Y00264 mRNA. Translation: CAA68374.1.
X13466
, X13467, X13468, X13469, X13470, X13471, X13472, X13473, X13474, X13475, X13476, X13477, X13478, X13479, X13487, X13488 Genomic DNA. Translation: CAA31830.1.
X06989 mRNA. Translation: