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Protein

Amyloid beta A4 protein

Gene

APP

Organism
Saimiri sciureus (Common squirrel monkey)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript 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 (By similarity). 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 (By similarity). May be 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 (By similarity). 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. 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 (By similarity).By similarity
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 bond2
Metal bindingi658Copper or zinc 2By similarity1
Metal bindingi662Copper or zinc 2By similarity1
Metal bindingi665Copper or zinc 2By similarity1
Metal bindingi666Copper or zinc 2By similarity1
Sitei685Implicated in free radical propagationBy similarity1

GO - Molecular functioni

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

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
Amyloid precursor proteinCurated
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
OrganismiSaimiri sciureus (Common squirrel monkey)
Taxonomic identifieri9521 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniPlatyrrhiniCebidaeSaimiriinaeSaimiri

Subcellular locationi

  • Membrane By similarity; Single-pass type I membrane protein By similarity
  • 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 is located to both the cytoplasm and nuclei of neurons. Associates with GPC1 in perinuclear compartments (By similarity).By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini18 – 680ExtracellularSequence analysisAdd BLAST663
Transmembranei681 – 704HelicalSequence analysisAdd BLAST24
Topological domaini705 – 751CytoplasmicSequence analysisAdd BLAST47

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Amyloid, Coated pit, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 17By similarityAdd BLAST17
ChainiPRO_000000017218 – 751Amyloid beta A4 proteinAdd BLAST734
ChainiPRO_000000017318 – 668Soluble APP-alphaSequence analysisAdd BLAST651
ChainiPRO_000000017418 – 652Soluble APP-betaSequence analysisAdd BLAST635
ChainiPRO_000038197218 – 286N-APPBy similarityAdd BLAST269
ChainiPRO_0000000175653 – 751C99Sequence analysisAdd BLAST99
ChainiPRO_0000000176653 – 694Beta-amyloid protein 42Sequence analysisAdd BLAST42
ChainiPRO_0000000177653 – 692Beta-amyloid protein 40Sequence analysisAdd BLAST40
ChainiPRO_0000000178669 – 751C83Sequence analysisAdd BLAST83
PeptideiPRO_0000000179669 – 694P3(42)Sequence analysisAdd BLAST26
PeptideiPRO_0000000180669 – 692P3(40)Sequence analysisAdd BLAST24
ChainiPRO_0000384580672 – 751C80Add BLAST80
ChainiPRO_0000000181693 – 751Gamma-secretase C-terminal fragment 59Sequence analysisAdd BLAST59
ChainiPRO_0000000182695 – 751Gamma-secretase C-terminal fragment 57Sequence analysisAdd BLAST57
ChainiPRO_0000000183702 – 751Gamma-secretase C-terminal fragment 50Sequence analysisAdd BLAST50
ChainiPRO_0000000184721 – 751C31Sequence analysisAdd 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 CK1 and CK2By similarity1
Modified residuei206Phosphoserine; by CK1 and CK2By similarity1
Disulfide bondi291 ↔ 341PROSITE-ProRule annotation
Disulfide bondi300 ↔ 324PROSITE-ProRule annotation
Disulfide bondi316 ↔ 337PROSITE-ProRule annotation
Modified residuei422PhosphoserineBy similarity1
Modified residuei478PhosphotyrosineBy similarity1
Glycosylationi523N-linked (GlcNAc...)Curated1
Glycosylationi552N-linked (GlcNAc...)Curated1
Modified residuei710PhosphothreonineBy similarity1
Modified residuei711Phosphoserine; by APP-kinase IBy similarity1
Modified residuei724Phosphothreonine; by CDK5 and MAPK10By similarity1
Modified residuei738Phosphotyrosine; by ABL1By similarity1
Cross-linki744Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity

Post-translational modificationi

Proteolytically processed under normal cellular conditions. Cleavage either by alpha-secretase, beta-secretase or theta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, and the retention of corresponding membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent processing of C80 and C83 by gamma-secretase yields P3 peptides. This is the major secretory pathway and is non-amyloidogenic. Alternatively, presenilin/nicastrin-mediated gamma-secretase processing of C99 releases the amyloid beta proteins, amyloid-beta 40 (Abeta40) and amyloid-beta 42 (Abeta42), major components of amyloid plaques, and the cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59) (By similarity).By similarity
Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-720 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- 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 (By similarity).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
Sitei652 – 653Cleavage; by beta-secretaseBy similarity2
Sitei653 – 654Cleavage; by caspase-6By similarity2
Sitei668 – 669Cleavage; by alpha-secretaseBy similarity2
Sitei671 – 672Cleavage; by theta-secretaseBy similarity2
Sitei692 – 693Cleavage; by gamma-secretase; site 1By similarity2
Sitei694 – 695Cleavage; by gamma-secretase; site 2By similarity2
Sitei701 – 702Cleavage; by gamma-secretase; site 3By similarity2
Sitei720 – 721Cleavage; by caspase-6, caspase-8 or caspase-9By similarity2

Keywords - PTMi

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

Interactioni

Subunit structurei

Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, and SHC1, NUMB and DAB1 (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Binding to Dab1 inhibits its serine phosphorylation (By similarity). 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 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 VDAC1 (By similarity).By similarity

Protein-protein interaction databases

MINTiMINT-1513021.

Structurei

3D structure databases

ProteinModelPortaliQ95241.
ModBaseiSearch...
MobiDBiSearch...

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
Regioni181 – 188Zinc-bindingBy similarity8
Regioni316 – 344Heparin-bindingBy similarityAdd BLAST29
Regioni363 – 428Heparin-bindingBy similarityAdd BLAST66
Regioni504 – 521Collagen-bindingBy similarityAdd BLAST18
Regioni713 – 732Interaction with G(o)-alphaBy similarityAdd BLAST20

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi705 – 715Basolateral sorting signalBy similarityAdd BLAST11
Motifi740 – 743NPXY 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.By similarity
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).By similarity

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

HOVERGENiHBG000051.

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 (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.
Isoform APP770 (identifier: Q95241-1) [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
MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG
60 70 80 90 100
KWDSDPSGTK TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR
110 120 130 140 150
DRKQCKTHPH IVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW
160 170 180 190 200
HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDHVDSAD
210 220 230 240 250
AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE EADDDEDDED
260 270 280 290 300
GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
310 320 330 340 350
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVIPTTAA
360 370 380 390 400
STPDAVDKYL ETPGDENEHA HFQKAKERLE AKHRERMSQV MREWEEAERQ
410 420 430 440 450
AKNLPKADKK AVIQHFQEKV ESLEQEAANE RQQLVETHMA RVEAMLNDRR
460 470 480 490 500
RLALENYITA LQAVPPRPRH VFNMLKKYVR AEQKDRQHTL KHFEHVRMVD
510 520 530 540 550
PKKAAQIRSQ VMTHLRVIYE RMNQSLSLLY NVPAVAEEIQ DEVDELLQKE
560 570 580 590 600
QNYSDDVLAN MISEPRISYG NDALMPSLTE TKTTVELLPV NGEFSLDDLQ
610 620 630 640 650
PWHSFGADSV PANTENEVEP VDARPAADRG LTTRPGSGLT NIKTEEISEV
660 670 680 690 700
KMDAEFRHDS GYEVHHQKLV FFAEDVGSNK GAIIGLMVGG VVIATVIVIT
710 720 730 740 750
LVMLKKKQYT SIHHGVVEVD AAVTPEERHL SKMQQNGYEN PTYKFFEQMQ

N
Length:751
Mass (Da):84,894
Last modified:February 1, 1997 - v1
Checksum:i6C3E431089569049
GO
Isoform APP695 (identifier: Q95241-2)
Sequence is not available
Length:
Mass (Da):

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S81024 mRNA. Translation: AAD14347.1.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
S81024 mRNA. Translation: AAD14347.1.

3D structure databases

ProteinModelPortaliQ95241.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

MINTiMINT-1513021.

Protein family/group databases

MEROPSiI02.015.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Phylogenomic databases

HOVERGENiHBG000051.

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_SAISC
AccessioniPrimary (citable) accession number: Q95241
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: February 1, 1997
Last modified: October 5, 2016
This is version 136 of the entry and version 1 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. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding.By similarity

Documents

  1. 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.