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Protein

Amyloid beta A4 protein

Gene

APP

Organism
Cavia porcellus (Guinea pig)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP (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 (By similarity). 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 (By similarity).By similarity
Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. 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. Also bind GPC1 in lipid rafts (By similarity).By similarity
Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain.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 bondBy similarity2
Metal bindingi677Copper or zinc 2By similarity1
Metal bindingi681Copper or zinc 2By similarity1
Metal bindingi684Copper or zinc 2By similarity1
Metal bindingi685Copper or zinc 2By similarity1
Sitei704Implicated 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 13 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)
Gene namesi
Name:APP
OrganismiCavia porcellus (Guinea pig)
Taxonomic identifieri10141 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaHystricognathiCaviidaeCavia
Proteomesi
  • UP000005447 Componenti: Unassembled WGS sequence

Subcellular locationi

  • Membrane By similarity; Single-pass type I membrane protein By similarity
  • Membraneclathrin-coated pit By similarity

  • Note: Cell surface protein that rapidly becomes internalized via clathrin-coated pits (By similarity). During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves to the Golgi complex where complete maturation occurs (O-glycosylated and sulfated) (By similarity). After alpha-secretase cleavage, soluble APP is released into the extracellular space and the C-terminal is internalized to endosomes and lysomes Some APP accumulates in secretory transport vesicles leaving the late Golgi compartment and returns to the cell surface. APP sorts to the basolateral surface in epithelial cells. Associates with GPC1 in perinuclear compartments (By similarity).By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini18 – 699ExtracellularSequence analysisAdd BLAST682
Transmembranei700 – 723HelicalSequence analysisAdd BLAST24
Topological domaini724 – 770CytoplasmicSequence 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_000000007618 – 770Amyloid beta A4 proteinAdd BLAST753
ChainiPRO_000000007718 – 687Soluble APP-alphaBy similarityAdd BLAST670
ChainiPRO_000000007818 – 671Soluble APP-betaBy similarityAdd BLAST654
ChainiPRO_000038196518 – 286N-APPBy similarityAdd BLAST269
ChainiPRO_0000000079672 – 770CTF-alphaBy similarityAdd BLAST99
ChainiPRO_0000000080672 – 713Beta-amyloid protein 42By similarityAdd BLAST42
ChainiPRO_0000000081672 – 711Beta-amyloid protein 40By similarityAdd BLAST40
ChainiPRO_0000000082688 – 770CTF-betaBy similarityAdd BLAST83
PeptideiPRO_0000000083688 – 713P3(42)By similarityAdd BLAST26
PeptideiPRO_0000000084688 – 711P3(40)By similarityAdd BLAST24
ChainiPRO_0000384573691 – 770C80Add BLAST80
ChainiPRO_0000000085712 – 770Gamma-secretase C-terminal fragment 59By similarityAdd BLAST59
ChainiPRO_0000000086714 – 770Gamma-secretase C-terminal fragment 57By similarityAdd BLAST57
ChainiPRO_0000000087740 – 770C31By similarityAdd BLAST31

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi38 ↔ 62PROSITE-ProRule annotation
Disulfide bondi73 ↔ 117PROSITE-ProRule annotation
Disulfide bondi98 ↔ 105PROSITE-ProRule annotation
Disulfide bondi133 ↔ 187PROSITE-ProRule annotation
Disulfide bondi144 ↔ 174PROSITE-ProRule annotation
Disulfide bondi158 ↔ 186PROSITE-ProRule annotation
Modified residuei198Phosphoserine; by CK2By similarity1
Modified residuei206Phosphoserine; by CK1By similarity1
Disulfide bondi291 ↔ 341PROSITE-ProRule annotation
Disulfide bondi300 ↔ 324PROSITE-ProRule annotation
Disulfide bondi316 ↔ 337PROSITE-ProRule annotation
Modified residuei441PhosphoserineBy similarity1
Modified residuei497PhosphotyrosineBy similarity1
Glycosylationi542N-linked (GlcNAc...)Sequence analysis1
Glycosylationi571N-linked (GlcNAc...)Sequence analysis1
Glycosylationi656O-linked (Xyl...) (chondroitin sulfate)By similarity1
Modified residuei729PhosphothreonineBy similarity1
Modified residuei730Phosphoserine; by APP-kinase IBy similarity1
Modified residuei743Phosphothreonine; by CDK5 and MAPK10By similarity1
Modified residuei757Phosphotyrosine; by ABL1By similarity1
Cross-linki763Glycyl 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 caspase-3 during neuronal apoptosis.By similarity
N- and O-glycosylated. O-linkage of chondroitin sulfate to the L-APP isoforms produces the APP proteoglycan core proteins, the appicans (By similarity).By similarity
Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific (By similarity). Phosphorylation can affect APP processing, neuronal differentiation and interaction with other proteins.By similarity2 Publications
Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond.By similarity
Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP).By similarity
Beta-amyloid peptides are degraded by IDE.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei671 – 672Cleavage; by beta-secretaseBy similarity2
Sitei672 – 673Cleavage; by caspase-6By similarity2
Sitei687 – 688Cleavage; by alpha-secretaseBy similarity2
Sitei690 – 691Cleavage; by theta-secretaseBy similarity2
Sitei713 – 714Cleavage; by gamma-secretaseBy similarity2
Sitei739 – 740Cleavage; by caspase-3By similarity2

Keywords - PTMi

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

Expressioni

Tissue specificityi

Isoform APP695 is the major isoform found in brain. The longer isoforms containing the BPTI domain are predominantly expressed in peripheral organs such as muscle and liver.

Inductioni

Increased levels during neuronal differentiation.

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. CTF-alpha product of APP interacts with GSAP (By similarity). Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-like protein BPP, FPRL1, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via BaSS) and DDB1 (By similarity). Associates with microtubules in the presence of ATP and in a kinesin-dependent manner (By similarity). Soluble Abeta40 binds all three isoforms of APOE, in vitro and in vivo. When lipidated, ApoE3 appears to be the preferred amyloid binding isoform, while the apoE4 isoform-beta-APP40 complex is capable of being transported across the blood-brain barrier. 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). Interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity).By similarity

Protein-protein interaction databases

STRINGi10141.ENSCPOP00000001291.

Structurei

3D structure databases

ProteinModelPortaliQ60495.
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
Regioni135 – 155Copper-bindingBy similarityAdd BLAST21
Regioni181 – 188Zinc-bindingBy similarity8
Regioni391 – 423Heparin-bindingBy similarityAdd BLAST33
Regioni491 – 522Heparin-bindingBy similarityAdd BLAST32
Regioni523 – 540Collagen-bindingBy similarityAdd BLAST18
Regioni732 – 751Interaction with G(o)-alphaBy similarityAdd BLAST20

Motif

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

Compositional bias

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

Domaini

The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells.
The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain. However, additional amino acids either N- or C-terminal to the NPXY motif are often required for complete interaction. The PID domain-containing proteins which bind APP require the YENPTY motif for full interaction. These interactions are independent of phosphorylation on the terminal tyrosine residue (By similarity). The NPXY site is also involved in clathrin-mediated endocytosis.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

eggNOGiKOG3540. Eukaryota.
ENOG410ZTKC. LUCA.
HOGENOMiHOG000232190.
HOVERGENiHBG000051.
InParanoidiQ60495.

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, missing exons 7,8 and 15, seem to exist. The L-isoforms, missing exon 15, are referred to as appicans.
Isoform APP770 (identifier: Q60495-1) [UniParc]FASTAAdd to basket

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

« Hide

        10         20         30         40         50
MLPSLALLLL TTWTARALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG
60 70 80 90 100
KWEPDPSGTK TCIGSKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR
110 120 130 140 150
SRKQCKTHPH FVIPYRCLVG EFVSDALLVP DKCKFLHQER MDVCETHLHW
160 170 180 190 200
HTVAKETCSE KSTNLHDYGM LLPCGIDKFR GVEFVCCPLA EESDNIDSAD
210 220 230 240 250
AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVADVEEE EADDDEDVED
260 270 280 290 300
GDEVEEEAEE PYEEATEKTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
310 320 330 340 350
RSMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVMSQNLL
360 370 380 390 400
KTSGEPVSQG PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA
410 420 430 440 450
KHRERMSQVM REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER
460 470 480 490 500
QQLVETHMAR VEAMLNDRRR LALENYITAL QAVPPRPRHV FNMLKKYVRA
510 520 530 540 550
EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER MNQSLSLLYN
560 570 580 590 600
VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
610 620 630 640 650
KTTVELLPVN GEFSLDDLQP WHPFGVDSVP ANTENEVEPV DARPAADRGL
660 670 680 690 700
TTRPGSGLTN IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG
710 720 730 740 750
AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS
760 770
KMQQNGYENP TYKFFEQMQN
Length:770
Mass (Da):86,883
Last modified:April 23, 2003 - v2
Checksum:i0AFD36C90F0D8B6C
GO
Isoform APP695 (identifier: Q60495-2) [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):78,701
Checksum:i5196A0C4017F16AB
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_007221289E → V in isoform APP695. Curated1
Alternative sequenceiVSP_007222290 – 364Missing in isoform APP695. CuratedAdd BLAST75

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X97631 mRNA. Translation: CAA66230.1.
X99198 mRNA. Translation: CAA67589.1.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X97631 mRNA. Translation: CAA66230.1.
X99198 mRNA. Translation: CAA67589.1.

3D structure databases

ProteinModelPortaliQ60495.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10141.ENSCPOP00000001291.

Protein family/group databases

MEROPSiI02.015.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Phylogenomic databases

eggNOGiKOG3540. Eukaryota.
ENOG410ZTKC. LUCA.
HOGENOMiHOG000232190.
HOVERGENiHBG000051.
InParanoidiQ60495.

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_CAVPO
AccessioniPrimary (citable) accession number: Q60495
Secondary accession number(s): Q60496
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 23, 2003
Last sequence update: April 23, 2003
Last modified: October 5, 2016
This is version 134 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates.

Keywords - Technical termi

Complete proteome, Reference proteome

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.