A4_FELCA
ID A4_FELCA Reviewed; 40 AA.
AC P86906;
DT 31-OCT-2012, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2012, sequence version 1.
DT 03-AUG-2022, entry version 47.
DE RecName: Full=Amyloid-beta precursor protein {ECO:0000250|UniProtKB:P05067};
DE AltName: Full=ABPP {ECO:0000250|UniProtKB:P05067};
DE Short=APP {ECO:0000250|UniProtKB:P05067};
DE AltName: Full=Alzheimer disease amyloid A4 protein homolog;
DE AltName: Full=Amyloid precursor protein {ECO:0000305};
DE AltName: Full=Amyloid-beta (A4) precursor protein {ECO:0000250|UniProtKB:P12023};
DE AltName: Full=Amyloid-beta A4 protein;
DE Contains:
DE RecName: Full=Amyloid-beta protein 40 {ECO:0000303|PubMed:22576872};
DE Short=Abeta40;
DE AltName: Full=Beta-APP40 {ECO:0000250|UniProtKB:P05067};
DE Flags: Fragment;
GN Name=APP {ECO:0000250|UniProtKB:P05067};
OS Felis catus (Cat) (Felis silvestris catus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Feliformia; Felidae; Felinae; Felis.
OX NCBI_TaxID=9685;
RN [1] {ECO:0000305}
RP PROTEIN SEQUENCE, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid {ECO:0000269|PubMed:22576872};
RX PubMed=22576872; DOI=10.1002/jms.2987;
RA Brinkmalm G., Portelius E., Ohrfelt A., Mattsson N., Persson R.,
RA Gustavsson M.K., Vite C.H., Gobom J., Mansson J.E., Nilsson J., Halim A.,
RA Larson G., Ruetschi U., Zetterberg H., Blennow K., Brinkmalm A.;
RT "An online nano-LC-ESI-FTICR-MS method for comprehensive characterization
RT of endogenous fragments from amyloid beta and amyloid precursor protein in
RT human and cat cerebrospinal fluid.";
RL J. Mass Spectrom. 47:591-603(2012).
CC -!- FUNCTION: Functions as a cell surface receptor and performs
CC physiological functions on the surface of neurons relevant to neurite
CC growth, neuronal adhesion and axonogenesis. Interaction between APP
CC molecules on neighboring cells promotes synaptogenesis. Involved in
CC cell mobility and transcription regulation through protein-protein
CC interactions (By similarity). Can promote transcription activation
CC through binding to APBB1-KAT5 and inhibit Notch signaling through
CC interaction with Numb (By similarity). Couples to apoptosis-inducing
CC pathways such as those mediated by G(o) and JIP (By similarity).
CC Inhibits G(o)-alpha ATPase activity (By similarity). Acts as a kinesin
CC I membrane receptor, mediating the axonal transport of beta-secretase
CC and presenilin 1 (By similarity). May be involved in copper
CC homeostasis/oxidative stress through copper ion reduction (By
CC similarity). In vitro, copper-metallated APP induces neuronal death
CC directly or is potentiated through Cu(2+)-mediated low-density
CC lipoprotein oxidation (By similarity). Can regulate neurite outgrowth
CC through binding to components of the extracellular matrix such as
CC heparin and collagen I and IV. Induces a AGER-dependent pathway that
CC involves activation of p38 MAPK, resulting in internalization of
CC amyloid-beta peptide and mitochondrial dysfunction in cultured cortical
CC neurons. Provides Cu(2+) ions for GPC1 which are required for release
CC of nitric oxide (NO) and subsequent degradation of the heparan sulfate
CC chains on GPC1 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P05067}.
CC -!- SUBUNIT: Binds, via its C-terminus, to the PID domain of several
CC cytoplasmic proteins, including APBB family members, the APBA family,
CC MAPK8IP1, SHC1 and NUMB and DAB1 (By similarity). Binding to DAB1
CC inhibits its serine phosphorylation (By similarity). Interacts (via
CC NPXY motif) with DAB2 (via PID domain); the interaction is impaired by
CC tyrosine phosphorylation of the NPXY motif. Also interacts with GPCR-
CC like protein BPP, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via
CC BaSS) and DDB1. In vitro, it binds MAPT via the MT-binding domains (By
CC similarity). Associates with microtubules in the presence of ATP and in
CC a kinesin-dependent manner (By similarity). Interacts, through a C-
CC terminal domain, with GNAO1. Interacts with CPEB1, ANKS1B, TNFRSF21 and
CC AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C.
CC Interacts with IDE. Can form homodimers; dimerization is enhanced in
CC the presence of Cu(2+) ions. Can form homodimers; this is promoted by
CC heparin binding (By similarity). Interacts with SORL1 (via N-terminal
CC ectodomain); this interaction retains APP in the trans-Golgi network
CC and reduces processing into soluble APP-alpha and amyloid-beta peptides
CC (By similarity). Interacts with PLD3 (By similarity). Interacts with
CC VDAC1 (By similarity). Interacts with NSG1; could regulate APP
CC processing (By similarity). Interacts with LRRK2 (By similarity).
CC Interacts (via cytoplasmic domain) with KIF5B (By similarity).
CC Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By
CC similarity). Interacts (via intracellular domain) with APBB3 (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:P05067,
CC ECO:0000250|UniProtKB:P12023}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P05067};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:P05067}.
CC Membrane {ECO:0000250|UniProtKB:P05067}; Single-pass type I membrane
CC protein {ECO:0000250|UniProtKB:P05067}. Perikaryon
CC {ECO:0000250|UniProtKB:P05067}. Cell projection, growth cone
CC {ECO:0000250|UniProtKB:P05067}. Membrane, clathrin-coated pit
CC {ECO:0000250|UniProtKB:P05067}. Early endosome
CC {ECO:0000250|UniProtKB:P05067}. Cytoplasmic vesicle
CC {ECO:0000250|UniProtKB:P05067}. Note=Cell surface protein that rapidly
CC becomes internalized via clathrin-coated pits. Only a minor proportion
CC is present at the cell membrane; most of the protein is present in
CC intracellular vesicles. During maturation, the immature APP (N-
CC glycosylated in the endoplasmic reticulum) moves to the Golgi complex
CC where complete maturation occurs (O-glycosylated and sulfated). After
CC alpha-secretase cleavage, soluble APP is released into the
CC extracellular space and the C-terminal is internalized to endosomes and
CC lysosomes. Some APP accumulates in secretory transport vesicles leaving
CC the late Golgi compartment and returns to the cell surface.
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- PTM: Proteolytically processed under normal cellular conditions.
CC Cleavage either by alpha-secretase, beta-secretase or theta-secretase
CC leads to generation and extracellular release of soluble APP peptides,
CC S-APP-alpha and S-APP-beta, and the retention of corresponding
CC membrane-anchored C-terminal fragments, C80, C83 and C99. Subsequent
CC processing of C80 and C83 by gamma-secretase yields P3 peptides. This
CC is the major secretory pathway and is non-amyloidogenic. Alternatively,
CC presenilin/nicastrin-mediated gamma-secretase processing of C99
CC releases the amyloid-beta proteins, amyloid-beta protein 40 and
CC amyloid-beta protein 42, major components of amyloid plaques, and the
CC cytotoxic C-terminal fragments, gamma-CTF(50), gamma-CTF(57) and gamma-
CC CTF(59). PSEN1 cleavage is more efficient with C83 than with C99 as
CC substrate (in vitro). Amyloid-beta protein 40 and Amyloid-beta protein
CC 42 are cleaved by ACE. Many other minor amyloid-beta peptides, amyloid-
CC beta 1-X peptides, are found in cerebral spinal fluid (CSF) including
CC the amyloid-beta X-15 peptides, produced from the cleavage by alpha-
CC secretase. {ECO:0000250|UniProtKB:P05067}.
CC -!- MASS SPECTROMETRY: [Amyloid-beta protein 40]: Mass=4341.336;
CC Mass_error=0.2; Method=MALDI; Evidence={ECO:0000269|PubMed:22576872};
CC -!- MASS SPECTROMETRY: [Amyloid-beta protein 40]: Mass=4341.1616;
CC Mass_error=0.0025; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:22576872};
CC -!- SIMILARITY: Belongs to the APP family. {ECO:0000255}.
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DR AlphaFoldDB; P86906; -.
DR BMRB; P86906; -.
DR STRING; 9685.ENSFCAP00000001445; -.
DR eggNOG; KOG3540; Eukaryota.
DR HOGENOM; CLU_014607_2_1_1; -.
DR InParanoid; P86906; -.
DR Proteomes; UP000011712; Unplaced.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IBA:GO_Central.
DR GO; GO:0005798; C:Golgi-associated vesicle; ISS:UniProtKB.
DR GO; GO:0030426; C:growth cone; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:InterPro.
DR GO; GO:0045121; C:membrane raft; IBA:GO_Central.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0030546; F:signaling receptor activator activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0007409; P:axonogenesis; IBA:GO_Central.
DR GO; GO:0007417; P:central nervous system development; IBA:GO_Central.
DR GO; GO:0050890; P:cognition; ISS:UniProtKB.
DR Gene3D; 4.10.230.10; -; 1.
DR InterPro; IPR008155; Amyloid_glyco.
DR InterPro; IPR013803; Amyloid_glyco_Abeta.
DR InterPro; IPR037071; Amyloid_glyco_Abeta_sf.
DR InterPro; IPR028866; APP.
DR PANTHER; PTHR23103; PTHR23103; 1.
DR PANTHER; PTHR23103:SF7; PTHR23103:SF7; 1.
DR Pfam; PF03494; Beta-APP; 1.
DR PRINTS; PR00204; BETAAMYLOID.
PE 1: Evidence at protein level;
KW Amyloid; Cell membrane; Cell projection; Coated pit; Cytoplasmic vesicle;
KW Direct protein sequencing; Endosome; Membrane; Reference proteome.
FT CHAIN <1..>40
FT /note="Amyloid-beta precursor protein"
FT /id="PRO_0000419960"
FT CHAIN 1..40
FT /note="Amyloid-beta protein 40"
FT /evidence="ECO:0000269|PubMed:22576872"
FT /id="PRO_0000419961"
FT SITE 7..8
FT /note="Cleavage; by ACE"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT NON_TER 1
FT /evidence="ECO:0000303|PubMed:22576872"
FT NON_TER 40
FT /evidence="ECO:0000303|PubMed:22576872"
SQ SEQUENCE 40 AA; 4344 MW; D5627C9F3C3768F1 CRC64;
DAEFRHESGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV
