A4_RABIT
ID A4_RABIT Reviewed; 58 AA.
AC Q28748;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 1.
DT 03-AUG-2022, entry version 123.
DE RecName: Full=Amyloid-beta precursor protein {ECO:0000250|UniProtKB:P05067};
DE AltName: Full=ABPP;
DE Short=APP;
DE AltName: Full=Alzheimer disease amyloid A4 protein homolog;
DE AltName: Full=Alzheimer disease amyloid protein;
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=Soluble APP-beta;
DE Short=S-APP-beta;
DE Contains:
DE RecName: Full=CTF-alpha;
DE Contains:
DE RecName: Full=Amyloid-beta protein 42;
DE Short=Abeta42;
DE AltName: Full=Beta-APP42;
DE Contains:
DE RecName: Full=Amyloid-beta protein 40;
DE Short=Abeta40;
DE AltName: Full=Beta-APP40;
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 59;
DE AltName: Full=Gamma-CTF(59);
DE Contains:
DE RecName: Full=Gamma-secretase C-terminal fragment 57;
DE AltName: Full=Gamma-CTF(57);
DE Flags: Fragment;
GN Name=APP;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=1656157; DOI=10.1016/0169-328x(91)90088-f;
RA Johnstone E.M., Chaney M.O., Norris F.H., Pascual R., Little S.P.;
RT "Conservation of the sequence of the Alzheimer's disease amyloid peptide in
RT dog, polar bear and five other mammals by cross-species polymerase chain
RT reaction analysis.";
RL Brain Res. Mol. Brain Res. 10:299-305(1991).
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). By acting as a kinesin I membrane
CC receptor, plays a role in axonal anterograde transport of cargo towards
CC synapes in axons (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). Amyloid-beta protein 42 interacts with FPR2
CC (By similarity). Interacts with LRRK2 (By similarity). Interacts (via
CC cytoplasmic domain) with KIF5B (By similarity). Interacts (via C-
CC terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts
CC (via intracellular domain) with APBB3 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P05067, 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 -!- SUBCELLULAR LOCATION: [Soluble APP-beta]: Secreted
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [Amyloid-beta protein 42]: Cell surface
CC {ECO:0000250|UniProtKB:P05067}. Note=Associates with FPR2 at the cell
CC surface and the complex is then rapidly internalized.
CC {ECO:0000250|UniProtKB:P05067}.
CC -!- SUBCELLULAR LOCATION: [Gamma-secretase C-terminal fragment 59]: Nucleus
CC {ECO:0000250|UniProtKB:P05067}. Cytoplasm
CC {ECO:0000250|UniProtKB:P05067}. Note=Located to both the cytoplasm and
CC nuclei of neurons. It can be translocated to the nucleus through
CC association with APBB1 (Fe65). In dopaminergic neurons, the
CC phosphorylated form is localized to the nucleus (By similarity).
CC {ECO:0000250|UniProtKB:P05067, ECO:0000250|UniProtKB:P12023}.
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 -!- SIMILARITY: Belongs to the APP family. {ECO:0000305}.
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DR EMBL; X56129; CAA39594.1; -; mRNA.
DR AlphaFoldDB; Q28748; -.
DR STRING; 9986.ENSOCUP00000009130; -.
DR eggNOG; KOG3540; Eukaryota.
DR InParanoid; Q28748; -.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0009986; C:cell surface; IEA:UniProtKB-SubCell.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0050890; P:cognition; ISS:UniProtKB.
DR GO; GO:0007399; P:nervous system development; IEA:InterPro.
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 2: Evidence at transcript level;
KW Amyloid; Cell membrane; Cell projection; Coated pit; Copper; Cytoplasm;
KW Cytoplasmic vesicle; Endosome; Membrane; Metal-binding; Nucleus;
KW Reference proteome; Secreted; Transmembrane; Transmembrane helix; Zinc.
FT CHAIN <1..>58
FT /note="Amyloid-beta precursor protein"
FT /id="PRO_0000226242"
FT CHAIN <1..5
FT /note="Soluble APP-beta"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000153"
FT CHAIN 6..>58
FT /note="CTF-alpha"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000154"
FT CHAIN 6..47
FT /note="Amyloid-beta protein 42"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000155"
FT CHAIN 6..45
FT /note="Amyloid-beta protein 40"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT /id="PRO_0000000156"
FT CHAIN 46..>58
FT /note="Gamma-secretase C-terminal fragment 59"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000157"
FT CHAIN 48..>58
FT /note="Gamma-secretase C-terminal fragment 57"
FT /evidence="ECO:0000250"
FT /id="PRO_0000000158"
FT TOPO_DOM <1..33
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 34..57
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 58..>58
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT BINDING 11
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 11
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 15
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 15
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 18
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 18
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 19
FT /ligand="Cu(2+)"
FT /ligand_id="ChEBI:CHEBI:29036"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT BINDING 19
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 12..13
FT /note="Cleavage; by ACE"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT NON_TER 1
FT NON_TER 58
SQ SEQUENCE 58 AA; 6300 MW; F434209D88EBA82D CRC64;
SEVKMDAEFR HDSGYEVHHQ KLVFFAEDVG SNKGAIIGLM VGGVVIATVI VITLVMLK
