A4_MACMU
ID A4_MACMU Reviewed; 76 AA.
AC P29216;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 1.
DT 25-MAY-2022, entry version 142.
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 Flags: Fragment;
GN Name=APP;
OS Macaca mulatta (Rhesus macaque).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9544;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=2106906; DOI=10.1016/0896-6273(90)90446-m;
RA Koo E.H., Sisodia S.S., Cork L.C., Unterbeck A., Bayney R.M., Price D.L.;
RT "Differential expression of amyloid precursor protein mRNAs in cases of
RT Alzheimer's disease and in aged nonhuman primates.";
RL Neuron 4:97-104(1990).
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). 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 -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Experimental confirmation may be lacking for some isoforms.;
CC Name=APP(770);
CC IsoId=P29216-1; Sequence=Displayed;
CC Name=APP(395);
CC IsoId=P29216-2; Sequence=Not described;
CC Name=APP(563);
CC IsoId=P29216-3; Sequence=Not described;
CC Name=APP(695);
CC IsoId=P29216-4; Sequence=Not described;
CC Name=APP(751);
CC IsoId=P29216-5; Sequence=Not described;
CC -!- DOMAIN: The OX-2 motif shows some similarity to a region in the N-
CC terminus of CD200/MOX2. {ECO:0000250|UniProtKB:P05067}.
CC -!- SIMILARITY: Belongs to the APP family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; X15985; CAA34116.1; -; mRNA.
DR PIR; S06678; S06678.
DR AlphaFoldDB; P29216; -.
DR BMRB; P29216; -.
DR SMR; P29216; -.
DR MEROPS; I02.015; -.
DR eggNOG; KOG3540; Eukaryota.
DR InParanoid; P29216; -.
DR Proteomes; UP000006718; Unplaced.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005769; C:early endosome; ISS:UniProtKB.
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:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; ISS:UniProtKB.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0050890; P:cognition; ISS:UniProtKB.
DR GO; GO:0007399; P:nervous system development; IEA:InterPro.
DR CDD; cd00109; KU; 1.
DR Gene3D; 4.10.410.10; -; 1.
DR InterPro; IPR008155; Amyloid_glyco.
DR InterPro; IPR028866; APP.
DR InterPro; IPR002223; Kunitz_BPTI.
DR InterPro; IPR036880; Kunitz_BPTI_sf.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR PANTHER; PTHR23103; PTHR23103; 1.
DR PANTHER; PTHR23103:SF7; PTHR23103:SF7; 1.
DR Pfam; PF00014; Kunitz_BPTI; 1.
DR PRINTS; PR00759; BASICPTASE.
DR SMART; SM00131; KU; 1.
DR SUPFAM; SSF57362; SSF57362; 1.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 1.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Amyloid; Cell membrane; Cell projection; Coated pit;
KW Cytoplasmic vesicle; Disulfide bond; Endosome; Membrane;
KW Protease inhibitor; Reference proteome; Serine protease inhibitor.
FT CHAIN <1..>76
FT /note="Amyloid-beta precursor protein"
FT /id="PRO_0000093795"
FT DOMAIN 1..76
FT /note="BPTI/Kunitz inhibitor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT MOTIF 56..76
FT /note="OX-2"
FT /evidence="ECO:0000250|UniProtKB:P05067"
FT SITE 13..14
FT /note="Reactive bond"
FT DISULFID 3..53
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 12..36
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 28..49
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT NON_TER 1
FT NON_TER 76
SQ SEQUENCE 76 AA; 8527 MW; 492BF3069AB082A1 CRC64;
EVCSEQAETG PCRAMISRWY FDVTEGKCAP FFYGGCGGNR NNFDTEEYCM AVCGSVMSQS
LRKTTREPLT RDPVKL
