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Amyloid-beta A4 protein (ABPP) (APP) (Alzheimer disease amyloid A4 protein homolog) (Amyloid precursor protein) (Amyloid-beta precursor protein) (Amyloidogenic glycoprotein) (AG) [Cleaved into: N-APP; Soluble APP-alpha (S-APP-alpha); Soluble APP-beta (S-APP-beta); C99 (APP-C99) (Beta-secretase C-terminal fragment) (Beta-CTF); Amyloid-beta protein 42 (Abeta42) (Beta-APP42); Amyloid-beta protein 40 (Abeta40) (Beta-APP40); C83 (Alpha-secretase C-terminal fragment) (Alpha-CTF); P3(42); P3(40); C80; Gamma-secretase C-terminal fragment 59 (APP-C59) (Amyloid intracellular domain 59) (AID(59)) (Gamma-CTF(59)); Gamma-secretase C-terminal fragment 57 (APP-C57) (Amyloid intracellular domain 57) (AID(57)) (Gamma-CTF(57)); Gamma-secretase C-terminal fragment 50 (Amyloid intracellular domain 50) (AID(50)) (Gamma-CTF(50)); C31]

 A4_MOUSE                Reviewed;         770 AA.
P12023; P97487; P97942; Q99K32;
01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
09-MAY-2003, sequence version 3.
03-JUL-2019, entry version 234.
RecName: Full=Amyloid-beta A4 protein;
AltName: Full=ABPP;
Short=APP;
AltName: Full=Alzheimer disease amyloid A4 protein homolog;
AltName: Full=Amyloid precursor protein {ECO:0000305};
AltName: Full=Amyloid-beta precursor protein {ECO:0000305};
AltName: Full=Amyloidogenic glycoprotein;
Short=AG;
Contains:
RecName: Full=N-APP;
Contains:
RecName: Full=Soluble APP-alpha;
Short=S-APP-alpha;
Contains:
RecName: Full=Soluble APP-beta;
Short=S-APP-beta;
Contains:
RecName: Full=C99;
AltName: Full=APP-C99;
AltName: Full=Beta-secretase C-terminal fragment;
Short=Beta-CTF;
Contains:
RecName: Full=Amyloid-beta protein 42;
Short=Abeta42;
AltName: Full=Beta-APP42;
Contains:
RecName: Full=Amyloid-beta protein 40;
Short=Abeta40;
AltName: Full=Beta-APP40;
Contains:
RecName: Full=C83;
AltName: Full=Alpha-secretase C-terminal fragment;
Short=Alpha-CTF;
Contains:
RecName: Full=P3(42);
Contains:
RecName: Full=P3(40);
Contains:
RecName: Full=C80;
Contains:
RecName: Full=Gamma-secretase C-terminal fragment 59;
AltName: Full=APP-C59;
AltName: Full=Amyloid intracellular domain 59;
Short=AID(59);
AltName: Full=Gamma-CTF(59);
Contains:
RecName: Full=Gamma-secretase C-terminal fragment 57;
AltName: Full=APP-C57;
AltName: Full=Amyloid intracellular domain 57;
Short=AID(57);
AltName: Full=Gamma-CTF(57);
Contains:
RecName: Full=Gamma-secretase C-terminal fragment 50;
AltName: Full=Amyloid intracellular domain 50;
Short=AID(50);
AltName: Full=Gamma-CTF(50);
Contains:
RecName: Full=C31;
Flags: Precursor;
Name=App;
Mus musculus (Mouse).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
Muroidea; Muridae; Murinae; Mus; Mus.
NCBI_TaxID=10090;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
TISSUE=Brain;
PubMed=3322280; DOI=10.1016/0006-291X(87)90419-0;
Yamada T., Sasaki H., Furuya H., Miyata T., Goto I., Sakaki Y.;
"Complementary DNA for the mouse homolog of the human amyloid beta
protein precursor.";
Biochem. Biophys. Res. Commun. 149:665-671(1987).
[2]
SEQUENCE REVISION.
Yamada T.;
Submitted (MAR-1988) to the EMBL/GenBank/DDBJ databases.
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
STRAIN=BALB/cJ; TISSUE=Brain;
PubMed=1756177; DOI=10.1016/0167-4781(91)90231-A;
de Strooper B., van Leuven F., van den Berghe H.;
"The amyloid beta protein precursor or proteinase nexin II from mouse
is closer related to its human homolog than previously reported.";
Biochim. Biophys. Acta 1129:141-143(1991).
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM APP695).
STRAIN=SAMP8; TISSUE=Hippocampus;
PubMed=11235921; DOI=10.1139/o00-094;
Kumar V.B., Vyas K., Franko M., Choudhary V., Buddhiraju C.,
Alvarez J., Morley J.E.;
"Molecular cloning, expression, and regulation of hippocampal amyloid
precursor protein of senescence accelerated mouse (SAMP8).";
Biochem. Cell Biol. 79:57-67(2001).
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-19.
PubMed=1555768; DOI=10.1016/0378-1119(92)90375-Y;
Izumi R., Yamada T., Yoshikai S., Sasaki H., Hattori M., Sakai Y.;
"Positive and negative regulatory elements for the expression of the
Alzheimer's disease amyloid precursor-encoding gene in mouse.";
Gene 112:189-195(1992).
[6]
PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM APP770).
TISSUE=Mammary tumor;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[7]
NUCLEOTIDE SEQUENCE [MRNA] OF 281-380, AND ALTERNATIVE SPLICING.
TISSUE=Brain, and Kidney;
PubMed=2493250; DOI=10.1016/0006-291X(89)92808-8;
Yamada T., Sasaki H., Dohura K., Goto I., Sakaki Y.;
"Structure and expression of the alternatively-spliced forms of mRNA
for the mouse homolog of Alzheimer's disease amyloid beta protein
precursor.";
Biochem. Biophys. Res. Commun. 158:906-912(1989).
[8]
NUCLEOTIDE SEQUENCE [MRNA] OF 289-364.
STRAIN=CD-1; TISSUE=Placenta;
PubMed=2569710; DOI=10.1093/nar/17.13.5396;
Fukuchi K., Martin G.M., Deeb S.S.;
"Sequence of the protease inhibitor domain of the A4 amyloid protein
precursor of Mus domesticus.";
Nucleic Acids Res. 17:5396-5396(1989).
[9]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 656-737.
STRAIN=129/Sv;
Wragg M.A., Busfield F., Duff K., Korenblat K., Capecchi M.,
Loring J.F., Goate A.M.;
"Introduction of six mutations into the mouse genome using 'Hit and
Run' gene-targeting: introduction of familial Alzheimer's disease
mutations into the mouse amyloid precursor protein gene and
humanization of the A-beta fragment.";
Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases.
[10]
TISSUE SPECIFICITY OF ALTERNATIVE SPLICED FORMS.
PubMed=8510506; DOI=10.1016/0169-328X(93)90020-P;
Sola C., Mengod G., Ghetti B., Palacios J.M., Triarhou L.C.;
"Regional distribution of the alternatively spliced isoforms of beta
APP RNA transcript in the brain of normal, heterozygous and homozygous
weaver mutant mice as revealed by in situ hybridization
histochemistry.";
Brain Res. Mol. Brain Res. 17:340-346(1993).
[11]
INTERACTION WITH KNS2.
PubMed=11144355; DOI=10.1016/S0896-6273(00)00124-0;
Kamal A., Stokin G.B., Yang Z., Xia C.-H., Goldstein L.S.;
"Axonal transport of amyloid precursor protein is mediated by direct
binding to the kinesin light chain subunit of kinesin-I.";
Neuron 28:449-459(2000).
[12]
PHOSPHORYLATION AT TYR-757.
PubMed=11279131; DOI=10.1074/jbc.M100792200;
Zambrano N., Bruni P., Minopoli G., Mosca R., Molino D., Russo C.,
Schettini G., Sudol M., Russo T.;
"The beta-amyloid precursor protein APP is tyrosine-phosphorylated in
cells expressing a constitutively active form of the Abl
protoncogene.";
J. Biol. Chem. 276:19787-19792(2001).
[13]
PROTEOLYTIC PROCESSING BY GAMMA SECRETASE, AND INTERACTION WITH APBB1.
PubMed=11553691; DOI=10.1046/j.1471-4159.2001.00516.x;
Cupers P., Orlans I., Craessaerts K., Annaert W., De Strooper B.;
"The amyloid precursor protein (APP)-cytoplasmic fragment generated by
gamma-secretase is rapidly degraded but distributes partially in a
nuclear fraction of neurons in culture.";
J. Neurochem. 78:1168-1178(2001).
[14]
C-TERMINAL PROTEIN-PROTEIN INTERACTION, AND MUTAGENESIS OF TYR-728;
THR-743; TYR-757; ASN-759 AND TYR-762.
PubMed=11517249;
Matsuda S., Yasukawa T., Homma Y., Ito Y., Niikura T., Hiraki T.,
Hirai S., Ohno S., Kita Y., Kawasumi M., Kouyama K., Yamamoto T.,
Kyriakis J.M., Nishimoto I.;
"C-jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1
scaffolds Alzheimer's amyloid precursor protein with JNK.";
J. Neurosci. 21:6597-6607(2001).
[15]
INTERACTION WITH DAB2, AND MUTAGENESIS OF GLY-756; TYR-757; ASN-759;
PRO-760 AND TYR-762.
PubMed=11247302; DOI=10.1034/j.1600-0854.2001.020206.x;
Morris S.M., Cooper J.A.;
"Disabled-2 colocalizes with the LDLR in clathrin-coated pits and
interacts with AP-2.";
Traffic 2:111-123(2001).
[16]
INTERACTION WITH MAPK8IP1, AND PHOSPHORYLATION.
PubMed=11912189; DOI=10.1074/jbc.M108372200;
Taru H., Iijima K., Hase M., Kirino Y., Yagi Y., Suzuki T.;
"Interaction of Alzheimer's beta-amyloid precursor family proteins
with scaffold proteins of the JNK signaling cascade.";
J. Biol. Chem. 277:20070-20078(2002).
[17]
INTERACTION OF CTF PEPTIDES WITH NUMB.
PubMed=12011466; DOI=10.1073/pnas.102192599;
Roncarati R., Sestan N., Scheinfeld M.H., Berechid B.E., Lopez P.A.,
Meucci O., McGlade J.C., Rakic P., D'Adamio L.;
"The gamma-secretase-generated intracellular domain of beta-amyloid
precursor protein binds Numb and inhibits Notch signaling.";
Proc. Natl. Acad. Sci. U.S.A. 99:7102-7107(2002).
[18]
PROTEOLYTIC DEGRADATION BY IDE.
PubMed=12634421; DOI=10.1073/pnas.0230450100;
Farris W., Mansourian S., Chang Y., Lindsley L., Eckman E.A.,
Frosch M.P., Eckman C.B., Tanzi R.E., Selkoe D.J., Guenette S.;
"Insulin-degrading enzyme regulates the levels of insulin, amyloid
beta-protein, and the beta-amyloid precursor protein intracellular
domain in vivo.";
Proc. Natl. Acad. Sci. U.S.A. 100:4162-4167(2003).
[19]
SUBCELLULAR LOCATION, AND FUNCTION.
PubMed=15677459; DOI=10.1074/jbc.M409179200;
Cappai R., Cheng F., Ciccotosto G.D., Needham B.E., Masters C.L.,
Multhaup G., Fransson L.A., Mani K.;
"The amyloid precursor protein (APP) of Alzheimer disease and its
paralog, APLP2, modulate the Cu/Zn-nitric oxide-catalyzed degradation
of glypican-1 heparan sulfate in vivo.";
J. Biol. Chem. 280:13913-13920(2005).
[20]
INTERACTION WITH CPEB1.
PubMed=16314516; DOI=10.1128/MCB.25.24.10930-10939.2005;
Cao Q., Huang Y.-S., Kan M.-C., Richter J.D.;
"Amyloid precursor proteins anchor CPEB to membranes and promote
polyadenylation-induced translation.";
Mol. Cell. Biol. 25:10930-10939(2005).
[21]
INTERACTION WITH APP.
PubMed=16174740; DOI=10.1073/pnas.0503689102;
Andersen O.M., Reiche J., Schmidt V., Gotthardt M., Spoelgen R.,
Behlke J., von Arnim C.A., Breiderhoff T., Jansen P., Wu X.,
Bales K.R., Cappai R., Masters C.L., Gliemann J., Mufson E.J.,
Hyman B.T., Paul S.M., Nykjaer A., Willnow T.E.;
"Neuronal sorting protein-related receptor sorLA/LR11 regulates
processing of the amyloid precursor protein.";
Proc. Natl. Acad. Sci. U.S.A. 102:13461-13466(2005).
[22]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-441, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Brain, Kidney, Lung, Pancreas, and Testis;
PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
"A tissue-specific atlas of mouse protein phosphorylation and
expression.";
Cell 143:1174-1189(2010).
[23]
INTERACTION WITH NGS1.
PubMed=21084623; DOI=10.1523/JNEUROSCI.4464-10.2010;
Norstrom E.M., Zhang C., Tanzi R., Sisodia S.S.;
"Identification of NEEP21 as a ss-amyloid precursor protein-
interacting protein in vivo that modulates amyloidogenic processing in
vitro.";
J. Neurosci. 30:15677-15685(2010).
[24]
SUBCELLULAR LOCATION, AND PROTEOLYTIC CLEAVAGE.
PubMed=23931995; DOI=10.1016/j.neuron.2013.05.035;
Das U., Scott D.A., Ganguly A., Koo E.H., Tang Y., Roy S.;
"Activity-induced convergence of APP and BACE-1 in acidic microdomains
via an endocytosis-dependent pathway.";
Neuron 79:447-460(2013).
[25]
INTERACTION WITH VDAC1.
PubMed=25168729; DOI=10.1016/j.neuroscience.2014.07.079;
Fernandez-Echevarria C., Diaz M., Ferrer I., Canerina-Amaro A.,
Marin R.;
"Abeta promotes VDAC1 channel dephosphorylation in neuronal lipid
rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer's
disease.";
Neuroscience 278:354-366(2014).
[26]
SUBCELLULAR LOCATION.
PubMed=25592972; DOI=10.15252/emmm.201404438;
Kizuka Y., Kitazume S., Fujinawa R., Saito T., Iwata N., Saido T.C.,
Nakano M., Yamaguchi Y., Hashimoto Y., Staufenbiel M., Hatsuta H.,
Murayama S., Manya H., Endo T., Taniguchi N.;
"An aberrant sugar modification of BACE1 blocks its lysosomal
targeting in Alzheimer's disease.";
EMBO Mol. Med. 7:175-189(2015).
[27]
SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND
INDUCTION BY HIGH-FAT DIET.
PubMed=26260791; DOI=10.1074/jbc.M115.655076;
Satoh K., Abe-Dohmae S., Yokoyama S., St George-Hyslop P.,
Fraser P.E.;
"ATP-binding cassette transporter A7 (ABCA7) loss of function alters
Alzheimer amyloid processing.";
J. Biol. Chem. 290:24152-24165(2015).
[28]
INTERACTION WITH SYT7.
PubMed=30429473; DOI=10.1038/s41467-018-06813-x;
Barthet G., Jorda-Siquier T., Rumi-Masante J., Bernadou F.,
Mueller U., Mulle C.;
"Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and
presynaptic plasticity.";
Nat. Commun. 9:4780-4780(2018).
-!- FUNCTION: Functions as a cell surface receptor and performs
physiological functions on the surface of neurons relevant to
neurite growth, neuronal adhesion and axonogenesis. Interaction
between APP molecules on neighboring cells promotes
synaptogenesis. Involved in cell mobility and transcription
regulation through protein-protein interactions. Can promote
transcription activation through binding to APBB1-KAT5 and inhibit
Notch signaling through interaction with Numb. Couples to
apoptosis-inducing pathways such as those mediated by G(O) and
JIP. 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. May be involved in copper
homeostasis/oxidative stress through copper ion reduction. 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 (By
similarity). Provides Cu(2+) ions for GPC1 which are required for
release of nitric oxide (NO) and subsequent degradation of the
heparan sulfate chains on GPC1. {ECO:0000250,
ECO:0000269|PubMed:15677459}.
-!- FUNCTION: Amyloid-beta peptides are lipophilic metal chelators
with metal-reducing activity. Binds transient metals such as
copper, zinc and iron. Rat and mouse amyloid-beta peptides bind
only weakly transient metals and have little reducing activity due
to substitutions of transient metal chelating residues. Amyloid-
beta protein 42 may activate mononuclear phagocytes in the brain
and elicit inflammatory responses. Promotes both tau aggregation
and TPK II-mediated phosphorylation. Also binds GPC1 in lipid
rafts (By similarity). {ECO:0000250}.
-!- FUNCTION: The gamma-CTF peptides as well as the caspase-cleaved
peptides, including C31, are potent enhancers of neuronal
apoptosis. {ECO:0000269|PubMed:15677459}.
-!- FUNCTION: N-APP binds TNFRSF21 triggering caspase activation and
degeneration of both neuronal cell bodies (via caspase-3) and
axons (via caspase-6). {ECO:0000250}.
-!- SUBUNIT: 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. Binding to DAB1 inhibits
its serine phosphorylation. 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, APPBP1, IB1, KNS2 (via its TPR domains), APPBP2 (via
BaSS) and DDB1 (By similarity). 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, through a C-terminal domain, with GNAO1
(By similarity). Amyloid-beta protein 42 binds CHRNA7 in
hippocampal neurons (By similarity). Amyloid-beta associates with
HADH2 (By similarity). Interacts with ANKS1B, TNFRSF21 and AGER
(By similarity). Interacts with CPEB1. Interacts with ITM2B.
Interacts with ITM2C. Interacts with IDE. Can form homodimers;
dimerization is enhanced in the presence of Cu(2+) ions. Can form
homodimers; this is promoted by heparin binding (By similarity).
Amyloid-beta protein 40 interacts with S100A9 (By similarity).
CTF-alpha product of APP interacts with GSAP (By similarity).
Interacts with SORL1. Interacts with PLD3 (By similarity).
Interacts with VDAC1 (PubMed:25168729). Interacts with NSG1; could
regulate APP processing (PubMed:21084623). Amyloid-beta protein 42
interacts with FPR2 (By similarity). Interacts with SYT7
(PubMed:30429473). Interacts (via transmembrane region) with
PSEN1; the interaction is direct (By similarity).
{ECO:0000250|UniProtKB:P05067, ECO:0000250|UniProtKB:P08592,
ECO:0000269|PubMed:21084623, ECO:0000269|PubMed:25168729,
ECO:0000269|PubMed:30429473}.
-!- INTERACTION:
P98084:Apba2; NbExp=2; IntAct=EBI-78814, EBI-81669;
Q9QXJ1:Apbb1; NbExp=2; IntAct=EBI-78814, EBI-81338;
Q03157:Aplp1; NbExp=4; IntAct=EBI-78814, EBI-399929;
Q06335:Aplp2; NbExp=3; IntAct=EBI-78814, EBI-446708;
P15253:CALR (xeno); NbExp=2; IntAct=EBI-78814, EBI-9005200;
P14211:Calr; NbExp=4; IntAct=EBI-78814, EBI-644340;
P97318:Dab1; NbExp=3; IntAct=EBI-78814, EBI-81680;
Q62108:Dlg4; NbExp=4; IntAct=EBI-78814, EBI-300895;
Q8BGT1:Flrt3; NbExp=2; IntAct=EBI-78814, EBI-16166902;
Q9D1T0:Lingo1; NbExp=2; IntAct=EBI-78814, EBI-2012981;
Q9UQF2:MAPK8IP1 (xeno); NbExp=2; IntAct=EBI-78814, EBI-78404;
Q9WVI9-1:Mapk8ip1; NbExp=3; IntAct=EBI-78814, EBI-288461;
Q61120:Shc3; NbExp=2; IntAct=EBI-78814, EBI-79107;
Q9JHI9:Slc40a1; NbExp=2; IntAct=EBI-78814, EBI-2931424;
-!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26260791};
Single-pass type I membrane protein
{ECO:0000250|UniProtKB:P05067}. Membrane
{ECO:0000250|UniProtKB:P05067}; Single-pass type I membrane
protein {ECO:0000250|UniProtKB:P05067}. Perikaryon
{ECO:0000250|UniProtKB:P08592}. Cell projection, growth cone
{ECO:0000250|UniProtKB:P08592}. Membrane, clathrin-coated pit
{ECO:0000250|UniProtKB:P05067}. Early endosome
{ECO:0000269|PubMed:25592972, ECO:0000269|PubMed:26260791}.
Cytoplasmic vesicle {ECO:0000250|UniProtKB:P05067}. Golgi
apparatus, trans-Golgi network {ECO:0000269|PubMed:23931995}.
Note=Cell surface protein that rapidly becomes internalized via
clathrin-coated pits. Only a minor proportion is present at the
cell membrane; most of the protein is present in intracellular
vesicles. 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. APP sorts to the basolateral surface in
epithelial cells. During neuronal differentiation, the Thr-743
phosphorylated form is located mainly in growth cones, moderately
in neurites and sparingly in the cell body. Casein kinase
phosphorylation can occur either at the cell surface or within a
post-Golgi compartment (By similarity). Associates with GPC1 in
perinuclear compartments (PubMed:15677459). Colocalizes with SORL1
in a vesicular pattern in cytoplasm and perinuclear regions (By
similarity). Upon neuronal activation, routed into BACE1-positive
recycling endosomes via a clathrin -dependent mechanism
(PubMed:23931995). {ECO:0000250|UniProtKB:P05067,
ECO:0000269|PubMed:15677459, ECO:0000269|PubMed:23931995}.
-!- SUBCELLULAR LOCATION: Soluble APP-beta: Secreted {ECO:0000305}.
-!- SUBCELLULAR LOCATION: Amyloid-beta protein 42: Cell surface.
Note=Associates with FPR2 at the cell surface and the complex is
then rapidly internalized. {ECO:0000250|UniProtKB:P05067}.
-!- SUBCELLULAR LOCATION: Gamma-secretase C-terminal fragment 59:
Nucleus {ECO:0000250|UniProtKB:P05067}. Cytoplasm
{ECO:0000250|UniProtKB:P05067}. Note=located to both the cytoplasm
and nuclei of neurons. It can be translocated to the nucleus
through association with APBB1 (Fe65).
{ECO:0000250|UniProtKB:P05067}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=4;
Comment=Additional isoforms seem to exist.;
Name=APP770;
IsoId=P12023-1; Sequence=Displayed;
Name=APP695;
IsoId=P12023-2; Sequence=VSP_000012, VSP_000013;
Name=APP751;
IsoId=P12023-3; Sequence=VSP_000014;
Name=APP714;
IsoId=P12023-4; Sequence=Not described;
-!- TISSUE SPECIFICITY: Expressed in the brain with expression in
cortex, cerebellum, hippocampus, olfactory bulb, neurons,
astrocytes and microglia (at protein level) (PubMed:26260791).
Isoform APP770 is expressed in kidney. Isoform APP751 is widely
expressed. Isoform APP695 is expressed in brain, kidney and liver.
Isoform APP695, isoform APP714 and isoform APP751 are expressed in
several different brain regions including hippocampus, substania
nigra pars compacta and cerebellum. In the cerebellum, these
isoforms are abundantly expressed in Purkinje cells.
{ECO:0000269|PubMed:26260791, ECO:0000269|PubMed:8510506}.
-!- DEVELOPMENTAL STAGE: Expressed in 4 to 24 week old mice.
{ECO:0000269|PubMed:26260791}.
-!- INDUCTION: Up-regulated in animals on a high-fat diet compared to
a regular diet. {ECO:0000269|PubMed:26260791}.
-!- DOMAIN: The transmembrane helix undergoes a conformation change
and unravels partially when bound to PSEN1, facilitating cleavage
by PSEN1. {ECO:0000250|UniProtKB:P05067}.
-!- DOMAIN: The basolateral sorting signal (BaSS) is required for
sorting of membrane proteins to the basolateral surface of
epithelial cells. {ECO:0000250|UniProtKB:P05067}.
-!- DOMAIN: The GFLD subdomain binds Cu(2+) ions; this promotes
homodimerization. {ECO:0000250|UniProtKB:P05067}.
-!- DOMAIN: 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 YENPXY site is also involved in clathrin-mediated
endocytosis. {ECO:0000250|UniProtKB:P05067}.
-!- DOMAIN: The C-terminal region can bind zinc ions; this favors
dimerization and formation of higher oligomers.
{ECO:0000250|UniProtKB:P05067}.
-!- PTM: 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 protein 40 and amyloid-beta protein 42,
major components of amyloid plaques, and the cytotoxic C-terminal
fragments, gamma-CTF(50), gamma-CTF(57) and gamma-CTF(59). PSEN1
cleavage is more efficient with C83 than with C99 as substrate (in
vitro) (By similarity). {ECO:0000250|UniProtKB:P05067,
ECO:0000269|PubMed:11553691, ECO:0000269|PubMed:23931995}.
-!- PTM: Proteolytically cleaved by caspases during neuronal
apoptosis. Cleavage at Asp-739 by either CASP6, CASP8 or CASP9
results in the production of the neurotoxic C31 peptide and the
increased production of amyloid-beta peptides.
{ECO:0000250|UniProtKB:P05067}.
-!- PTM: N- and O-glycosylated. {ECO:0000250|UniProtKB:P05067}.
-!- PTM: 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. The Thr-743 phosphorylated form causes a conformational
change which reduces binding of Fe65 family members (By
similarity). Phosphorylation on Tyr-757 is required for SHC
binding. {ECO:0000250|UniProtKB:P05067}.
-!- PTM: Extracellular binding and reduction of copper, results in a
corresponding oxidation of Cys-144 and Cys-158, and the formation
of a disulfide bond. {ECO:0000250}.
-!- PTM: 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).
{ECO:0000250}.
-!- PTM: Amyloid-beta peptides are degraded by IDE.
{ECO:0000269|PubMed:12634421}.
-!- MISCELLANEOUS: Chelation of metal ions, notably copper, iron and
zinc, can induce histidine-bridging between amyloid-beta molecules
resulting in amyloid-beta-metal aggregates. Rat and mouse amyloid-
beta peptides have an arginine residue substituted for the
bridging histidine residue and are thus less capable of forming
amyloid aggregates. Extracellular zinc-binding increases binding
of heparin to APP and inhibits collagen-binding (By similarity).
{ECO:0000250|UniProtKB:P05067, ECO:0000305}.
-!- SIMILARITY: Belongs to the APP family. {ECO:0000255|PROSITE-
ProRule:PRU01217}.
-----------------------------------------------------------------------
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-----------------------------------------------------------------------
EMBL; M18373; AAA37139.1; -; mRNA.
EMBL; X59379; -; NOT_ANNOTATED_CDS; mRNA.
EMBL; U84012; AAB41502.1; -; mRNA.
EMBL; D10603; BAA01456.1; -; Genomic_DNA.
EMBL; BC005490; AAH05490.1; -; mRNA.
EMBL; M24397; AAA39929.1; -; mRNA.
EMBL; X15210; CAA33280.1; -; mRNA.
EMBL; U82624; AAB40919.1; -; Genomic_DNA.
CCDS; CCDS28285.1; -. [P12023-2]
PIR; A27485; A27485.
PIR; A32282; A32282.
PIR; S04855; S04855.
RefSeq; NP_001185752.1; NM_001198823.1. [P12023-1]
PDB; 2ROZ; NMR; -; A=739-770.
PDB; 2YSZ; NMR; -; A=739-770.
PDB; 2YT0; NMR; -; A=739-770.
PDB; 2YT1; NMR; -; A=739-770.
PDB; 4YN0; X-ray; 2.20 A; B=370-592.
PDB; 5MYK; X-ray; 1.60 A; C=674-689.
PDBsum; 2ROZ; -.
PDBsum; 2YSZ; -.
PDBsum; 2YT0; -.
PDBsum; 2YT1; -.
PDBsum; 4YN0; -.
PDBsum; 5MYK; -.
SMR; P12023; -.
BioGrid; 198167; 83.
ComplexPortal; CPX-1105; Amyloid-beta protein 40/42 complex.
ComplexPortal; CPX-1106; Amyloid-beta protein 40 complex.
ComplexPortal; CPX-1107; Amyloid-beta protein 42 complex.
ComplexPortal; CPX-1121; Amyloid-beta protein 40/42 oligomeric complex.
ComplexPortal; CPX-1139; Amyloid-beta protein 42 oligomeric complex.
ComplexPortal; CPX-1181; Amyloid-beta protein 40 oligomeric complex.
CORUM; P12023; -.
ELM; P12023; -.
IntAct; P12023; 79.
MINT; P12023; -.
STRING; 10090.ENSMUSP00000005406; -.
MEROPS; I02.015; -.
iPTMnet; P12023; -.
PhosphoSitePlus; P12023; -.
PaxDb; P12023; -.
PeptideAtlas; P12023; -.
PRIDE; P12023; -.
Ensembl; ENSMUST00000005406; ENSMUSP00000005406; ENSMUSG00000022892. [P12023-2]
Ensembl; ENSMUST00000227723; ENSMUSP00000154061; ENSMUSG00000022892. [P12023-1]
GeneID; 11820; -.
KEGG; mmu:11820; -.
UCSC; uc007ztn.2; mouse. [P12023-1]
CTD; 351; -.
MGI; MGI:88059; App.
eggNOG; KOG3540; Eukaryota.
eggNOG; ENOG410ZW2A; LUCA.
GeneTree; ENSGT00530000063252; -.
HOGENOM; HOG000232190; -.
InParanoid; P12023; -.
KO; K04520; -.
OMA; KQCKTHA; -.
OrthoDB; 953529at2759; -.
PhylomeDB; P12023; -.
TreeFam; TF317274; -.
Reactome; R-MMU-114608; Platelet degranulation.
Reactome; R-MMU-3000178; ECM proteoglycans.
Reactome; R-MMU-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
Reactome; R-MMU-416476; G alpha (q) signalling events.
Reactome; R-MMU-418594; G alpha (i) signalling events.
Reactome; R-MMU-432720; Lysosome Vesicle Biogenesis.
Reactome; R-MMU-444473; Formyl peptide receptors bind formyl peptides and many other ligands.
Reactome; R-MMU-445989; TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
Reactome; R-MMU-879415; Advanced glycosylation endproduct receptor signaling.
Reactome; R-MMU-8957275; Post-translational protein phosphorylation.
Reactome; R-MMU-933542; TRAF6 mediated NF-kB activation.
Reactome; R-MMU-9609523; Insertion of tail-anchored proteins into the endoplasmic reticulum membrane.
ChiTaRS; App; mouse.
EvolutionaryTrace; P12023; -.
PRO; PR:P12023; -.
Proteomes; UP000000589; Chromosome 16.
Bgee; ENSMUSG00000022892; Expressed in 335 organ(s), highest expression level in cingulate cortex.
ExpressionAtlas; P12023; baseline and differential.
Genevisible; P12023; MM.
GO; GO:0045177; C:apical part of cell; IDA:MGI.
GO; GO:0097449; C:astrocyte projection; ISO:MGI.
GO; GO:0030424; C:axon; IDA:UniProtKB.
GO; GO:0009986; C:cell surface; IDA:MGI.
GO; GO:0005911; C:cell-cell junction; IDA:MGI.
GO; GO:0035253; C:ciliary rootlet; IDA:MGI.
GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
GO; GO:0030134; C:COPII-coated ER to Golgi transport vesicle; IDA:MGI.
GO; GO:0005737; C:cytoplasm; IDA:MGI.
GO; GO:0031410; C:cytoplasmic vesicle; IDA:MGI.
GO; GO:0043198; C:dendritic shaft; IEA:Ensembl.
GO; GO:0043197; C:dendritic spine; IEA:Ensembl.
GO; GO:0005769; C:early endosome; IDA:MGI.
GO; GO:0005768; C:endosome; ISO:MGI.
GO; GO:0005615; C:extracellular space; ISO:MGI.
GO; GO:0005794; C:Golgi apparatus; IDA:MGI.
GO; GO:0005798; C:Golgi-associated vesicle; IDA:UniProtKB.
GO; GO:0030426; C:growth cone; ISO:MGI.
GO; GO:1990812; C:growth cone filopodium; ISO:MGI.
GO; GO:1990761; C:growth cone lamellipodium; ISO:MGI.
GO; GO:0016021; C:integral component of membrane; IDA:MGI.
GO; GO:0044304; C:main axon; ISO:MGI.
GO; GO:0016020; C:membrane; IDA:MGI.
GO; GO:0045121; C:membrane raft; ISO:MGI.
GO; GO:0031594; C:neuromuscular junction; IDA:MGI.
GO; GO:0043005; C:neuron projection; IDA:MGI.
GO; GO:0005641; C:nuclear envelope lumen; ISO:MGI.
GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:MGI.
GO; GO:0005886; C:plasma membrane; IDA:MGI.
GO; GO:0048786; C:presynaptic active zone; IDA:SynGO.
GO; GO:0043235; C:receptor complex; ISO:MGI.
GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
GO; GO:0005791; C:rough endoplasmic reticulum; ISO:MGI.
GO; GO:0005790; C:smooth endoplasmic reticulum; IEA:GOC.
GO; GO:0051233; C:spindle midzone; IDA:MGI.
GO; GO:0008021; C:synaptic vesicle; IDA:MGI.
GO; GO:0003677; F:DNA binding; IDA:MGI.
GO; GO:0019899; F:enzyme binding; ISO:MGI.
GO; GO:0070851; F:growth factor receptor binding; ISO:MGI.
GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
GO; GO:0042802; F:identical protein binding; ISO:MGI.
GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IPI:ARUK-UCL.
GO; GO:0016504; F:peptidase activator activity; ISO:MGI.
GO; GO:0051425; F:PTB domain binding; ISO:MGI.
GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; ISO:MGI.
GO; GO:0030546; F:signaling receptor activator activity; IDA:ARUK-UCL.
GO; GO:0005102; F:signaling receptor binding; ISO:MGI.
GO; GO:0046914; F:transition metal ion binding; IEA:InterPro.
GO; GO:0008344; P:adult locomotory behavior; IMP:MGI.
GO; GO:1990000; P:amyloid fibril formation; ISO:MGI.
GO; GO:0048143; P:astrocyte activation; ISO:MGI.
GO; GO:0002265; P:astrocyte activation involved in immune response; ISO:MGI.
GO; GO:0008088; P:axo-dendritic transport; IMP:MGI.
GO; GO:0016199; P:axon midline choice point recognition; IMP:MGI.
GO; GO:0007409; P:axonogenesis; IMP:MGI.
GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
GO; GO:0006878; P:cellular copper ion homeostasis; IMP:MGI.
GO; GO:0009987; P:cellular process; ISO:MGI.
GO; GO:1904646; P:cellular response to amyloid-beta; ISO:MGI.
GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
GO; GO:0071280; P:cellular response to copper ion; IEA:Ensembl.
GO; GO:0071287; P:cellular response to manganese ion; IEA:Ensembl.
GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
GO; GO:0071874; P:cellular response to norepinephrine stimulus; ISO:MGI.
GO; GO:0008203; P:cholesterol metabolic process; IMP:MGI.
GO; GO:0050890; P:cognition; IDA:MGI.
GO; GO:0048669; P:collateral sprouting in absence of injury; IGI:MGI.
GO; GO:0016358; P:dendrite development; IMP:MGI.
GO; GO:0006897; P:endocytosis; IMP:MGI.
GO; GO:0030198; P:extracellular matrix organization; IGI:MGI.
GO; GO:0030900; P:forebrain development; IMP:MGI.
GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; IMP:MGI.
GO; GO:0007612; P:learning; ISO:MGI.
GO; GO:0007611; P:learning or memory; ISO:MGI.
GO; GO:0007626; P:locomotory behavior; IGI:MGI.
GO; GO:0060291; P:long-term synaptic potentiation; TAS:ARUK-UCL.
GO; GO:0007617; P:mating behavior; IGI:MGI.
GO; GO:0007613; P:memory; TAS:ARUK-UCL.
GO; GO:0014005; P:microglia development; ISO:MGI.
GO; GO:0090647; P:modulation of age-related behavioral decline; ISO:MGI.
GO; GO:0098815; P:modulation of excitatory postsynaptic potential; ISO:MGI.
GO; GO:0006378; P:mRNA polyadenylation; IDA:MGI.
GO; GO:1903523; P:negative regulation of blood circulation; IGI:ARUK-UCL.
GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:MGI.
GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; ISO:MGI.
GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:MGI.
GO; GO:0050885; P:neuromuscular process controlling balance; IGI:MGI.
GO; GO:0051402; P:neuron apoptotic process; IGI:MGI.
GO; GO:0031175; P:neuron projection development; IDA:MGI.
GO; GO:1990535; P:neuron projection maintenance; ISO:MGI.
GO; GO:0016322; P:neuron remodeling; IMP:MGI.
GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
GO; GO:1905908; P:positive regulation of amyloid fibril formation; ISO:MGI.
GO; GO:1902004; P:positive regulation of amyloid-beta formation; ISO:MGI.
GO; GO:0061890; P:positive regulation of astrocyte activation; ISO:MGI.
GO; GO:0045080; P:positive regulation of chemokine biosynthetic process; ISO:MGI.
GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:MGI.
GO; GO:1904472; P:positive regulation of endothelin secretion; IGI:ARUK-UCL.
GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:MGI.
GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IMP:MGI.
GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
GO; GO:0045821; P:positive regulation of glycolytic process; IEA:Ensembl.
GO; GO:0050725; P:positive regulation of interleukin-1 beta biosynthetic process; ISO:MGI.
GO; GO:0045410; P:positive regulation of interleukin-6 biosynthetic process; ISO:MGI.
GO; GO:0046330; P:positive regulation of JNK cascade; ISO:MGI.
GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISO:MGI.
GO; GO:1903980; P:positive regulation of microglial cell activation; ISO:MGI.
GO; GO:0045931; P:positive regulation of mitotic cell cycle; IMP:MGI.
GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISO:MGI.
GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISO:MGI.
GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:MGI.
GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; ISO:MGI.
GO; GO:0042327; P:positive regulation of phosphorylation; ISO:MGI.
GO; GO:0032092; P:positive regulation of protein binding; ISO:MGI.
GO; GO:0051247; P:positive regulation of protein metabolic process; ISO:MGI.
GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
GO; GO:2000406; P:positive regulation of T cell migration; ISO:MGI.
GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
GO; GO:0042535; P:positive regulation of tumor necrosis factor biosynthetic process; IGI:ARUK-UCL.
GO; GO:0051260; P:protein homooligomerization; ISO:MGI.
GO; GO:0006468; P:protein phosphorylation; IMP:MGI.
GO; GO:0007176; P:regulation of epidermal growth factor-activated receptor activity; IGI:MGI.
GO; GO:0010468; P:regulation of gene expression; IDA:MGI.
GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; ISO:MGI.
GO; GO:0040014; P:regulation of multicellular organism growth; IMP:MGI.
GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; ISO:MGI.
GO; GO:1905606; P:regulation of presynapse assembly; ISO:MGI.
GO; GO:0043393; P:regulation of protein binding; IMP:MGI.
GO; GO:0150003; P:regulation of spontaneous synaptic transmission; ISO:MGI.
GO; GO:0050803; P:regulation of synapse structure or activity; IMP:MGI.
GO; GO:0006417; P:regulation of translation; IDA:MGI.
GO; GO:0070555; P:response to interleukin-1; ISO:MGI.
GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
GO; GO:0006979; P:response to oxidative stress; IGI:MGI.
GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IGI:MGI.
GO; GO:0001967; P:suckling behavior; IGI:MGI.
GO; GO:0050808; P:synapse organization; ISO:MGI.
GO; GO:0051124; P:synaptic growth at neuromuscular junction; IGI:MGI.
GO; GO:0032640; P:tumor necrosis factor production; ISO:MGI.
GO; GO:0008542; P:visual learning; IMP:MGI.
CDD; cd00109; KU; 1.
Gene3D; 1.20.120.770; -; 1.
Gene3D; 2.30.29.30; -; 1.
Gene3D; 3.30.1490.140; -; 1.
Gene3D; 3.90.570.10; -; 1.
Gene3D; 4.10.230.10; -; 1.
Gene3D; 4.10.410.10; -; 1.
InterPro; IPR036669; Amyloid_Cu-bd_sf.
InterPro; IPR008155; Amyloid_glyco.
InterPro; IPR013803; Amyloid_glyco_Abeta.
InterPro; IPR037071; Amyloid_glyco_Abeta_sf.
InterPro; IPR011178; Amyloid_glyco_Cu-bd.
InterPro; IPR024329; Amyloid_glyco_E2_domain.
InterPro; IPR008154; Amyloid_glyco_extra.
InterPro; IPR015849; Amyloid_glyco_heparin-bd.
InterPro; IPR036454; Amyloid_glyco_heparin-bd_sf.
InterPro; IPR019745; Amyloid_glyco_intracell_CS.
InterPro; IPR028866; APP.
InterPro; IPR019543; APP_amyloid_C.
InterPro; IPR019744; APP_CUBD_CS.
InterPro; IPR036176; E2_sf.
InterPro; IPR002223; Kunitz_BPTI.
InterPro; IPR036880; Kunitz_BPTI_sf.
InterPro; IPR011993; PH-like_dom_sf.
InterPro; IPR020901; Prtase_inh_Kunz-CS.
PANTHER; PTHR23103; PTHR23103; 1.
PANTHER; PTHR23103:SF7; PTHR23103:SF7; 1.
Pfam; PF10515; APP_amyloid; 1.
Pfam; PF12924; APP_Cu_bd; 1.
Pfam; PF12925; APP_E2; 1.
Pfam; PF02177; APP_N; 1.
Pfam; PF03494; Beta-APP; 1.
Pfam; PF00014; Kunitz_BPTI; 1.
PRINTS; PR00203; AMYLOIDA4.
PRINTS; PR00759; BASICPTASE.
PRINTS; PR00204; BETAAMYLOID.
SMART; SM00006; A4_EXTRA; 1.
SMART; SM00131; KU; 1.
SUPFAM; SSF109843; SSF109843; 1.
SUPFAM; SSF56491; SSF56491; 1.
SUPFAM; SSF57362; SSF57362; 1.
SUPFAM; SSF89811; SSF89811; 1.
PROSITE; PS00319; APP_CUBD; 1.
PROSITE; PS51869; APP_E1; 1.
PROSITE; PS51870; APP_E2; 1.
PROSITE; PS00320; APP_INTRA; 1.
PROSITE; PS00280; BPTI_KUNITZ_1; 1.
PROSITE; PS50279; BPTI_KUNITZ_2; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Amyloid; Apoptosis; Cell adhesion;
Cell membrane; Cell projection; Coated pit; Complete proteome; Copper;
Cytoplasm; Cytoplasmic vesicle; Disulfide bond; Endocytosis; Endosome;
Glycoprotein; Golgi apparatus; Heparin-binding; Iron; Isopeptide bond;
Membrane; Metal-binding; Notch signaling pathway; Nucleus;
Phosphoprotein; Protease inhibitor; Reference proteome; Secreted;
Serine protease inhibitor; Signal; Transmembrane; Transmembrane helix;
Ubl conjugation; Zinc.
SIGNAL 1 17 {ECO:0000250|UniProtKB:P05067}.
CHAIN 18 770 Amyloid-beta A4 protein.
/FTId=PRO_0000000114.
CHAIN 18 687 Soluble APP-alpha. {ECO:0000255}.
/FTId=PRO_0000000115.
CHAIN 18 671 Soluble APP-beta. {ECO:0000255}.
/FTId=PRO_0000000116.
CHAIN 18 286 N-APP. {ECO:0000250}.
/FTId=PRO_0000381968.
CHAIN 672 770 C99. {ECO:0000250}.
/FTId=PRO_0000000117.
CHAIN 672 713 Amyloid-beta protein 42. {ECO:0000250}.
/FTId=PRO_0000000118.
CHAIN 672 711 Amyloid-beta protein 40. {ECO:0000250}.
/FTId=PRO_0000000119.
CHAIN 688 770 C83. {ECO:0000250}.
/FTId=PRO_0000000120.
PEPTIDE 688 713 P3(42). {ECO:0000250}.
/FTId=PRO_0000000121.
PEPTIDE 688 711 P3(40). {ECO:0000250}.
/FTId=PRO_0000000122.
CHAIN 691 770 C80.
/FTId=PRO_0000384576.
CHAIN 712 770 Gamma-secretase C-terminal fragment 59.
/FTId=PRO_0000000123.
CHAIN 714 770 Gamma-secretase C-terminal fragment 57.
/FTId=PRO_0000000124.
CHAIN 721 770 Gamma-secretase C-terminal fragment 50.
/FTId=PRO_0000000125.
CHAIN 740 770 C31. {ECO:0000250}.
/FTId=PRO_0000000126.
TOPO_DOM 18 701 Extracellular. {ECO:0000305}.
TRANSMEM 702 722 Helical. {ECO:0000250|UniProtKB:P05067}.
TOPO_DOM 723 770 Cytoplasmic. {ECO:0000305}.
DOMAIN 28 189 E1. {ECO:0000255|PROSITE-
ProRule:PRU01217}.
DOMAIN 291 341 BPTI/Kunitz inhibitor.
{ECO:0000255|PROSITE-ProRule:PRU00031}.
DOMAIN 374 565 E2. {ECO:0000255|PROSITE-
ProRule:PRU01218}.
REGION 28 123 GFLD subdomain. {ECO:0000255|PROSITE-
ProRule:PRU01217}.
REGION 96 110 Heparin-binding.
{ECO:0000250|UniProtKB:P05067}.
REGION 131 189 CuBD subdomain. {ECO:0000255|PROSITE-
ProRule:PRU01217}.
REGION 181 188 Zinc-binding. {ECO:0000250}.
REGION 391 423 Heparin-binding. {ECO:0000250}.
REGION 491 522 Heparin-binding. {ECO:0000250}.
REGION 523 540 Collagen-binding.
{ECO:0000250|UniProtKB:P05067}.
REGION 695 722 Interaction with PSEN1.
{ECO:0000250|UniProtKB:P05067}.
REGION 732 751 Interaction with G(o)-alpha.
{ECO:0000250}.
REGION 756 770 Interaction with DAB2.
{ECO:0000269|PubMed:11247302}.
MOTIF 724 734 Basolateral sorting signal.
MOTIF 757 762 YENPXY motif; contains endocytosis
signal. {ECO:0000250|UniProtKB:P05067}.
COMPBIAS 230 260 Asp/Glu-rich (acidic).
COMPBIAS 274 280 Poly-Thr.
METAL 147 147 Copper 1. {ECO:0000255|PROSITE-
ProRule:PRU01217}.
METAL 151 151 Copper 1. {ECO:0000255|PROSITE-
ProRule:PRU01217}.
METAL 168 168 Copper 1. {ECO:0000255|PROSITE-
ProRule:PRU01217}.
METAL 677 677 Copper or zinc 2.
{ECO:0000250|UniProtKB:P05067}.
METAL 685 685 Copper or zinc 2.
{ECO:0000250|UniProtKB:P05067}.
SITE 170 170 Required for Cu(2+) reduction.
{ECO:0000255|PROSITE-ProRule:PRU01217}.
SITE 197 198 Cleavage; by caspases.
{ECO:0000250|UniProtKB:P05067}.
SITE 219 220 Cleavage; by caspases.
{ECO:0000250|UniProtKB:P05067}.
SITE 301 302 Reactive bond. {ECO:0000250}.
SITE 671 672 Cleavage; by beta-secretase.
{ECO:0000250|UniProtKB:P05067}.
SITE 687 688 Cleavage; by alpha-secretase.
{ECO:0000250|UniProtKB:P08592}.
SITE 690 691 Cleavage; by theta-secretase.
{ECO:0000250|UniProtKB:P08592}.
SITE 704 704 Implicated in free radical propagation.
{ECO:0000250}.
SITE 706 706 Susceptible to oxidation.
{ECO:0000250|UniProtKB:P05067}.
SITE 711 712 Cleavage; by gamma-secretase; site 1.
{ECO:0000250|UniProtKB:P08592}.
SITE 713 714 Cleavage; by gamma-secretase; site 2.
{ECO:0000250|UniProtKB:P05067}.
SITE 720 721 Cleavage; by gamma-secretase; site 3.
{ECO:0000250|UniProtKB:P05067}.
SITE 739 740 Cleavage; by a caspase.
{ECO:0000250|UniProtKB:P05067}.
MOD_RES 198 198 Phosphoserine; by CK2.
{ECO:0000250|UniProtKB:P05067}.
MOD_RES 206 206 Phosphoserine; by CK1.
{ECO:0000250|UniProtKB:P05067}.
MOD_RES 441 441 Phosphoserine.
{ECO:0000244|PubMed:21183079}.
MOD_RES 497 497 Phosphotyrosine.
{ECO:0000250|UniProtKB:P05067}.
MOD_RES 729 729 Phosphothreonine.
{ECO:0000250|UniProtKB:P08592}.
MOD_RES 730 730 Phosphoserine; by APP-kinase I.
{ECO:0000250|UniProtKB:P08592}.
MOD_RES 743 743 Phosphothreonine; by CDK5 and MAPK10.
{ECO:0000250|UniProtKB:P05067}.
MOD_RES 757 757 Phosphotyrosine; by ABL1.
{ECO:0000269|PubMed:11279131}.
CARBOHYD 542 542 N-linked (GlcNAc...) asparagine.
{ECO:0000244|PDB:4YN0}.
CARBOHYD 571 571 N-linked (GlcNAc...) asparagine.
{ECO:0000305}.
DISULFID 38 62 {ECO:0000255|PROSITE-ProRule:PRU01217}.
DISULFID 73 117 {ECO:0000255|PROSITE-ProRule:PRU01217}.
DISULFID 98 105 {ECO:0000255|PROSITE-ProRule:PRU01217}.
DISULFID 133 187 {ECO:0000255|PROSITE-ProRule:PRU01217}.
DISULFID 144 174 {ECO:0000255|PROSITE-ProRule:PRU01217}.
DISULFID 158 186 {ECO:0000255|PROSITE-ProRule:PRU01217}.
DISULFID 291 341 {ECO:0000255|PROSITE-ProRule:PRU00031}.
DISULFID 300 324 {ECO:0000255|PROSITE-ProRule:PRU00031}.
DISULFID 316 337 {ECO:0000255|PROSITE-ProRule:PRU00031}.
CROSSLNK 763 763 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin).
{ECO:0000250|UniProtKB:P08592}.
VAR_SEQ 289 289 E -> V (in isoform APP695).
{ECO:0000303|PubMed:11235921,
ECO:0000303|PubMed:1756177,
ECO:0000303|PubMed:3322280}.
/FTId=VSP_000012.
VAR_SEQ 290 364 Missing (in isoform APP695).
{ECO:0000303|PubMed:11235921,
ECO:0000303|PubMed:1756177,
ECO:0000303|PubMed:3322280}.
/FTId=VSP_000013.
VAR_SEQ 346 380 Missing (in isoform APP751).
{ECO:0000305}.
/FTId=VSP_000014.
MUTAGEN 728 728 Y->A: No effect on MAPK8IP1 binding.
{ECO:0000269|PubMed:11517249}.
MUTAGEN 732 733 HH->GL,GP: Almost complete loss of
binding to G(o) alpha subunit. No
inhibition of GTPase activity.
MUTAGEN 743 743 T->E: No effect on MAPK8IP1 binding.
{ECO:0000269|PubMed:11517249}.
MUTAGEN 756 756 G->F,H,N,S,W: Greatly impairs interaction
with DAB2. {ECO:0000269|PubMed:11247302}.
MUTAGEN 756 756 G->Y: Impairs interaction with DAB2.
{ECO:0000269|PubMed:11247302}.
MUTAGEN 757 757 Y->F: Greatly promotes interaction with
DAB2. {ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
MUTAGEN 757 757 Y->G,H,V: Greatly impairs interaction
with DAB2. {ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
MUTAGEN 757 757 Y->G: No MAPK8IP1 nor APBA1 nor APBB1 nor
DAB1 binding.
{ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
MUTAGEN 757 757 Y->I,W: Impairs interaction with DAB2.
{ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
MUTAGEN 759 759 N->A: No MAPK8IP1 nor APBA1 nor Dab1
binding. No effect on APBB1 binding.
{ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
MUTAGEN 759 759 N->G,L,M,P: Greatly impairs interaction
with DAB2. {ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
MUTAGEN 760 760 P->E,F,I,K,L,Q,R,V,W,Y: Greatly impairs
interaction with DAB2.
{ECO:0000269|PubMed:11247302}.
MUTAGEN 762 762 Y->A: No MAPK8IP1 nor APBA1 nor Dab1
binding. No effect on APBB1 binding.
{ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
MUTAGEN 762 762 Y->W: Greatly impairs interaction with
DAB2. {ECO:0000269|PubMed:11247302,
ECO:0000269|PubMed:11517249}.
CONFLICT 211 211 G -> V (in Ref. 1; AAA37139).
{ECO:0000305}.
CONFLICT 375 375 V -> A (in Ref. 4; AAB41502).
{ECO:0000305}.
HELIX 382 419 {ECO:0000244|PDB:4YN0}.
TURN 420 422 {ECO:0000244|PDB:4YN0}.
HELIX 425 481 {ECO:0000244|PDB:4YN0}.
HELIX 487 518 {ECO:0000244|PDB:4YN0}.
HELIX 520 550 {ECO:0000244|PDB:4YN0}.
HELIX 552 581 {ECO:0000244|PDB:4YN0}.
HELIX 744 753 {ECO:0000244|PDB:2ROZ}.
SEQUENCE 770 AA; 86722 MW; 988D89E089092A3E CRC64;
MLPSLALLLL AAWTVRALEV PTDGNAGLLA EPQIAMFCGK LNMHMNVQNG KWESDPSGTK
TCIGTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHTH IVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDSVDSAD AEEDDSDVWW GGADTDYADG GEDKVVEVAE EEEVADVEEE
EADDDEDVED GDEVEEEAEE PYEEATERTT STATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCVPFF YGGCGGNRNN FDTEEYCMAV CGSVSTQSLL KTTSEPLPQD
PDKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPHHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHPFGVDSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
IKTEEISEVK MDAEFGHDSG FEVRHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL
VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN


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