Home
GeneCards Guide
Suite
- GeneALaCart
- GeneDecks
- GeneIP
- GeneNote
- GeneAnnot
- GeneLoc
- GeneTide
Terms and Conditions
- Terms of Use
- 3rd Party Notice
About Us
User Feedback
Mirror sites

Set Analyses:

Generates a file of GeneCards annotations for your list of genes

Advanced Search

APP Gene

protein-coding GIFtS: 75

GC21M012656

amyloid beta (A4) precursor protein
(Previous name: Alzheimer disease )
Symbol approved by the HUGO Gene Nomenclature Committee (HGNC) database
(Previous symbol: AD1)

		Products

(According to ¹HGNC, ²Entrez Gene,
³UniProtKB/Swiss-Prot, ⁴UniProtKB/TrEMBL, ⁵OMIM, ⁶GeneLoc , and/or ⁷Ensembl, ⁸miRBase, and/or ⁹Nature:405,311-319 and CroW21)
About This Section

Aliases & Descriptions
amyloid beta (A4) precursor protein¹ ²		beta-amyloid peptide²
AD1² ³ ⁵		preA4²
CVAP² ³ ⁵		ABETA²
Alzheimer disease amyloid protein² ³		CTFgamma²
Cerebral vascular amyloid peptide² ³		OTTHUMP00000096096²
Protease nexin-II² ³		PN2²
PN-II² ³		amyloid beta A4 protein²
APPI² ³		peptidase nexin-II²
ABPP² ³		A4³
AAA² ⁵		PreA4³
Alzheimer disease¹		human mRNA for amyloid A4 precursor of Alzheimer's disease9

External Ids:	HGNC: 620¹	Entrez Gene: 351²	Ensembl: ENSG00000142192⁷	UniProtKB: P05067³

Export aliases for APP gene to outside databases

Previous GC identifers: GC21M023831 GC21M026174 GC21M027252

(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for APP:

This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a

number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to

promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of

patients with Alzheimer disease. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease

and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different

isoforms have been found for this gene. (provided by RefSeq)

UniProtKB/Swiss-Prot: A4_HUMAN, P05067

Function: 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. Can promote transcription activation through binding to APBB1-KAT5 and inhibits 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. Involved in copper homeostasis/oxidative stress through copper ion

reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated

low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular

matrix such as heparin and collagen I and IV. 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

Function: Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such

as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is

a more effective reductant than beta-amyloid 40. 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. Beta-APP42 may

activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK

II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity

Function: Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in

the brain (By similarity)

Function: The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of

neuronal apoptosis

Function: N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via

caspase-3) and axons (via caspase-6)

summary for APP:

Amyloid beta (Abeta) peptides are the major component of amyloid plaques found in the brains of Alzheimer's

patients. Abeta is formed from the progressive cleavage of amyloid precursor protein (APP) by beta- and

gamma-secretase. Two Abeta peptides are formed from APP degradation; Abeta40 and Abeta42. Abeta40 is the

most abundant form, but Abeta42 is more fibrillogenic, thus is associated with disease states. Mutations in

APP have been linked to early onset Alzheimer's disease, as proteolytic cleavage of the altered protein

increases the levels of Abeta42 relative to Abeta40. Furthermore, Abeta proteins have been associated with

other diseases including Lewy body dementia, inclusion body myositis and cerebral amyloid angiopathy.

Gene Wiki entry for APP (Amyloid precursor protein)

(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 60), Regulatory elements and Epigenetics data according to Qiagen and/or SABiosciences, Whole Chromsome Sequence According to Nature (Cited Here with Permission):405,311-319 and CroW21)
About This Section

Regulatory elements:

SABiosciences Regulatory transcription factor binding sites in the APP gene promoter:
         deltaCREB   CREB   C/EBPbeta   TBP   c-Myc   Max1   TFIID   NF-1   p53   ATF
         Other transcription factors

Search SABiosciences Chromatin IP Primers for APP

Epigenetics:

QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays for APP

Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 21q21.2|21q21.3 Ensembl cytogenetic band: 21q21.3 HGNC cytogenetic band: 21q21.2
Nature(405: 311-319) cytogenetic band: 21q21.3

APP Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
APP gene location

GeneLoc gene densities for chromosome 21 GeneLoc Exon Structure

(about GC identifiers)

GC21M012656:	GeneLoc	Nature:405,311-319
Start:	12,656,350 bp from pter	12,830,594 bp from centromere
End:	12,947,658 bp from pter	13,120,880 bp from centromere
Size:	291,309 bases	290,287 bases
Orientation:	minus strand	minus strand

1 alternative location:

Chr21- 27,252,861-27,543,446

RefSeq DNA sequence:

NC_000021.8 NT_011512.11

Whole chromosome sequencing:
cDNA sequence:	Y00264
genomic clones:	pT364 to Q22F1

(According to ¹UniProtKB, neXtProt, and/or Ensembl, Phosphorylation sites according to ²Phosphosite, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from Millipore, Sigma-Aldrich, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, and/or ProSpec,
Biochemical Assays by Millipore, Sigma-Aldrich, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Dec 2010 and Entrez Gene, Antibodies by Millipore, Sigma-Aldrich, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, and/or Epitomics)
About This Section

UniProtKB/Swiss-Prot: A4_HUMAN, P05067 (See protein sequence)

Recommended Name: Amyloid beta A4 protein precursor

Size: 770 amino acids; 86943 Da

Subunit: Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members,

the APBA family, MAPK8IP1, SHC1 and, NUMB and DAB1 (By similarity). Binding to DAB1 inhibits its serine

phosphorylation (By similarity). Also interacts with GPCR-like protein BPP, FPRL1, APPBP1, IB1, KNS2 (via its TPR

domains) (By similarity), APPBP2 (via BaSS) and DDB1. 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. Amyloid beta-42 binds CHRNA7 in hippocampal neurons. Beta-amyloid

associates with HADH2. Soluble APP binds, via its N-terminal head, to FBLN1. Interacts with CPEB1 and AGER (By

similarity). Interacts with ANKS1B and TNFRSF21. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can

form homodimers; this is promoted by heparin binding

Subcellular location: Membrane; Single-pass type I membrane protein. Membrane, clathrin-coated pit. Note=Cell surface

protein that rapidly becomes internalized via clathrin-coated pits. 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. Gamma-CTF(59) peptide is located to both the

cytoplasm and nuclei of neurons. It can be translocated to the nucleus through association with APBB1 (Fe65).

Beta-APP42 associates with FRPL1 at the cell surface and the complex is then rapidly internalized. 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

Mass spectrometry: Mass=6461.6; Method=MALDI; Range=712-767; Source=PubMed:12214090;

Mass spectrometry: Mass=6451.6; Method=MALDI; Range=714-770; Source=PubMed:12214090;

Mass spectrometry: Mass=6436.8; Method=MALDI; Range=715-769; Source=PubMed:12214090;

Mass spectrometry: Mass=5752.5; Method=MALDI; Range=719-767; Source=PubMed:12214090;

Miscellaneous: Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between

beta-amyloid molecules resulting in beta-amyloid-metal aggregates. The affinity for copper is much higher than for

other transient metals and is increased under acidic conditions. Extracellular zinc-binding increases binding of

heparin to APP and inhibits collagen-binding

Sequence caution: Sequence=AAA58727.1; Type=Miscellaneous discrepancy; Note=Contamination by an Alu repeat;

PDB structures from and Proteopedia :

1AAP (3D)

1AMB (3D)

1AMC (3D)

1AML (3D)

1BA4 (3D)

1BA6 (3D)

1BJB (3D)

1BJC (3D)

1BRC (3D)

1CA0 (3D)

1HZ3 (3D)

1IYT (3D)

1MWP (3D)

1OWT (3D)

1QCM (3D)

1QWP (3D)

1QXC (3D)

1QYT (3D)

1RW6 (3D)

1TAW (3D)

1TKN (3D)

1UO7 (3D)

1UO8 (3D)

1UOA (3D)

1UOI (3D)

1X11 (3D)

1Z0Q (3D)

1ZE7 (3D)

1ZE9 (3D)

1ZJD (3D)

2BEG (3D)

2BOM (3D)

2BP4 (3D)

2FJZ (3D)

2FK1 (3D)

2FK2 (3D)

2FK3 (3D)

2FKL (3D)

2FMA (3D)

2G47 (3D)

2IPU (3D)

2OTK (3D)

2R0W (3D)

2WK3 (3D)

3DXC (3D)

3DXD (3D)

3DXE (3D)

3GCI (3D)

3IFL (3D)

3IFN (3D)

3IFO (3D)

3IFP (3D)

3JTI (3D)

3KTM (3D)

3L33 (3D)

3L81 (3D)

Secondary accessions: B2R5V1 P09000 P78438 Q13764 Q13778 Q13793 Q16011 Q16014 Q16019 Q16020 Q6GSC0

Q8WZ99 Q9BT38 Q9UC33 Q9UCA9 Q9UCB6 Q9UCC8 Q9UCD1 Q9UQ58

Alternative splicing: 10 isoforms: P05067-1 P05067-2 P05067-3 P05067-4 P05067-5 P05067-6 P05067-7 P05067-8

P05067-9 P05067-10 (Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms)

Explore the universe of human proteins at neXtProt for APP: NX_P05067

Post-translational modifications:

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)¹

Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-6, -8 or -9

results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides¹

N- and O-glycosylated. O-linkage of chondroitin sulfate to the L-APP isoforms produces the APP proteoglycan core

proteins, the appicans. The chondroitin sulfate chain of appicans contains 4-O-sulfated galactose in the linkage

region and chondroitin sulfate E in the repeated disaccharide region (By similarity)¹

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. Phosphorylated on Thr-743 in

neuronal cells by Cdc5 kinase and Mapk10, in dividing cells by Cdc2 kinase in a cell-cycle dependent manner with

maximal levels at the G2/M phase and, in vitro, by GSK-3-beta. The Thr-743 phosphorylated form causes a conformational

change which reduces binding of Fe65 family members. Phosphorylation on Tyr-757 is required for SHC binding.

Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP. This

phosphorylation is inhibited by heparin¹

Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the

formation of a disulfide bond. In vitro, the APP-Cu(+) complex in the presence of hydrogen peroxide results in an

increased production of beta-amyloid-containing peptides¹

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)¹

Beta-amyloid peptides are degraded by IDE¹

View phosphorylation sites using PhosphoSite²

REFSEQ proteins (5 alternative transcripts):

NP_000475.1 NP_001129601.1 NP_001129602.1 NP_958816.1 NP_958817.1

ENSEMBL proteins:

ENSP00000388538 ENSP00000397795 ENSP00000346129 ENSP00000351796 ENSP00000406539 ENSP00000398879

ENSP00000352760 ENSP00000350578 ENSP00000345463 ENSP00000396923 ENSP00000284981 ENSP00000387483

ENSP00000413101

Human Recombinant Proteins

	Millipore Purified and/or Recombinant APP Protein
	Sigma-Aldrich Proteins for APP
	R&D Systems Recombinant & Natural Proteins for APP (APP+1, APP)
	Browse recombinant and purified proteins available from Enzo Life Sciences
	OriGene Purified Protein: APP OriGene Protein Over-expression Lysate (see all 3): APP
	GenScript Purified and Recombinant Proteins for APP
	Novus Biologicals Proteins for APP
	Novus Biologicals Lysate for APP
	Sino Biological Recombinant Protein for APP
	Browse ProSpec Recombinant Proteins

5/24 Gene Ontology (GO) cellular component terms (GO ID links to tree view) (see all 24):

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0005576	extracellular region	TAS	--
GO:0005624	membrane fraction	--	--
GO:0005737	cytoplasm	ISS	--
GO:0005794	Golgi apparatus	ISS	--
GO:0005886	plasma membrane	IDA	12805363

About this table

APP for ontologies About GeneDecksing

Antibodies for APP:

	Millipore Mono- and Polyclonal Antibodies for the study of APP
	Sigma-Aldrich Antibody Arrays and Antibodies for APP
	R&D Systems Antibodies for APP (APP 695+1, APP+1, APP)
	Cell Signaling Technology (CST) Antibodies for APP
	OriGene Antibodies (see all 19): APP
	GenScript Superior Antibodies for APP
	Novus Biologicals Antibodies for APP
	Epitomics antibodies for APP

Assays for APP:

	Millipore Kits and Assays for the Analysis of APP
	Browse ELISAs at Sigma-Aldrich
	OriGene Custom Immunoassay Development Browse OriGene Fluorogenic Cell Assay Kits
	R&D Systems ELISAs for APP
	GenScript Custom Assay Services for APP
	Browse Enzo Life Sciences for kits & assays
	Uscn ELISAs and CLIAs for APP

(According to InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
About This Section

APP for domains About GeneDecksing

5/10 InterPro domains/families (see all 10):

IPR002223 Prot_inh_Kunz-m

IPR008154 Amyloid_glyco_extra

IPR020901 Prtase_inh_Kunz-CS

IPR011178 Amyloid_glyco_Cu-bd

IPR013803 Amyloid_glyco_Abeta

Graphical View of Domain Structure for InterPro Entry P05067

ProtoNet protein and cluster: P05067

2 Blocks protein families:

IPB002223 Pancreatic trypsin inhibitor (Kunitz)

IPB008155 Amyloidogenic glycoprotein (Amyloid A4)

UniProtKB/Swiss-Prot: A4_HUMAN, P05067

Domain: The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface

of epithelial cells

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 NPXY site is also involved

in clathrin-mediated endocytosis

Similarity: Belongs to the APP family

Similarity: Contains 1 BPTI/Kunitz inhibitor domain

(According to UniProtKB, IUBMB,and/or Genatlas, Animal models from MGI Dec 24 2010,
shRNA from OriGene, Sigma-Aldrich, RNAi from Millipore, siRNAs from Sigma-Aldrich, OriGene, Qiagen, Super-pooled esiRNAs from Sigma-Aldrich, microRNA from Sigma-Aldrich, Qiagen, SABiosciences, Clones from Millipore, Sigma-Aldrich, OriGene, GenScript, Sino Biological, Cell Lines from GenScript, Ontologies according to Gene Ontology Consortium 01 Dec 2010 via Entrez Gene.)
About This Section