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Category Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21

GIFtS
-

APP Gene

protein-coding GIFtS: 76
GCID: GC21M027252

amyloid beta (A4) precursor protein

(Previous name: Alzheimer disease )
(Previous symbol: AD1)

Explore 138 diseases affiliated with
APP via

MalaCards

our new
Human Malady Compendium

(According to ¹HGNC, ²Entrez Gene,
³UniProtKB/Swiss-Prot, ⁴UniProtKB/TrEMBL, ⁵OMIM, ⁶GeneLoc, ⁷Ensembl, ⁸DME, ⁹miRBase, ¹⁰fRNAdb, and/or ¹¹Nature:405,311-319 and CroW21)
About This Section

Aliases
Amyloid Beta (A4) Precursor Protein¹ ²		Human MRNA For Amyloid A4 Precursor Of Alzheimer'S Disease11
AD1¹ ² ³ ⁵		ABETA²
CVAP² ³ ⁵		CTFgamma²
Alzheimer Disease Amyloid Protein² ³		PN2²
Cerebral Vascular Amyloid Peptide² ³		Amyloid Beta A4 Protein²
Protease Nexin-II² ³		Beta-Amyloid Peptide²
ABPP² ³		Peptidase Nexin-II²
APPI² ³		PreA4³
PN-II² ³		A4³
AAA² ⁵		PreA4³
Alzheimer Disease¹

External Ids:	HGNC: 620¹	Entrez Gene: 351²	Ensembl: ENSG00000142192⁷	OMIM: 104760⁵	UniProtKB: P05067³

Export aliases for APP gene to outside databases

Previous GC identifers: GC21M023831 GC21M026174 GC21M012656

(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
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, Jul 2008)

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.

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

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 Also bind GPC1 in lipid rafts

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 69), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics, Whole Chromsome Sequence According to Nature (Cited Here with Permission):405,311-319 and CroW21)
About This Section

RefSeq DNA sequence:

NC_000021.8 NC_018932.1 NT_011512.11

Regulatory elements:

SABiosciences Regulatory transcription factor binding sites in the APP gene promoter:
TBP
Other transcription factors

SwitchGear Promoter luciferase reporter plasmids (see all 16): APP promoter sequence

Search SABiosciences Chromatin IP Primers for APP

Epigenetics:

QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat APP

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

Entrez Gene cytogenetic band: 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 information about chromosome 21 GeneLoc Exon Structure

(about GC identifiers)

GC21M027252:	GeneLoc	Nature:405,311-319
Start:	27,252,861 bp from pter	12,830,594 bp from centromere
End:	27,543,446 bp from pter	13,120,880 bp from centromere
Size:	290,586 bases	290,287 bases
Orientation:	minus strand	minus strand

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

(According to ¹UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to ²PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE MOPED and PaxDb, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Uscn,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Mar 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, and/or Uscn)
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). 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, 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. Beta-amyloid protein 40 interacts with S100A9

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. Associates with GPC1 in perinuclear compartments

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;

6/82 PDB 3D structures from and Proteopedia for APP (see all 82):

1AAP (3D)

1AMB (3D)

1AMC (3D)

1AML (3D)

1BA4 (3D)

1BA6 (3D)

Secondary accessions: B2R5V1 B4DII8 D3DSD1 D3DSD2 D3DSD3 P09000 P78438 Q13764 Q13778 Q13793 Q16011

Q16014 Q16019 Q16020 Q6GSC0 Q8WZ99 Q9BT38 Q9UC33 Q9UCA9 Q9UCB6 Q9UCC8 Q9UCD1 Q9UQ58

Alternative splicing: 11 isoforms: P05067-1 P05067-2 P05067-3 P05067-4 P05067-5 P05067-6 P05067-7 P05067-8

P05067-9 P05067-10 P05067-11 (A major isoform)

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). Many other minor beta-amyloid peptides,

beta-amyloid 1-X peptides, are found in cerebral spinal fluid (CSF) including the beta-amyloid X-15 peptides, produced

from the cleavage by alpha-secretase and all terminatiing at Gln-686¹

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-glycosylation on Ser and Thr residues with core 1 or possibly core 8 glycans. Partial tyrosine

glycosylation (Tyr-681) is found on some minor, short beta-amyloid peptides (beta-amyloid 1-15, 1-16, 1-17, 1-18, 1-19

and 1-20) but not found on beta-amyloid 38, beta-amyloid 40 nor on beta-amyloid 42. Modification on a tyrosine is

unusual and is more prevelant in AD patients. Glycans had Neu5AcHex(Neu5Ac)HexNAc-O-Tyr,

Neu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr and O-AcNeu5AcNeu5AcHex(Neu5Ac)HexNAc-O-Tyr structures, where O-Ac is

O-acetylation of Neu5Ac. Neu5AcNeu5Ac is most likely Neu5Ac 2,8Neu5Ac linked. O-glycosylations in the vicinity of the

cleavage sites may influence the proteolytic processing. Appicans are L-APP isoforms with O-linked chondroitin sulfate¹

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 modification sites using PhosphoSitePlus²

View neXtProt modification sites for NX_P05067

APP Protein expression data from MOPED and PaxDb: About this image

REFSEQ proteins (10 alternative transcripts):

NP_000475.1 NP_001129488.1 NP_001129601.1 NP_001129602.1 NP_001129603.1 NP_001191230.1 NP_001191231.1 NP_001191232.1

NP_958816.1 NP_958817.1

ENSEMBL proteins:

ENSP00000284981 ENSP00000346129 ENSP00000345463 ENSP00000350578 ENSP00000398879

ENSP00000397795 ENSP00000396923 ENSP00000406539 ENSP00000351796 ENSP00000352760

ENSP00000387483 ENSP00000388538

Reactome Protein details: P05067
Human Recombinant Protein Products:

	EMD Millipore Purified and/or Recombinant APP Protein
	R&D Systems Recombinant & Natural Proteins for APP (APP+1, APP)
	Browse recombinant and purified proteins available from Enzo Life Sciences
	OriGene Purified Proteins (see all 2): APP OriGene Protein Over-expression Lysate (see all 3): APP OriGene Custom Protein Services for APP
	GenScript Custom Purified and Recombinant Proteins Services for APP
	Novus Biologicals APP Proteins Novus Biologicals APP Lysates
	Sino Biological Recombinant Protein for APP
	ProSpec Recombinant Protein for APP
	Uscn Proteins for APP

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

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:0005829	cytosol	TAS	--

APP for ontologies About GeneDecksing

APP Antibody Products:

	EMD Millipore Mono- and Polyclonal Antibodies for the study of APP
	R&D Systems Antibodies for APP (APP 695+1, APP+1, APP)
	Cell Signaling Technology (CST) Antibodies for APP
	OriGene Antibodies (see all 27): APP OriGene Custom Antibody Services for APP
	GenScript Superior Antibodies for APP
	Novus Biologicals APP Antibodies
	Abcam antibodies for APP
	Uscn Antibodies for APP
	ThermoFisher Antibodies for APP

Assay Products for APP:

	EMD Millipore Kits and Assays for the Analysis of APP
	OriGene Custom Immunoassay Development Browse OriGene Fluorogenic Cell Assay Kits
	R&D Systems ELISAs for APP (see all)
	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

5/11 InterPro domains/families (see all 11):

IPR024329 Amyloid_glyco_E2_domain

IPR019745 Amyloid_glyco_intracell_CS

IPR002223 Prot_inh_Kunz-m

IPR008155 Amyloid_glyco

IPR008154 Amyloid_glyco_extra

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 ¹UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or ²DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013,
bound targets from SABiosciences, miRNA Gene Targets from miRTarBase shRNA from OriGene, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, LifeMap BioReagents, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene.)
About This Section

Function Summary: