Reviewed, UniProtKB/Swiss-Prot P05067 (A4_HUMAN)

Names and origin

Protein names

Recommended name:
    Amyloid beta A4 protein
Alternative name(s):
    Alzheimer disease amyloid protein
    ABPP
    APPI
      Short name=APP
    PreA4
    Cerebral vascular amyloid peptide
      Short name=CVAP
    Protease nexin-II
      Short name=PN-II
Cleaved into the following 12 chains:
    1- Recommended name:
            Soluble APP-alpha
                Short name=S-APP-alpha
    2- Recommended name:
            Soluble APP-beta
                Short name=S-APP-beta
    3- Recommended name:
            C99
    4- Recommended name:
            Beta-amyloid protein 42
        Alternative name(s):
            Beta-APP42
    5- Recommended name:
            Beta-amyloid protein 40
        Alternative name(s):
            Beta-APP40
    6- Recommended name:
            C83
    7- Recommended name:
            P3(42)
    8- Recommended name:
            P3(40)
    9- Recommended name:
            Gamma-secretase C-terminal fragment 59
        Alternative name(s):
            Gamma-CTF(59)
            Amyloid intracellular domain 59
              Short name=AICD-59
              Short name=AID(59)
    10- Recommended name:
            Gamma-secretase C-terminal fragment 57
        Alternative name(s):
            Gamma-CTF(57)
            Amyloid intracellular domain 57
              Short name=AICD-57
              Short name=AID(57)
    11- Recommended name:
            Gamma-secretase C-terminal fragment 50
        Alternative name(s):
            Gamma-CTF(50)
            Amyloid intracellular domain 50
              Short name=AICD-50
              Short name=AID(50)
    12- Recommended name:
            C31

Gene names

Name:	APP
Synonyms:	A4, AD1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	770 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

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/Tip60 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. 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. 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. Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain By similarity. The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.
Subunit structure	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 By similarity. Interacts with ANKS1B.
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 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.
Tissue specificity	Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex-opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra-striate and motor cortices. Expressed in cerebrospinal fluid, and plasma. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells. Isoform APP751 is the most abundant form in T-lymphocytes. Appican is expressed in astrocytes.
Induction	Increased levels during neuronal differentiation.
Domain	The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells. 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.
Post-translational modification	Proteolytically processed under normal cellular conditions. Cleavage by alpha-secretase or alternatively by beta-secretase leads to generation and extracellular release of soluble APP peptides, S-APP-alpha and S-APP-beta, respectively, and the retention of corresponding membrane-anchored C-terminal fragments, C83 and C99. Subsequent processing of 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). 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 peptides. 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. 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 heparin. 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 peptides.
Involvement in disease	Defects in APP are a cause of autosomal dominant Alzheimer disease (AD) [MIM:104300]. AD is the most prevelant form of dementia, characterized by neurofibrillary tangles and amyloid plaques deposition in the brain. Identical lesions occur in the neurons of aged Down syndrome but at an earlier age than in AD. The major constituent of these neuritic plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. Mutations occurring at the beta-amyloid N-terminal, such as the Swedish double mutation, appear to increase levels of beta-amyloid by facilitating beta-secretase cleavage resulting in elevated levels of both beta-APP42 and beta-APP40. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31, are also implicated in AD neuronal death. Alzheimer disease caused by mutations in APP is a rare occurrence and usually causes the familial or early-onset form of the disease (FAD). Flemish-type AD is characterized by, in addition to presenile dementia, cerebral hemorrhaging due to cerebral amyloid angiopathy which is similar to, but distinct from, cerebroarterial amyloidosis Dutch type. Only about 5% of all cases of Alzheimer disease are caused by FAD mutations, the rest are sporadic. Defects in APP are the cause of hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWAD) [MIM:609065]. HCHWAD is characterized by amyloid deposits in cerebral vessels. The principal clinical characteristics are recurring cerebral hemorrhages, sometimes preceded by migrainous headaches or mental cleavage. Beta-APP40 is the predominant form of cerebrovascular amyloid. Defects in APP are the cause of hereditary cerebroarterial amyloidosis Iowa type [MIM:605714]. Hereditary cerebroarterial amyloidosis Iowa type is an autosomal dominant dementia beginning in the sixth or seventh decade of life. The patients have progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. They do not present cerebral hemorrhaging.
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 similarities	Belongs to the APP family. Contains 1 BPTI/Kunitz inhibitor domain.
Mass spectrometry	Molecular weight is 6461.6 Da from positions 712 - 767. Determined by MALDI. Ref.56 Molecular weight is 6451.6 Da from positions 714 - 770. Determined by MALDI. Ref.56 Molecular weight is 6436.8 Da from positions 715 - 769. Determined by MALDI. Ref.56 Molecular weight is 5752.5 Da from positions 719 - 767. Determined by MALDI. Ref.56
Sequence caution	The sequence AAA58727.1 differs from that shown. Reason: Miscellaneous discrepancy. Contamination by an Alu repeat.

Ontologies

Keywords
Biological process	Apoptosis Cell adhesion Endocytosis Notch signaling pathway
Cellular component	Coated pit Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Alzheimer disease Amyloid Disease mutation
Domain	Signal Transmembrane
Ligand	Copper Heparin-binding Iron Metal-binding Zinc
Molecular function	Protease inhibitor Serine protease inhibitor
PTM	Glycoprotein Phosphoprotein Proteoglycan
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	cellular copper ion homeostasis Traceable author statement. Source: UniProtKB neuromuscular process Non-traceable author statement. Source: UniProtKB
Cellular component	cell surface Inferred from direct assay. Source: UniProtKB extracellular region Ref.73 Traceable author statement. Source: ProtInc integral to plasma membrane Ref.73 Traceable author statement. Source: ProtInc platelet alpha granule lumen Inferred from Experiment. Source: Reactome
Molecular function	acetylcholine receptor binding Ref.55 Inferred from physical interaction. Source: UniProtKB identical protein binding Inferred from physical interaction. Source: IntAct serine-type endopeptidase inhibitor activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-77613,EBI-77613
APBA1	Q02410	2	EBI-77613,EBI-368690
APBB1	O00213	2	EBI-77613,EBI-81694
Apbb1	P46933	1	EBI-77613,EBI-286177	From a different organism.
APBB2	Q92870	1	EBI-77613,EBI-79277
Apbb3	O35827	1	EBI-77613,EBI-286163	From a different organism.
APOA1	P02647	5	EBI-77613,EBI-701692
CHRNA7	P36544	1	EBI-77613,EBI-79333
Chrna7	Q05941	1	EBI-77613,EBI-79422	From a different organism.
HSD17B10	Q99714	2	EBI-77613,EBI-79964
MAPK8IP1	Q9UQF2	3	EBI-77613,EBI-78404
Mapk8ip1	Q9WVI9-1	1	EBI-77613,EBI-288461	From a different organism.
PRNP	P04156	1	EBI-77613,EBI-977302
SHC1	P29353	4	EBI-77613,EBI-78835
SHC3	Q92529	2	EBI-77613,EBI-79084
TGFB1	P01137	1	EBI-77613,EBI-779636
TGFB2	P61812	2	EBI-77613,EBI-779581
TP53BP2	Q13625	2	EBI-77613,EBI-77642

Alternative products

This entry describes 10 isoforms produced by alternative splicing. [Align] [Select]

Notes: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.

Isoform APP770 (identifier: P05067-1)

Also known as: PreA4 770;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Notes: A major isoform.

Isoform APP305 (identifier: P05067-2)

The sequence of this isoform differs from the canonical sequence as follows:
     290-305: VCSEQAETGPCRAMIS → KWYKEVHSGQARWLML
     306-770: Missing.

Isoform L-APP677 (identifier: P05067-3)

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-364: Missing.
     637-654: Missing.

Notes: The L-isoforms are referred to as appicans.

Isoform APP695 (identifier: P05067-4)

Also known as: PreA4 695;

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-364: Missing.

Notes: A major isoform.

Isoform L-APP696 (identifier: P05067-5)

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-345: Missing.
     637-654: Missing.

Notes: The L-isoforms are referred to as appicans.

Isoform APP714 (identifier: P05067-6)

The sequence of this isoform differs from the canonical sequence as follows:
     289-289: E → V
     290-345: Missing.

Isoform L-APP733 (identifier: P05067-7)

The sequence of this isoform differs from the canonical sequence as follows:
     345-345: M → I
     346-364: Missing.
     637-654: Missing.

Notes: The L-isoforms are referred to as appicans.

Isoform APP751 (identifier: P05067-8)

Also known as: PreA4 751;

The sequence of this isoform differs from the canonical sequence as follows:
     345-345: M → I
     346-364: Missing.

Notes: A major isoform.

Isoform L-APP752 (identifier: P05067-9)

The sequence of this isoform differs from the canonical sequence as follows:
     637-654: Missing.

Isoform APP639 (identifier: P05067-10)

The sequence of this isoform differs from the canonical sequence as follows:
     19-74: Missing.
     289-363: Missing.
     364-364: L → V

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Signal peptide	1 – 17	17
	Chain	18 – 770	753	Amyloid beta A4 protein
	Chain	18 – 687	670	Soluble APP-alpha
	Chain	18 – 671	654	Soluble APP-beta
	Chain	672 – 770	99	C99
	Chain	672 – 713	42	Beta-amyloid protein 42
	Chain	672 – 711	40	Beta-amyloid protein 40
	Chain	688 – 770	83	C83
	Peptide	688 – 713	26	P3(42)
	Peptide	688 – 711	24	P3(40)
	Chain	712 – 770	59	Gamma-secretase C-terminal fragment 59
	Chain	714 – 770	57	Gamma-secretase C-terminal fragment 57
	Chain	721 – 770	50	Gamma-secretase C-terminal fragment 50 By similarity
	Chain	740 – 770	31	C31
Regions
	Topological domain	18 – 699	682	Extracellular Potential
	Transmembrane	700 – 723	24	Potential
	Topological domain	724 – 770	47	Cytoplasmic Potential
	Domain	291 – 341	51	BPTI/Kunitz inhibitor
	Region	96 – 110	15	Heparin-binding
	Region	181 – 188	8	Zinc-binding
	Region	391 – 423	33	Heparin-binding
	Region	491 – 522	32	Heparin-binding
	Region	523 – 540	18	Collagen-binding
	Region	732 – 751	20	Interaction with G(o)-alpha
	Motif	724 – 734	11	Basolateral sorting signal
	Motif	759 – 762	4	NPXY motif; contains endocytosis signal
	Compositional bias	230 – 260	31	Asp/Glu-rich (acidic)
	Compositional bias	274 – 280	7	Poly-Thr
Sites
	Metal binding	137	1	Copper
	Metal binding	147	1	Copper
	Metal binding	149	1	Copper
	Metal binding	151	1	Copper Probable
	Metal binding	677	1	Copper or zinc
	Metal binding	681	1	Copper or zinc Probable
	Metal binding	684	1	Copper or zinc
	Metal binding	685	1	Copper or zinc
	Site	144	1	Required for Cu(2+) reduction
	Site	301 – 302	2	Reactive bond
	Site	671 – 672	2	Cleavage; by beta-secretase
	Site	672 – 673	2	Cleavage; by caspase-6; when associated with variant 670-N-L-671
	Site	687 – 688	2	Cleavage; by alpha-secretase
	Site	704	1	Implicated in free radical propagation By similarity
	Site	706	1	Susceptible to oxidation
	Site	711 – 712	2	Cleavage; by gamma-secretase; site 1
	Site	713 – 714	2	Cleavage; by gamma-secretase; site 2
	Site	720 – 721	2	Cleavage; by gamma-secretase; site 3
	Site	739 – 740	2	Cleavage; by caspase-6, caspase-8 or caspase-9
Amino acid modifications
	Modified residue	198	1	Phosphoserine; by CK2
	Modified residue	206	1	Phosphoserine; by CK1
	Modified residue	729	1	Phosphothreonine By similarity
	Modified residue	730	1	Phosphoserine; by APP-kinase I By similarity
	Modified residue	743	1	Phosphothreonine; by CDK5 and MAPK10
	Modified residue	757	1	Phosphotyrosine
	Modified residue	762	1	Phosphotyrosine
	Glycosylation	542	1	N-linked (GlcNAc...)
	Glycosylation	571	1	N-linked (GlcNAc...) Probable
	Glycosylation	656	1	O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms
	Disulfide bond	144 ↔ 158
	Disulfide bond	291 ↔ 341
	Disulfide bond	300 ↔ 324