Reviewed, UniProtKB/Swiss-Prot P08592 (A4_RAT)

Names and origin

Protein names

Recommended name:
    Amyloid beta A4 protein
Alternative name(s):
    Alzheimer disease amyloid A4 protein homolog
    ABPP
      Short name=APP
    Amyloidogenic glycoprotein
      Short name=AG
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)
    10- Recommended name:
            Gamma-secretase C-terminal fragment 57
        Alternative name(s):
            Gamma-CTF(57)
    11- Recommended name:
            Gamma-secretase C-terminal fragment 50
        Alternative name(s):
            Gamma-CTF(50)
    12- Recommended name:
            C31

Gene names

Name:

App

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

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 By similarity. Can promote transcription activation through binding to APBB1/Tip60 and inhibit Notch signaling through interaction with Numb By similarity. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1 By similarity. 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 By similarity. Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. Rat and mouse beta-amyloid peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation By similarity. Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain. The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis By similarity.
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), APPBP2 (via BaSS) By similarity 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 By similarity. Beta-amyloid associates with HADH2 By similarity. Interacts with CPEB1 and ANKS1B By similarity.
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 By similarity. Beta-APP42 associates with FPRL1 at the cell surface and the complex is then rapidly internalized By similarity. APP sorts to the basolateral surface in epithelial cells By similarity. During neuronal differentiation, the Thr-743 phosphorylated form is located mainly in growth cones, moderately in neurites and sparingly in the cell body.
Tissue specificity	In the brain, non-L-APP isoforms are expressed in neurons, isoform APP695 being the predominant form. In astrocytes and microglial cells, almost 50% is L-appican).
Developmental stage	From 6 days to 7 months, levels of KPI-containing isoforms increase in the brain cortex and hippocampus. Levels of L-APP increase in all brian regions during the same period, but levels are low compared to non-L-APP isoforms.
Induction	Phosphorylation of mature, glycosylated APP occurs 48-72 hours after treatment of neuronal cells with nerve growth factor which correlates with the timing of neurite outgrowth.
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 By similarity. Cleavage at Asp-739 by either caspase-3, -8 or -9 results in the production of the neurotoxic C31 peptide and the increased production of beta-amyloid peptides By similarity. N-glycosylated. 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. 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. 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 By similarity.
Miscellaneous	Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates. Rat and mouse beta-amyloid peptides have an arginine residue substituted for the bridging histidine residue and are thus less capable of forming amyloid aggegates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding By similarity.
Sequence similarities	Belongs to the APP family. Contains 1 BPTI/Kunitz inhibitor domain.
Mass spectrometry	Molecular weight is 5911.3 Da from positions 721 - 770. Determined by MALDI. Ref.6 Molecular weight is 6024.4 Da from positions 720 - 770. Determined by MALDI. Ref.6

Ontologies

Keywords
Biological process	Apoptosis Cell adhesion Endocytosis Notch signaling pathway
Cellular component	Coated pit Membrane
Coding sequence diversity	Alternative splicing
Disease	Amyloid
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)
Molecular function	protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Apbb1	P46933	1	EBI-286155,EBI-286177
Apbb3	O35827	1	EBI-286155,EBI-286163

Alternative products

This entry describes 8 isoforms produced by alternative splicing. [Align] [Select]

Isoform APP770 (identifier: P08592-1)

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.

Isoform APP695 (identifier: P08592-2)

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

Isoform L-APP677 (identifier: P08592-3)

The sequence of this isoform is not available.

Notes: L-isoforms are referred to as appicans.

Isoform L-APP696 (identifier: P08592-4)

The sequence of this isoform is not available.

Notes: L-isoforms are referred to as appicans.

Isoform APP714 (identifier: P08592-5)

The sequence of this isoform is not available.

Isoform L-APP733 (identifier: P08592-6)

The sequence of this isoform is not available.

Notes: L-isoforms are referred to as appicans.

Isoform APP751 (identifier: P08592-7)

The sequence of this isoform is not available.

Isoform L-APP752 (identifier: P08592-8)

The sequence of this isoform is not available.

Notes: L-isoforms are referred to as appicans.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Signal peptide

1 – 17

17

By similarity

Chain

18 – 770

753

Amyloid beta A4 protein

Chain

18 – 687

670

Soluble APP-alpha By similarity

Chain

18 – 671

654

Soluble APP-beta Potential

Chain

672 – 770

99

C99 Potential

Chain

672 – 713

42

Beta-amyloid protein 42 By similarity

Chain

672 – 711

40

Beta-amyloid protein 40 By similarity

Chain

688 – 770

83

C83 By similarity

Peptide

688 – 713

26

P3(42) By similarity

Peptide

688 – 711

24

P3(40) By similarity

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

Chain

740 – 770

31

C31 By similarity

Regions

Topological domain

18 – 699

682

Extracellular Potential

Transmembrane

700 – 723

24

Potential

Topological domain

724 – 770

47

Cytoplasmic By similarity

Domain

291 – 341

51

BPTI/Kunitz inhibitor

Region

96 – 110

15

Heparin-binding By similarity

Region

135 – 155

21

Copper-binding By similarity

Region

181 – 188

8

Zinc-binding By similarity

Region

391 – 423

33

Heparin-binding By similarity

Region

491 – 522

32

Heparin-binding By similarity

Region

523 – 540

18

Collagen-binding By similarity

Region

732 – 751

20

Interaction with G(o)-alpha

Motif

724 – 734

11

Basolateral sorting signal By similarity

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 By similarity

Metal binding

147

1

Copper By similarity

Metal binding

149

1

Copper By similarity

Metal binding

151

1

Copper Probable

Metal binding

677

1

Copper or zinc By similarity

Metal binding

685

1

Copper or zinc By similarity

Site

144

1

Required for Cu(2+) reduction By similarity

Site

301 – 302

2

Reactive bond By similarity

Site

671 – 672

2

Cleavage; by beta-secretase By similarity

Site

672 – 673

2

Cleavage; by caspase-6

Site

687 – 688

2

Cleavage; by alpha-secretase By similarity

Site

711 – 712

2

Cleavage; by gamma-secretase; site 1 By similarity

Site

713 – 714

2

Cleavage; by gamma-secretase; site 2 By similarity

Site

720 – 721

2

Cleavage; by gamma-secretase; site 3 By similarity

Site

739 – 740

2

Cleavage; by caspase-6, caspase-8 or caspase-9 By similarity

Amino acid modifications

Modified residue

198

1

Phosphoserine; by CK2 By similarity

Modified residue

206

1

Phosphoserine; by CK1 By similarity

Modified residue

729

1

Phosphothreonine

Modified residue

730

1

Phosphoserine; by APP-kinase I

Modified residue

743

1

Phosphothreonine; by CDK5 and MAPK10

Modified residue

757

1

Phosphotyrosine By similarity

Modified residue

762

1

Phosphotyrosine By similarity

Glycosylation

542

1

N-linked (GlcNAc...) Potential

Glycosylation

571

1

N-linked (GlcNAc...) Potential

Glycosylation

656

1

O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms

Disulfide bond

144 ↔ 158

By similarity

Disulfide bond

291 ↔ 341

By similarity

Disulfide bond

300 ↔ 324

By similarity

Disulfide bond

316 ↔ 337

By similarity

Natural variations

Alternative sequence

289

1

E → V in isoform APP695.

Alternative sequence

290 – 364

75

Missing in isoform APP695.

Experimental info

Mutagenesis

656

1

S → A: No chondroitin sulfate linkage to isoform L-APP733

Mutagenesis

704

1

G → V: Little oxidized neuronal proteins. Scarce beta-APP42 peptide aggregation. No neurotoxicity

Mutagenesis

732 – 733

2

HH → GL or GP: Almost complete loss of binding to GNAO1. No inhibition of GTPase activity

Mutagenesis

743

1

T → A: No effect on neurite growth and maturation

Mutagenesis

743

1

T → E: Inhibits neurite growth and maturation

Mutagenesis

757

1

Y → G: No DBB1 binding

Mutagenesis

759

1

N → A: Some DBB1 binding

Mutagenesis

762

1

Y → A: Some DBB1 binding

Secondary structure

1

.

.

.

.

770

Helix Strand Turn

Details...

Turn

679 – 686

8

Helix

687 – 695

9