Q95241 (A4_SAISC) Reviewed, UniProtKB/Swiss-Prot
Last modified April 3, 2013. Version 115. History...
Names and origin
|Protein names||Recommended name:|
Amyloid beta A4 protein
Alzheimer disease amyloid A4 protein homolog
Cleaved into the following 14 chains:
|Organism||Saimiri sciureus (Common squirrel monkey)|
|Taxonomic identifier||9521 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Platyrrhini › Cebidae › Saimiriinae › Saimiri|
|Sequence length||751 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at transcript level|
General annotation (Comments)
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-KAT5 and inhibit Notch signaling through interaction with Numb By similarity. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP By similarity. 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 By similarity. May be involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu2+-mediated low-density lipoprotein oxidation By similarity. 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. Provides Cu2+ ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1 By similarity.
Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron By similarity.
The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis By similarity.
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6) By similarity.
Binds, via its C-terminus, to the PID domain of several cytoplasmic proteins, including APBB family members, the APBA family, MAPK8IP1, and SHC1, NUMB and DAB1 By similarity. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. 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 with CPEB1, ANKS1B, TNFRSF21 and AGER By similarity. Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; this is promoted by heparin binding By similarity. Beta-amyloid protein 40 interacts with S100A9 By similarity.
Membrane; Single-pass type I membrane protein By similarity. 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-CTF59 peptide is located to both the is located to both the cytoplasm and nuclei of neurons. Associates with GPC1 in perinuclear compartments By similarity.
The basolateral sorting signal (BaSS) is required for sorting of membrane proteins to the basolateral surface of epithelial cells By similarity.
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 By similarity.
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-CTF50, gamma-CTF57 and gamma-CTF59 By similarity.
Proteolytically cleaved by caspases during neuronal apoptosis By similarity. Cleavage at Asp-720 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- and O-glycosylated 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 By similarity.
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) By similarity.
Beta-amyloid peptides are degraded by IDE By similarity.
Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between beta-amyloid molecules resulting in beta-amyloid-metal aggregates By similarity. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding By similarity.
Belongs to the APP family.
Contains 1 BPTI/Kunitz inhibitor domain.
|This entry describes 2 isoforms produced by alternative splicing. [Select]|
Note: Additional isoforms seem to exist.
|Isoform APP770 (identifier: Q95241-1) |
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: Q95241-2) |
The sequence of this isoform is not available.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Signal peptide||1 – 17||17||By similarity|
|Chain||18 – 751||734||Amyloid beta A4 protein||PRO_0000000172|
|Chain||18 – 668||651||Soluble APP-alpha Potential||PRO_0000000173|
|Chain||18 – 652||635||Soluble APP-beta Potential||PRO_0000000174|
|Chain||18 – 286||269||N-APP By similarity||PRO_0000381972|
|Chain||653 – 751||99||C99 Potential||PRO_0000000175|
|Chain||653 – 694||42||Beta-amyloid protein 42 Potential||PRO_0000000176|
|Chain||653 – 692||40||Beta-amyloid protein 40 Potential||PRO_0000000177|
|Chain||669 – 751||83||C83 Potential||PRO_0000000178|
|Peptide||669 – 694||26||P3(42) Potential||PRO_0000000179|
|Peptide||669 – 692||24||P3(40) Potential||PRO_0000000180|
|Chain||672 – 751||80||C80||PRO_0000384580|
|Chain||693 – 751||59||Gamma-secretase C-terminal fragment 59 Potential||PRO_0000000181|
|Chain||695 – 751||57||Gamma-secretase C-terminal fragment 57 Potential||PRO_0000000182|
|Chain||702 – 751||50||Gamma-secretase C-terminal fragment 50 Potential||PRO_0000000183|
|Chain||721 – 751||31||C31 Potential||PRO_0000000184|
|Topological domain||18 – 680||663||Extracellular Potential|
|Transmembrane||681 – 704||24||Helical; Potential|
|Topological domain||705 – 751||47||Cytoplasmic Potential|
|Domain||291 – 341||51||BPTI/Kunitz inhibitor|
|Region||96 – 110||15||Heparin-binding By similarity|
|Region||181 – 188||8||Zinc-binding By similarity|
|Region||316 – 344||29||Heparin-binding By similarity|
|Region||363 – 428||66||Heparin-binding By similarity|
|Region||504 – 521||18||Collagen-binding By similarity|
|Region||713 – 732||20||Interaction with G(o)-alpha By similarity|
|Motif||705 – 715||11||Basolateral sorting signal By similarity|
|Motif||740 – 743||4||NPXY motif; contains endocytosis signal|
|Compositional bias||230 – 260||31||Asp/Glu-rich (acidic)|
|Compositional bias||274 – 280||7||Poly-Thr|
|Metal binding||147||1||Copper 1 By similarity|
|Metal binding||151||1||Copper 1 By similarity|
|Metal binding||168||1||Copper 1 By similarity|
|Metal binding||658||1||Copper or zinc 2 By similarity|
|Metal binding||662||1||Copper or zinc 2 By similarity|
|Metal binding||665||1||Copper or zinc 2 By similarity|
|Metal binding||666||1||Copper or zinc 2 By similarity|
|Site||144||1||Required for Cu(2+) reduction By similarity|
|Site||301 – 302||2||Reactive bond|
|Site||652 – 653||2||Cleavage; by beta-secretase By similarity|
|Site||653 – 654||2||Cleavage; by caspase-6 By similarity|
|Site||668 – 669||2||Cleavage; by alpha-secretase By similarity|
|Site||671 – 672||2||Cleavage; by theta-secretase By similarity|
|Site||685||1||Implicated in free radical propagation By similarity|
|Site||687||1||Susceptible to oxidation By similarity|
|Site||692 – 693||2||Cleavage; by gamma-secretase; site 1 By similarity|
|Site||694 – 695||2||Cleavage; by gamma-secretase; site 2 By similarity|
|Site||701 – 702||2||Cleavage; by gamma-secretase; site 3 By similarity|
|Site||720 – 721||2||Cleavage; by caspase-6, caspase-8 or caspase-9 By similarity|
Amino acid modifications
|Modified residue||198||1||Phosphoserine; by CK1 and CK2 By similarity|
|Modified residue||206||1||Phosphoserine; by CK1 and CK2 By similarity|
|Modified residue||710||1||Phosphothreonine By similarity|
|Modified residue||711||1||Phosphoserine; by APP-kinase I By similarity|
|Modified residue||724||1||Phosphothreonine; by CDK5 and MAPK10 By similarity|
|Modified residue||738||1||Phosphotyrosine; by ABL1 By similarity|
|Glycosylation||523||1||N-linked (GlcNAc...) Probable|
|Glycosylation||552||1||N-linked (GlcNAc...) Probable|
|Disulfide bond||38 ↔ 62||By similarity|
|Disulfide bond||73 ↔ 117||By similarity|
|Disulfide bond||98 ↔ 105||By similarity|
|Disulfide bond||133 ↔ 187||By similarity|
|Disulfide bond||144 ↔ 174||By similarity|
|Disulfide bond||158 ↔ 186||By similarity|
|Disulfide bond||291 ↔ 341||By similarity|
|Disulfide bond||300 ↔ 324||By similarity|
|Disulfide bond||316 ↔ 337||By similarity|
|S81024 mRNA. Translation: AAD14347.1.|
3D structure databases
|SMR||Q95241. Positions 28-189, 287-342, 355-546, 653-694, 720-751. |
Protein family/group databases
Protocols and materials databases
Family and domain databases
|Gene3D||3.30.1490.140. 1 hit. |
3.90.570.10. 1 hit.
184.108.40.206. 1 hit.
4.10.410.10. 1 hit.
|InterPro||IPR008155. Amyloid_glyco. |
|Pfam||PF10515. APP_amyloid. 1 hit. |
PF12924. APP_Cu_bd. 1 hit.
PF12925. APP_E2. 1 hit.
PF02177. APP_N. 1 hit.
PF03494. Beta-APP. 1 hit.
PF00014. Kunitz_BPTI. 1 hit.
|PRINTS||PR00203. AMYLOIDA4. |
|SMART||SM00006. A4_EXTRA. 1 hit. |
SM00131. KU. 1 hit.
|SUPFAM||SSF56491. A4_extra. 1 hit. |
SSF89811. Amyloid_glyco_Cu-bd. 1 hit.
SSF57362. Prot_inh_Kunz-m. 1 hit.
SSF109843. SSF109843. 1 hit.
|PROSITE||PS00319. A4_EXTRA. 1 hit. |
PS00320. A4_INTRA. 1 hit.
PS00280. BPTI_KUNITZ_1. 1 hit.
PS50279. BPTI_KUNITZ_2. 1 hit.
|Accession||Primary (citable) accession number: Q95241|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families