Q95241 (A4_SAISC) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Amyloid beta A4 protein

Alternative name(s):
ABPP
Short name=APP
Alzheimer disease amyloid A4 protein homolog

Cleaved into the following 14 chains:

1. N-APP
2. Soluble APP-alpha
   Short name=S-APP-alpha
3. Soluble APP-beta
   Short name=S-APP-beta
4. C99
5. Beta-amyloid protein 42
   Alternative name(s):
   Beta-APP42
6. Beta-amyloid protein 40
   Alternative name(s):
   Beta-APP40
7. C83
8. P3(42)
9. P3(40)
10. C80
11. Gamma-secretase C-terminal fragment 59
    Alternative name(s):
    Gamma-CTF(59)
12. Gamma-secretase C-terminal fragment 57
    Alternative name(s):
    Gamma-CTF(57)
13. Gamma-secretase C-terminal fragment 50
    Alternative name(s):
    Gamma-CTF(50)
14. C31

Gene names

Name:

APP

Organism

Saimiri sciureus (Common squirrel monkey)

Taxonomic identifier

9521 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Platyrrhini › Cebidae › Saimiriinae › Saimiri

Protein attributes

Sequence length	751 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at transcript 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-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.
Subunit structure	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.
Subcellular location	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.
Domain	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.
Post-translational modification	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.
Miscellaneous	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.
Sequence similarities	Belongs to the APP family. Contains 1 BPTI/Kunitz inhibitor domain.

Ontologies

Keywords
Biological process	Apoptosis Cell adhesion Endocytosis Notch signaling pathway
Cellular component	Amyloid Coated pit Membrane
Coding sequence diversity	Alternative splicing
Domain	Signal Transmembrane Transmembrane helix
Ligand	Copper Heparin-binding Iron Metal-binding Zinc
Molecular function	Protease inhibitor Serine protease inhibitor
PTM	Disulfide bond Glycoprotein Phosphoprotein Proteoglycan
Gene Ontology (GO)
Biological_process	G2 phase of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB Notch signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW adult locomotory behavior Inferred from sequence or structural similarity. Source: UniProtKB apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW axon cargo transport Inferred from sequence or structural similarity. Source: UniProtKB axon midline choice point recognition Inferred from sequence or structural similarity. Source: UniProtKB cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW cellular copper ion homeostasis Inferred from sequence or structural similarity. Source: UniProtKB collateral sprouting in absence of injury Inferred from sequence or structural similarity. Source: UniProtKB dendrite development Inferred from sequence or structural similarity. Source: UniProtKB endocytosis Inferred from sequence or structural similarity. Source: UniProtKB extracellular matrix organization Inferred from sequence or structural similarity. Source: UniProtKB ionotropic glutamate receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB mRNA polyadenylation Inferred from sequence or structural similarity. Source: UniProtKB mating behavior Inferred from sequence or structural similarity. Source: UniProtKB neuron remodeling Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB protein phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of epidermal growth factor-activated receptor activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of multicellular organism growth Inferred from sequence or structural similarity. Source: UniProtKB regulation of synapse structure and activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of translation Inferred from sequence or structural similarity. Source: UniProtKB visual learning Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	Golgi apparatus Inferred from sequence or structural similarity. Source: UniProtKB axon Inferred from sequence or structural similarity. Source: UniProtKB coated pit Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	DNA binding Inferred from sequence or structural similarity. Source: UniProtKB heparin binding Inferred from electronic annotation. Source: UniProtKB-KW serine-type endopeptidase inhibitor activity Inferred from electronic annotation. Source: UniProtKB-KW transition metal ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

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
Molecule processing
	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
Regions
	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
Sites
	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

Sequences

	Sequence		Length	Mass (Da)
	Isoform APP770 [UniParc]. Last modified February 1, 1997. Version 1. Checksum: 6C3E431089569049	FASTA	751	84,894
	10 20 30 40 50 60 MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK 70 80 90 100 110 120 TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR DRKQCKTHPH IVIPYRCLVG 130 140 150 160 170 180 EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR 190 200 210 220 230 240 GVEFVCCPLA EESDHVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE 250 260 270 280 290 300 EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC 310 320 330 340 350 360 RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSVIPTTAA STPDAVDKYL 370 380 390 400 410 420 ETPGDENEHA HFQKAKERLE AKHRERMSQV MREWEEAERQ AKNLPKADKK AVIQHFQEKV 430 440 450 460 470 480 ESLEQEAANE RQQLVETHMA RVEAMLNDRR RLALENYITA LQAVPPRPRH VFNMLKKYVR 490 500 510 520 530 540 AEQKDRQHTL KHFEHVRMVD PKKAAQIRSQ VMTHLRVIYE RMNQSLSLLY NVPAVAEEIQ 550 560 570 580 590 600 DEVDELLQKE QNYSDDVLAN MISEPRISYG NDALMPSLTE TKTTVELLPV NGEFSLDDLQ 610 620 630 640 650 660 PWHSFGADSV PANTENEVEP VDARPAADRG LTTRPGSGLT NIKTEEISEV KMDAEFRHDS 670 680 690 700 710 720 GYEVHHQKLV FFAEDVGSNK GAIIGLMVGG VVIATVIVIT LVMLKKKQYT SIHHGVVEVD 730 740 750 AAVTPEERHL SKMQQNGYEN PTYKFFEQMQ N
	Isoform APP695 (Sequence not available).		–	–

References

[1]	"Beta-amyloid precursor protein gene in squirrel monkeys with cerebral amyloid angiopathy." Levy E., Amorim A., Frangione B., Walker L.C. Neurobiol. Aging 16:805-808(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Kidney and Liver.

Cross-references

Sequence databases
EMBL GenBank DDBJ	S81024 mRNA. Translation: AAD14347.1.
3D structure databases
ProteinModelPortal	Q95241.
SMR	Q95241. Positions 28-189, 287-342, 355-546, 653-694, 720-751.
ModBase	Search...
Protein family/group databases
MEROPS	I02.015.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Phylogenomic databases
HOVERGEN	HBG000051.
Family and domain databases
Gene3D	3.30.1490.140. 1 hit. 3.90.570.10. 1 hit. 4.10.230.10. 1 hit. 4.10.410.10. 1 hit.
InterPro	IPR008155. Amyloid_glyco. IPR013803. Amyloid_glyco_Abeta. IPR011178. Amyloid_glyco_Cu-bd. IPR024329. Amyloid_glyco_E2_domain. IPR008154. Amyloid_glyco_extra. IPR019744. Amyloid_glyco_extracell_CS. IPR015849. Amyloid_glyco_heparin-bd. IPR019745. Amyloid_glyco_intracell_CS. IPR019543. APP_amyloid_C. IPR002223. Prot_inh_Kunz-m. IPR020901. Prtase_inh_Kunz-CS. [Graphical view]
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. [Graphical view]
PRINTS	PR00203. AMYLOIDA4. PR00759. BASICPTASE. PR00204. BETAAMYLOID.
SMART	SM00006. A4_EXTRA. 1 hit. SM00131. KU. 1 hit. [Graphical view]
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. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

A4_SAISC

Accession

Primary (citable) accession number: Q95241

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 15, 1998
Last sequence update:	February 1, 1997
Last modified:	April 3, 2013
This is version 115 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program