A4_RAT - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: A4_RAT
• UniProt AC: P08592
• Protein Name: Amyloid-beta A4 protein
• Gene Name: App
• Organism: Rattus norvegicus (Rat).
• Sequence Length: 770
• Subcellular Localization: Membrane ; Single-pass type I membrane protein . Membrane, clathrin-coated pit . Cell surface protein that rapidly becomes internalized via clathrin-coated pits. During maturation, the immature APP (N-glycosylated in the endoplasmic reticulum) moves
• Protein Description: 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. 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. 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 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 (By similarity).; Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse amyloid-beta peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Amyloid-beta protein 42 may activate mononuclear phagocytes in the brain and elicits inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also binds GPC1 in lipid rafts (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.; N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6)..
• Protein Sequence: MLPSLALLLLAAWTVRALEVPTDGNAGLLAEPQIAMFCGKLNMHMNVQNGKWESDPSGTKTCIGTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHTHIVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDSIDSADAEEDDSDVWWGGADTDYADGGEDKVVEVAEEEEVADVEEEEAEDDEDVEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSVSSQSLLKTTSEPLPQDPVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPHHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHPFGVDSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
198	Phosphorylation	EESDSIDSADAEEDD CCCCCCCCCCCCCCC	26.78	-
206	Phosphorylation	ADAEEDDSDVWWGGA CCCCCCCCCCCCCCC	46.51	-
217	Sulfation	WGGADTDYADGGEDK CCCCCCCCCCCCCCC	14.53	-
262	Sulfation	EEEAEEPYEEATERT HHHHCCCHHHHHHHC	29.67	-
336	Sulfation	NNFDTEEYCMAVCGS CCCCHHHHHHHHHCC	4.94	-
395	Acetylation	HAHFQKAKERLEAKH HHHHHHHHHHHHHHH	50.86	22902405
441	Phosphorylation	HFQEKVESLEQEAAN HHHHHHHHHHHHHHH	39.95	22108457
497	Phosphorylation	VFNMLKKYVRAEQKD HHHHHHHHHHHHHHH	8.12	-
542	N-linked_Glycosylation	RVIYERMNQSLSLLY HHHHHHHHHHHHHHH	34.21	-
571	N-linked_Glycosylation	ELLQKEQNYSDDVLA HHHHHHCCCCHHHHH	39.09	-
656	O-linked_Glycosylation	GLTTRPGSGLTNIKT CCCCCCCCCCCCCCH	33.06	-
729	Phosphorylation	MLKKKQYTSIHHGVV HHCCCCCCCCCCCEE	20.79	30240740
730	Phosphorylation	LKKKQYTSIHHGVVE HCCCCCCCCCCCEEE	18.26	30240740
743	Phosphorylation	VEVDAAVTPEERHLS EEECCCCCHHHHHHH	21.91	12665528
751	Ubiquitination	PEERHLSKMQQNGYE HHHHHHHHHHHCCCC	47.27	-
757	Phosphorylation	SKMQQNGYENPTYKF HHHHHCCCCCCHHHH	21.78	-
762	Phosphorylation	NGYENPTYKFFEQMQ CCCCCCHHHHHHHHC	13.68	-
763	Ubiquitination	GYENPTYKFFEQMQN CCCCCHHHHHHHHCC	46.16	PubMed

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
198	S	Phosphorylation	Kinase	CK2	-	Uniprot
206	S	Phosphorylation	Kinase	CK1	-	Uniprot
729	T	Phosphorylation	Kinase	CAMK2A	P11275	PSP
730	S	Phosphorylation	Kinase	PRKCA	P05696	GPS
730	S	Phosphorylation	Kinase	APP-KINASE I	-	Uniprot
743	T	Phosphorylation	Kinase	CDK1	P39951	PSP
743	T	Phosphorylation	Kinase	CDK5	Q03114	Uniprot
743	T	Phosphorylation	Kinase	GSK3B	P49841	PSP
743	T	Phosphorylation	Kinase	MAPK8	P45983	GPS
743	T	Phosphorylation	Kinase	MAPK10	P49187	Uniprot
757	Y	Phosphorylation	Kinase	ABL1	-	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
144	C	Oxidation	Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond.	-
158	C	Oxidation	Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond.	-
743	T	Phosphorylation	In dopaminergic (DA) neurons, phosphorylation on Thr-743 by LRKK2 promotes the production and the nuclear translocation of the APP intracellular domain (AICD) which induces DA neuron apoptosis (By similarity).	10341243
743	T	Phosphorylation	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.	10936190
743	T	Phosphorylation	The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (By similarity).	10341243

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of A4_RAT !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
TNR16_RAT	Ngfr	physical	19549834

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

Phosphorylation

"Phosphorylation of the cytoplasmic domain of Alzheimer's beta-amyloidprecursor protein at Ser655 by a novel protein kinase.";
Isohara T., Horiuchi A., Watanabe T., Ando K., Czernik A.J., Uno I.,Greengard P., Nairn A.C., Suzuki T.;
Biochem. Biophys. Res. Commun. 258:300-305(1999).
Cited for: PHOSPHORYLATION AT SER-730.
PubMed: 10329382

"Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursorprotein by cyclin-dependent kinase 5.";
Iijima K., Ando K., Takeda S., Satoh Y., Seki T., Itohara S.,Greengard P., Kirino Y., Nairn A.C., Suzuki T.;
J. Neurochem. 75:1085-1091(2000).
Cited for: PHOSPHORYLATION AT THR-743.
PubMed: 10936190