A4_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: A4_MOUSE
• UniProt AC: P12023
• Protein Name: Amyloid-beta A4 protein
• Gene Name: App
• Organism: Mus musculus (Mouse).
• 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. Can promote transcription activation through binding to APBB1-KAT5 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. 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 cortical neurons (By similarity). 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.; 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 elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also binds GPC1 in lipid rafts (By similarity).; 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: MLPSLALLLLAAWTVRALEVPTDGNAGLLAEPQIAMFCGKLNMHMNVQNGKWESDPSGTKTCIGTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHTHIVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDSVDSADAEEDDSDVWWGGADTDYADGGEDKVVEVAEEEEVADVEEEEADDDEDVEDGDEVEEEAEEPYEEATERTTSTATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTEGKCVPFFYGGCGGNRNNFDTEEYCMAVCGSVSTQSLLKTTSEPLPQDPDKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPHHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHPFGVDSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN

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
107	Phosphorylation	RGRKQCKTHTHIVIP HCHHHCCCCCEEEEE	39.37	-
109	Phosphorylation	RKQCKTHTHIVIPYR HHHCCCCCEEEEECH	20.66	-
115	Phosphorylation	HTHIVIPYRCLVGEF CCEEEEECHHHHCCH	11.66	-
124	Phosphorylation	CLVGEFVSDALLVPD HHHCCHHHHCCCCCC	23.61	28973931
193	Phosphorylation	CCPLAEESDSVDSAD EEECCCCCCCCCCCC	27.04	29899451
195	Phosphorylation	PLAEESDSVDSADAE ECCCCCCCCCCCCCC	36.78	29899451
198	Phosphorylation	EESDSVDSADAEEDD CCCCCCCCCCCCCCC	26.37	-
206	Phosphorylation	ADAEEDDSDVWWGGA CCCCCCCCCCCCCCC	46.51	-
217	Sulfation	WGGADTDYADGGEDK CCCCCCCCCCCCCCC	14.53	-
262	Sulfation	EEEAEEPYEEATERT HHHHCCCHHHHHHCC	29.67	-
336	Sulfation	NNFDTEEYCMAVCGS CCCCHHHHHHHHHCC	4.94	-
441	Phosphorylation	HFQEKVESLEQEAAN HHHHHHHHHHHHHHH	39.95	25521595
456	Phosphorylation	ERQQLVETHMARVEA HHHHHHHHHHHHHHH	14.96	28059163
497	Phosphorylation	VFNMLKKYVRAEQKD HHHHHHHHHHHHHHH	8.12	-
542	N-linked_Glycosylation	RVIYERMNQSLSLLY HHHHHHHHHHHHHHH	34.21	-
571	N-linked_Glycosylation	ELLQKEQNYSDDVLA HHHHHHCCCCHHHHH	39.09	-
679	Phosphorylation	DAEFGHDSGFEVRHQ CCCCCCCCCCEEEEE	39.44	21527912
697	Phosphorylation	FFAEDVGSNKGAIIG EEEECCCCCCCHHHH	34.91	-
714	Phosphorylation	VGGVVIATVIVITLV HHHHHHHHHHHHHHH	10.31	26239621
719	Phosphorylation	IATVIVITLVMLKKK HHHHHHHHHHHHCCC	11.47	26239621
726	Ubiquitination	TLVMLKKKQYTSIHH HHHHHCCCCCCCCCC	47.12	22790023
728	Phosphorylation	VMLKKKQYTSIHHGV HHHCCCCCCCCCCCE	16.01	-
729	Phosphorylation	MLKKKQYTSIHHGVV HHCCCCCCCCCCCEE	20.79	-
730	Phosphorylation	LKKKQYTSIHHGVVE HCCCCCCCCCCCEEE	18.26	-
743	Phosphorylation	VEVDAAVTPEERHLS EEECCCCCHHHHHHH	21.91	14722157
751	Ubiquitination	PEERHLSKMQQNGYE HHHHHHHHHHHCCCC	47.27	22790023
757	Phosphorylation	SKMQQNGYENPTYKF HHHHHCCCCCCHHHH	21.78	21849536
761	Phosphorylation	QNGYENPTYKFFEQM HCCCCCCHHHHHHHH	51.42	25159016
762	Phosphorylation	NGYENPTYKFFEQMQ CCCCCCHHHHHHHHC	13.68	25159016
763	Ubiquitination	GYENPTYKFFEQMQN CCCCCHHHHHHHHCC	46.16	22790023

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
679	S	Phosphorylation	Kinase	PKACA	P17612	PSP
730	S	Phosphorylation	Kinase	APP-KINASE I	-	Uniprot
743	T	Phosphorylation	Kinase	CDK5	P49615	Uniprot
743	T	Phosphorylation	Kinase	LRRK2	Q5S006	Uniprot
743	T	Phosphorylation	Kinase	MAPK10	Q61831	Uniprot
757	Y	Phosphorylation	Kinase	ABL1	P00520	Uniprot
757	Y	Phosphorylation	Kinase	NTRK1	Q3UFB7	GPS
-	K	Ubiquitination	E3 ubiquitin ligase	Fbxo2	Q80UW2	PMID:24469452

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.	28720718
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 (By similarity).	28720718
743	T	Phosphorylation	The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (By similarity).	28720718

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_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CHIP_MOUSE	Stub1	physical	17317785
GGA1_MOUSE	Gga1	physical	17005855
SYUA_MOUSE	Snca	physical	18769546
RANB9_MOUSE	Ranbp9	physical	19251705

Drug and Disease Associations

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

Related Literatures of Post-Translational Modification

Phosphorylation

"The beta-amyloid precursor protein APP is tyrosine-phosphorylated incells expressing a constitutively active form of the Ablprotoncogene.";
Zambrano N., Bruni P., Minopoli G., Mosca R., Molino D., Russo C.,Schettini G., Sudol M., Russo T.;
J. Biol. Chem. 276:19787-19792(2001).
Cited for: PHOSPHORYLATION AT TYR-757.
PubMed: 11279131