dbPTM

AAPK1_MOUSE - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	AAPK1_MOUSE
UniProt AC	Q5EG47
Protein Name	5'-AMP-activated protein kinase catalytic subunit alpha-1
Gene Name	Prkaa1
Organism	Mus musculus (Mouse).
Sequence Length	559
Subcellular Localization	Cytoplasm. Nucleus . In response to stress, recruited by p53/TP53 to specific promoters.
Protein Description	Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. In response to nutrient limitation, phosphorylates transcription factor FOXO3 promoting FOXO3 mitochontrial import. [PubMed: 23283301 AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.]
Protein Sequence	MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGRLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRAAIKDIREHEWFKQDLPKYLFPEDPSYSSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLATSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTFSKMSLQLYQVDSRTYLLDFRSIDDEITEAKSGTATPQRSGSISNYRSCQRSDSDAEAQGKPSDVSLTSSVTSLDSSPVDVAPRPGSHTIEFFEMCANLIKILAQ

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
32	Phosphorylation	GHYILGDTLGVGTFG EEEECCCCEECCCCC	24.50	14891981
80	Malonylation	RREIQNLKLFRHPHI HHHHHCCCCCCCHHH	53.80	26320211
80	Acetylation	RREIQNLKLFRHPHI HHHHHCCCCCCCHHH	53.80	23236377
80	Succinylation	RREIQNLKLFRHPHI HHHHHCCCCCCCHHH	53.80	23954790
172	Phosphorylation	KIADFGLSNMMSDGE HHHCCCHHHCCCCCC	24.06	21460850
173	Phosphorylation	IADFGLSNMMSDGEF HHCCCHHHCCCCCCH	34.91	17242355
176	Phosphorylation	FGLSNMMSDGEFLRT CCHHHCCCCCCHHHH	31.53	25159016
183	Phosphorylation	SDGEFLRTSCGSPNY CCCCHHHHCCCCCCC	30.43	17023420
184	Phosphorylation	DGEFLRTSCGSPNYA CCCHHHHCCCCCCCC	15.28	22322096
187	Phosphorylation	FLRTSCGSPNYAAPE HHHHCCCCCCCCCCH	17.82	22322096
190	Phosphorylation	TSCGSPNYAAPEVIS HCCCCCCCCCCHHHC	13.92	25619855
197	Phosphorylation	YAAPEVISGRLYAGP CCCCHHHCCCCCCCC	24.04	25777480
313	Glutathionylation	EVCEKFECSEEEVLS HHHHHCCCCHHHHHH	7.55	22833525
352	Phosphorylation	MNEAKDFYLATSPPD HHHHHCEEEECCCCC	12.93	20415495
355	Phosphorylation	AKDFYLATSPPDSFL HHCEEEECCCCCCCC	38.89	26239621
356	Phosphorylation	KDFYLATSPPDSFLD HCEEEECCCCCCCCC	28.91	26824392
360	Phosphorylation	LATSPPDSFLDDHHL EECCCCCCCCCCCCC	33.22	26643407
368	Phosphorylation	FLDDHHLTRPHPERV CCCCCCCCCCCCCCC	37.49	20415495
382	Phosphorylation	VPFLVAETPRARHTL CCEEEECCHHHCCCH	14.34	27180971
388	Phosphorylation	ETPRARHTLDELNPQ CCHHHCCCHHHHCCC	30.28	25338131
396	Ubiquitination	LDELNPQKSKHQGVR HHHHCCCCCCCCCCH	63.83	22790023
397	Phosphorylation	DELNPQKSKHQGVRK HHHCCCCCCCCCCHH	30.07	-
442	Phosphorylation	WKVVNPYYLRVRRKN EEEECCEEEEEEECC	6.84	51249
467	Phosphorylation	LQLYQVDSRTYLLDF EEEEEECCCEEEEEE	27.89	29514104
476	Phosphorylation	TYLLDFRSIDDEITE EEEEEECCCCHHHHH	30.29	25159016
482	Phosphorylation	RSIDDEITEAKSGTA CCCCHHHHHCCCCCC	28.04	6402945
485	Phosphorylation	DDEITEAKSGTATPQ CHHHHHCCCCCCCCC	43.09	19144319
486	Phosphorylation	DEITEAKSGTATPQR HHHHHCCCCCCCCCC	48.72	22322096
488	Phosphorylation	ITEAKSGTATPQRSG HHHCCCCCCCCCCCC	34.15	22322096
490	Phosphorylation	EAKSGTATPQRSGSI HCCCCCCCCCCCCCC	21.57	22322096
494	Phosphorylation	GTATPQRSGSISNYR CCCCCCCCCCCCCCC	31.48	22322096
496	Phosphorylation	ATPQRSGSISNYRSC CCCCCCCCCCCCCCC	24.88	17023420
497	Phosphorylation	TPQRSGSISNYRSCQ CCCCCCCCCCCCCCC	3.36	17242355
498	Phosphorylation	PQRSGSISNYRSCQR CCCCCCCCCCCCCCC	29.52	22322096
500	Phosphorylation	RSGSISNYRSCQRSD CCCCCCCCCCCCCCC	9.34	28833060
502	Phosphorylation	GSISNYRSCQRSDSD CCCCCCCCCCCCCCC	12.30	21209093
506	Phosphorylation	NYRSCQRSDSDAEAQ CCCCCCCCCCCHHHC	18.65	19942859
508	Phosphorylation	RSCQRSDSDAEAQGK CCCCCCCCCHHHCCC	39.71	8568555
517	Phosphorylation	AEAQGKPSDVSLTSS HHHCCCCCCCEECCC	54.88	25293948
520	Phosphorylation	QGKPSDVSLTSSVTS CCCCCCCEECCCCEE	30.81	21743459
522	Phosphorylation	KPSDVSLTSSVTSLD CCCCCEECCCCEECC	16.08	21743459
523	Phosphorylation	PSDVSLTSSVTSLDS CCCCEECCCCEECCC	28.27	21743459
524	Phosphorylation	SDVSLTSSVTSLDSS CCCEECCCCEECCCC	24.95	15001819
526	Phosphorylation	VSLTSSVTSLDSSPV CEECCCCEECCCCCC	26.06	21743459
527	Phosphorylation	SLTSSVTSLDSSPVD EECCCCEECCCCCCC	28.20	8568557
530	Phosphorylation	SSVTSLDSSPVDVAP CCCEECCCCCCCCCC	41.66	21743459
531	Phosphorylation	SVTSLDSSPVDVAPR CCEECCCCCCCCCCC	28.71	21743459

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
183	T	Phosphorylation	Kinase	CAMKK2	Q8C078	Uniprot
183	T	Phosphorylation	Kinase	LKB1	Q15831	PSP
183	T	Phosphorylation	Kinase	STK11	Q9WTK7	GPS
184	S	Phosphorylation	Kinase	PKACA	P17612	PSP
360	S	Phosphorylation	Kinase	ULK1	O70405	Uniprot
368	T	Phosphorylation	Kinase	ULK1	O70405	Uniprot
397	S	Phosphorylation	Kinase	ULK1	O70405	Uniprot
488	T	Phosphorylation	Kinase	ULK1	O70405	Uniprot
494	S	Phosphorylation	Kinase	PKACA	P17612	PSP
494	S	Phosphorylation	Kinase	PRKD1	Q15139	PSP
496	S	Phosphorylation	Kinase	PKACA	P17612	PSP
496	S	Phosphorylation	Kinase	PKACA	P05132	PSP
496	S	Phosphorylation	Kinase	PRKACA	P27791	GPS
506	S	Phosphorylation	Kinase	PKACA	P17612	PSP

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
183	T	Phosphorylation	16054095
Also phosphorylated at Thr-183 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio.
183	T	Phosphorylation	16054095
CAMKK1 can also phosphorylate Thr-183, but at a much lower level.
183	T	Phosphorylation	16054095
Phosphorylated at Thr-183 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39.

Disease-associated PTM Sites based on SAP

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

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of AAPK1_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
NRBF2_HUMAN	NRBF2	physical	20368287
TRIP6_HUMAN	TRIP6	physical	20368287
CIDEA_MOUSE	Cidea	physical	18480843
AAKB1_MOUSE	Prkab1	physical	18480843
AAKG1_MOUSE	Prkag1	physical	18480843
FMNL1_HUMAN	FMNL1	physical	26496610
FLNA_HUMAN	FLNA	physical	26496610
GNS_HUMAN	GNS	physical	26496610
PYC_HUMAN	PC	physical	26496610
PMS2_HUMAN	PMS2	physical	26496610
AAKB1_HUMAN	PRKAB1	physical	26496610
AAKB2_HUMAN	PRKAB2	physical	26496610
AAKG1_HUMAN	PRKAG1	physical	26496610
RAGP1_HUMAN	RANGAP1	physical	26496610
RBBP6_HUMAN	RBBP6	physical	26496610
TRI27_HUMAN	TRIM27	physical	26496610
TAF11_HUMAN	TAF11	physical	26496610
PABP2_HUMAN	PABPN1	physical	26496610
TAGL2_HUMAN	TAGLN2	physical	26496610
ARK72_HUMAN	AKR7A2	physical	26496610
BCLF1_HUMAN	BCLAF1	physical	26496610
PSME4_HUMAN	PSME4	physical	26496610
NFU1_HUMAN	NFU1	physical	26496610
GDAP1_HUMAN	GDAP1	physical	26496610
GEMI6_HUMAN	GEMIN6	physical	26496610
UBP45_HUMAN	USP45	physical	26496610
RBM45_HUMAN	RBM45	physical	26496610
RC3H1_MOUSE	Rc3h1	physical	26496200
CYC_MOUSE	Cycs	physical	27758862

Drug and Disease Associations

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

Regulatory Network of AAPK1_MOUSE

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"Large-scale phosphorylation analysis of mouse liver."; Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-184 AND SER-508, ANDMASS SPECTROMETRY.	17242355 [Abstract]
"The kinase LKB1 mediates glucose homeostasis in liver and therapeuticeffects of metformin."; Shaw R.J., Lamia K.A., Vasquez D., Koo S.-H., Bardeesy N.,Depinho R.A., Montminy M., Cantley L.C.; Science 310:1642-1646(2005). Cited for: FUNCTION IN PHOSPHORYLATION OF CRTC2, AND PHOSPHORYLATION AT THR-183.	16308421 [Abstract]
"The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases."; Hurley R.L., Anderson K.A., Franzone J.M., Kemp B.E., Means A.R.,Witters L.A.; J. Biol. Chem. 280:29060-29066(2005). Cited for: PHOSPHORYLATION AT THR-183, AND ENZYME REGULATION.	15980064 [Abstract]
"Calmodulin-dependent protein kinase kinase-beta is an alternativeupstream kinase for AMP-activated protein kinase."; Hawley S.A., Pan D.A., Mustard K.J., Ross L., Bain J., Edelman A.M.,Frenguelli B.G., Hardie D.G.; Cell Metab. 2:9-19(2005). Cited for: ENZYME REGULATION, AND PHOSPHORYLATION AT THR-183.	16054095 [Abstract]

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