dbPTM

AAPK1_RAT - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	AAPK1_RAT
UniProt AC	P54645
Protein Name	5'-AMP-activated protein kinase catalytic subunit alpha-1
Gene Name	Prkaa1
Organism	Rattus norvegicus (Rat).
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 (By similarity). 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	MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGRLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRATIKDIREHEWFKQDLPKYLFPEDPSYSSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLATSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTFSKMSLQLYQVDSRTYLLDFRSIDDEITEAKSGTATPQRSGSISNYRSCQRSDSDAEAQGKPSEVSLTSSVTSLDSSPVDVAPRPGSHTIEFFEMCANLIKILAQ

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
32	Phosphorylation	GHYILGDTLGVGTFG EEEECCCCEECCCCC	24.50	23984901
37	Phosphorylation	GDTLGVGTFGKVKVG CCCEECCCCCEEEEC	27.15	23984901
65	Phosphorylation	LNRQKIRSLDVVGKI HCHHHCCCCHHHHHH	32.18	23984901
80	Acetylation	RREIQNLKLFRHPHI HHHHHCCCCCCCHHH	53.80	22989633
172	Phosphorylation	KIADFGLSNMMSDGE HHHCCCHHHCCCCCC	24.06	21373642
176	Phosphorylation	FGLSNMMSDGEFLRT CCHHHCCCCCCHHHH	31.53	28432305
183	Phosphorylation	SDGEFLRTSCGSPNY CCCCHHHHCCCCCCC	30.43	17023420
184	Phosphorylation	DGEFLRTSCGSPNYA CCCHHHHCCCCCCCC	15.28	27097102
187	Phosphorylation	FLRTSCGSPNYAAPE HHHHCCCCCCCCCCH	17.82	27097102
190	Phosphorylation	TSCGSPNYAAPEVIS HCCCCCCCCCCHHHC	13.92	28432305
269	Phosphorylation	VDPMKRATIKDIREH CCCCCCCCHHHHHHC	32.37	12764152
355	Phosphorylation	AKDFYLATSPPDSFL HHCEEEECCCCCCCC	38.89	28432305
356	Phosphorylation	KDFYLATSPPDSFLD HCEEEECCCCCCCCC	28.91	27097102
360	Phosphorylation	LATSPPDSFLDDHHL EECCCCCCCCCCCCC	33.22	27097102
368	Phosphorylation	FLDDHHLTRPHPERV CCCCCCCCCCCCCCC	37.49	27097102
382	Phosphorylation	VPFLVAETPRARHTL CCEEEECCHHHCCCH	14.34	-
397	Phosphorylation	DELNPQKSKHQGVRK HHHCCCCCCCCCCHH	30.07	21460634
406	Acetylation	HQGVRKAKWHLGIRS CCCCHHHHHCCCCCC	37.88	-
441	Phosphorylation	EWKVVNPYYLRVRRK EEEEECCEEEEEEEC	15.21	51245
467	Phosphorylation	LQLYQVDSRTYLLDF EEEEEECCCEEEEEE	27.89	-
476	Phosphorylation	TYLLDFRSIDDEITE EEEEEECCCCHHHHH	30.29	25575281
482	Phosphorylation	RSIDDEITEAKSGTA CCCCHHHHHCCCCCC	28.04	28432305
486	Phosphorylation	DEITEAKSGTATPQR HHHHHCCCCCCCCCC	48.72	22108457
488	Phosphorylation	ITEAKSGTATPQRSG HHHCCCCCCCCCCCC	34.15	22108457
490	Phosphorylation	EAKSGTATPQRSGSI HCCCCCCCCCCCCCC	21.57	22108457
494	Phosphorylation	GTATPQRSGSISNYR CCCCCCCCCCCCCCC	31.48	25403869
496	Phosphorylation	ATPQRSGSISNYRSC CCCCCCCCCCCCCCC	24.88	17023420
498	Phosphorylation	PQRSGSISNYRSCQR CCCCCCCCCCCCCCC	29.52	23984901
500	Phosphorylation	RSGSISNYRSCQRSD CCCCCCCCCCCCCCC	9.34	23984901
506	Phosphorylation	NYRSCQRSDSDAEAQ CCCCCCCCCCCHHHC	18.65	28432305
508	Phosphorylation	RSCQRSDSDAEAQGK CCCCCCCCCHHHCCC	39.71	28432305
517	Phosphorylation	AEAQGKPSEVSLTSS HHHCCCCCEEEEEEC	54.86	27097102
520	Phosphorylation	QGKPSEVSLTSSVTS CCCCCEEEEEECCEE	23.13	27097102
522	Phosphorylation	KPSEVSLTSSVTSLD CCCEEEEEECCEECC	16.08	27097102
523	Phosphorylation	PSEVSLTSSVTSLDS CCEEEEEECCEECCC	28.27	27097102
524	Phosphorylation	SEVSLTSSVTSLDSS CEEEEEECCEECCCC	24.95	27097102
526	Phosphorylation	VSLTSSVTSLDSSPV EEEEECCEECCCCCC	26.06	27097102
527	Phosphorylation	SLTSSVTSLDSSPVD EEEECCEECCCCCCC	28.20	27097102
530	Phosphorylation	SSVTSLDSSPVDVAP ECCEECCCCCCCCCC	41.66	27097102
531	Phosphorylation	SVTSLDSSPVDVAPR CCEECCCCCCCCCCC	28.71	27097102

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
172	T	Phosphorylation	Kinase	AMPK_GROUP	-	PhosphoELM
183	T	Phosphorylation	Kinase	PRKAA1	P54645	GPS
183	T	Phosphorylation	Kinase	AMPK-FAMILY	-	GPS
183	T	Phosphorylation	Kinase	LKB1	D4AE59	Uniprot
183	T	Phosphorylation	Kinase	LKB1	Q9WTK7	PSP
183	T	Phosphorylation	Kinase	CAMK2B	P08413	PSP
183	T	Phosphorylation	Kinase	CAMKK1	P97756	PSP
183	T	Phosphorylation	Kinase	CAMKK2	Q96RR4	PSP
183	T	Phosphorylation	Kinase	CAMKK2	Q8C078	PSP
183	T	Phosphorylation	Kinase	CAMKK2	O88831	Uniprot
183	T	Phosphorylation	Kinase	STK11	Q15831	GPS
269	T	Phosphorylation	Kinase	PRKAA1	P54645	GPS
269	T	Phosphorylation	Kinase	STK11	Q9WTK7	GPS
360	S	Phosphorylation	Kinase	ULK1	O75385	PSP
360	S	Phosphorylation	Kinase	ULK1	-	Uniprot
368	T	Phosphorylation	Kinase	ULK1	O75385	PSP
368	T	Phosphorylation	Kinase	ULK1	-	Uniprot
397	S	Phosphorylation	Kinase	ULK1	O75385	PSP
397	S	Phosphorylation	Kinase	ULK1	-	Uniprot
486	S	Phosphorylation	Kinase	ULK1	O75385	PSP
486	S	Phosphorylation	Kinase	ULK1	-	Uniprot
488	T	Phosphorylation	Kinase	ULK1	O75385	PSP
488	T	Phosphorylation	Kinase	ULK1	-	Uniprot
496	S	Phosphorylation	Kinase	PRKACA	P27791	GPS
496	S	Phosphorylation	Kinase	STK11	Q9WTK7	GPS
496	S	Phosphorylation	Kinase	PKACA	P17612	PSP
496	S	Phosphorylation	Kinase	AKT1	P47196	PSP
496	S	Phosphorylation	Kinase	AKT1	P31749	PSP
496	S	Phosphorylation	Kinase	PRKAA1	P54645	GPS

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
183	T	Phosphorylation	8910387
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	8910387
CAMKK1 can also phosphorylate Thr-183, but at a much lower level.
183	T	Phosphorylation	8910387
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_RAT !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
CFTR_HUMAN	CFTR	physical	10862786
TSC2_RAT	Tsc2	physical	19914239
FLCN_RAT	Flcn	physical	19914239

Drug and Disease Associations

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

Regulatory Network of AAPK1_RAT

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"Ulk1-mediated phosphorylation of AMPK constitutes a negativeregulatory feedback loop."; Loffler A.S., Alers S., Dieterle A.M., Keppeler H., Franz-Wachtel M.,Kundu M., Campbell D.G., Wesselborg S., Alessi D.R., Stork B.; Autophagy 7:696-706(2011). Cited for: PHOSPHORYLATION BY ULK1 AND ULK, AND PHOSPHORYLATION AT SER-360;THR-368; SER-397; SER-486 AND THR-488.	21460634 [Abstract]
"Identification of phosphorylation sites in AMP-activated proteinkinase (AMPK) for upstream AMPK kinases and study of their roles bysite-directed mutagenesis."; Woods A., Vertommen D., Neumann D., Turk R., Bayliss J.,Schlattner U., Wallimann T., Carling D., Rider M.H.; J. Biol. Chem. 278:28434-28442(2003). Cited for: PHOSPHORYLATION AT THR-269 AND SER-496, MUTAGENESIS OF THR-183;THR-269 AND SER-496, AND MASS SPECTROMETRY.	12764152 [Abstract]
"Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream ofAMP-activated protein kinase in mammalian cells."; Woods A., Dickerson K., Heath R., Hong S.-P., Momcilovic M.,Johnstone S.R., Carlson M., Carling D.; Cell Metab. 2:21-33(2005). Cited for: PHOSPHORYLATION AT THR-183, AND ENZYME REGULATION.	16054096 [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: PHOSPHORYLATION AT THR-183, AND ENZYME REGULATION.	16054095 [Abstract]
"Complexes between the LKB1 tumor suppressor, STRAD alpha/beta andMO25 alpha/beta are upstream kinases in the AMP-activated proteinkinase cascade."; Hawley S.A., Boudeau J., Reid J.L., Mustard K.J., Udd L., Makela T.P.,Alessi D.R., Hardie D.G.; J. Biol. 2:28.1-28.16(2003). Cited for: FUNCTION, ENZYME REGULATION, AND PHOSPHORYLATION AT THR-183.	14511394 [Abstract]
"LKB1 is the upstream kinase in the AMP-activated protein kinasecascade."; Woods A., Johnstone S.R., Dickerson K., Leiper F.C., Fryer L.G.,Neumann D., Schlattner U., Wallimann T., Carlson M., Carling D.; Curr. Biol. 13:2004-2008(2003). Cited for: PHOSPHORYLATION AT THR-183, AND ENZYME REGULATION.	14614828 [Abstract]
"Characterization of the AMP-activated protein kinase kinase from ratliver and identification of threonine 172 as the major site at whichit phosphorylates AMP-activated protein kinase."; Hawley S.A., Davison M., Woods A., Davies S.P., Beri R.K., Carling D.,Hardie D.G.; J. Biol. Chem. 271:27879-27887(1996). Cited for: PHOSPHORYLATION AT THR-183, AND ENZYME REGULATION.	8910387 [Abstract]

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