P54646 (AAPK2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
5'-AMP-activated protein kinase catalytic subunit alpha-2
Short name=AMPK subunit alpha-2
EC=2.7.11.1

Alternative name(s):
Acetyl-CoA carboxylase kinase
Short name=ACACA kinase
EC=2.7.11.27
Hydroxymethylglutaryl-CoA reductase kinase
Short name=HMGCR kinase
EC=2.7.11.31

Gene names

Name:	PRKAA2
Synonyms:	AMPK, AMPK2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [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 › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	552 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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: 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 ULK1. 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 phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Ref.1 Ref.5 Ref.6 Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 Ref.14 Ref.18 Ref.19 Ref.22
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. ATP + [hydroxymethylglutaryl-CoA reductase (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)] phosphate. ATP + [acetyl-CoA carboxylase] = ADP + [acetyl-CoA carboxylase] phosphate.
Cofactor	Magnesium By similarity.
Enzyme regulation	Activated by phosphorylation on Thr-172. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (Ref.7). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation. Ref.7 Ref.10 Ref.25 Ref.27
Subunit structure	AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.
Subcellular location	Cytoplasm By similarity. Nucleus. Note: In response to stress, recruited by p53/TP53 to specific promoters. Ref.11
Domain	The AIS (autoinhibitory sequence) region some sequence similarity with the ubiquitin-associated domains and represses kinase activity.
Post-translational modification	Ubiquitinated By similarity. Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Ref.10 Ref.20
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Autophagy Biological rhythms Cholesterol biosynthesis Cholesterol metabolism Fatty acid biosynthesis Fatty acid metabolism Lipid biosynthesis Lipid metabolism Steroid biosynthesis Steroid metabolism Sterol biosynthesis Sterol metabolism Transcription Transcription regulation Wnt signaling pathway
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Chromatin regulator Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW autophagy Inferred from electronic annotation. Source: UniProtKB-KW carnitine shuttle Traceable author statement. Source: Reactome cell cycle arrest Traceable author statement. Source: Reactome cellular lipid metabolic process Traceable author statement. Source: Reactome cellular response to glucose starvation Inferred from sequence or structural similarity. Source: UniProtKB cholesterol biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW energy reserve metabolic process Traceable author statement. Source: Reactome fatty acid biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW fatty acid homeostasis Inferred from sequence or structural similarity. Source: UniProtKB glucose homeostasis Inferred from sequence or structural similarity. Source: UniProtKB insulin receptor signaling pathway Traceable author statement. Source: Reactome lipid biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of TOR signaling cascade Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of autophagy Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of glycolysis Inferred from sequence or structural similarity. Source: UniProtKB regulation of circadian rhythm Inferred from sequence or structural similarity. Source: UniProtKB regulation of energy homeostasis Inferred from sequence or structural similarity. Source: UniProtKB regulation of fatty acid biosynthetic process Traceable author statement. Source: Reactome regulation of fatty acid oxidation Traceable author statement. Source: Reactome regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW rhythmic process Inferred from electronic annotation. Source: UniProtKB-KW small molecule metabolic process Traceable author statement. Source: Reactome transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleoplasm Traceable author statement. Source: Reactome
Molecular_function	AMP-activated protein kinase activity Inferred from direct assay PubMed 18439900. Source: UniProtKB ATP binding Inferred from electronic annotation. Source: UniProtKB-KW [acetyl-CoA carboxylase] kinase activity Inferred from electronic annotation. Source: EC [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity Inferred from electronic annotation. Source: EC chromatin binding Inferred from sequence or structural similarity. Source: UniProtKB histone serine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 552

552

5'-AMP-activated protein kinase catalytic subunit alpha-2

PRO_0000085594

Regions

Domain

16 – 268

253

Protein kinase

Nucleotide binding

22 – 30

9

ATP By similarity

Region

291 – 376

86

AIS By similarity

Sites

Active site

139

1

Proton acceptor By similarity

Binding site

45

1

ATP By similarity

Amino acid modifications

Modified residue

172

1

Phosphothreonine; by LKB1 and CaMKK2 Ref.10

Modified residue

173

1

Phosphoserine By similarity

Modified residue

258

1

Phosphothreonine By similarity

Modified residue

377

1

Phosphoserine Ref.15 Ref.17

Modified residue

491

1

Phosphoserine By similarity

Modified residue

500

1

Phosphoserine By similarity

Natural variations

Natural variant

371

1

P → T in breast cancer samples; infiltrating ductal carcinoma; somatic mutation. Ref.28 Ref.29

VAR_035623

Natural variant

407

1

R → Q in a gastric adenocarcinoma sample; somatic mutation. Ref.29

VAR_040355

Natural variant

523

1

S → G in a breast cancer sample; somatic mutation. Ref.28

VAR_035624

Experimental info

Mutagenesis

172

1

T → D: Phosphomimetic mutant.

Sequence conflict

180

1

A → T in AAA64745. Ref.1

Sequence conflict

271

1

D → G in AAA64745. Ref.1

Sequence conflict

403 – 404

2

HL → RQ in AAA64745. Ref.1

Secondary structure

1

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552

Helix Strand Turn

Details...

Beta strand

16 – 24

9

Beta strand

26 – 35

10

Turn

36 – 38

3

Beta strand

41 – 48

8

Helix

49 – 54

6

Helix

58 – 69

12

Beta strand

79 – 84

6

Beta strand

86 – 94

9

Helix

101 – 108

8

Helix

113 – 133

21

Helix

142 – 144

3

Beta strand

145 – 147

3

Beta strand

153 – 155

3

Helix

160 – 162

3

Helix

183 – 185

3

Helix

192 – 209

18

Helix

219 – 228

10

Helix

239 – 248

10

Helix

253 – 255

3

Helix

259 – 264

6

Helix

266 – 269

4

Helix

274 – 276

3

Sequences

	Sequence		Length	Mass (Da)
	P54646 [UniParc]. Last modified April 16, 2002. Version 2. Checksum: C46AAFC1D5104975	FASTA	552	62,320
	10 20 30 40 50 60 MAEKQKHDGR VKIGHYVLGD TLGVGTFGKV KIGEHQLTGH KVAVKILNRQ KIRSLDVVGK 70 80 90 100 110 120 IKREIQNLKL FRHPHIIKLY QVISTPTDFF MVMEYVSGGE LFDYICKHGR VEEMEARRLF 130 140 150 160 170 180 QQILSAVDYC HRHMVVHRDL KPENVLLDAH MNAKIADFGL SNMMSDGEFL RTSCGSPNYA 190 200 210 220 230 240 APEVISGRLY AGPEVDIWSC GVILYALLCG TLPFDDEHVP TLFKKIRGGV FYIPEYLNRS 250 260 270 280 290 300 VATLLMHMLQ VDPLKRATIK DIREHEWFKQ DLPSYLFPED PSYDANVIDD EAVKEVCEKF 310 320 330 340 350 360 ECTESEVMNS LYSGDPQDQL AVAYHLIIDN RRIMNQASEF YLASSPPSGS FMDDSAMHIP 370 380 390 400 410 420 PGLKPHPERM PPLIADSPKA RCPLDALNTT KPKSLAVKKA KWHLGIRSQS KPYDIMAEVY 430 440 450 460 470 480 RAMKQLDFEW KVVNAYHLRV RRKNPVTGNY VKMSLQLYLV DNRSYLLDFK SIDDEVVEQR 490 500 510 520 530 540 SGSSTPQRSC SAAGLHRPRS SFDSTTAESH SLSGSLTGSL TGSTLSSVSP RLGSHTMDFF 550 EMCASLITTL AR

References

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[1]	"Characterization and chromosomal localization of the human homologue of a rat AMP-activated protein kinase-encoding gene: a major regulator of lipid metabolism in mammals." Aguan K., Scott J., See C.G., Sarkar N.H. Gene 149:345-350(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION. Tissue: Heart.
[2]	"Molecular cloning, expression and chromosomal localisation of human AMP-activated protein kinase." Beri R.K., Marley A.E., See C.G., Sopwith W.F., Aguan K., Carling D., Scott J., Carey F. FEBS Lett. 356:117-121(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skeletal muscle.
[3]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line." Imamura K., Ogura T., Kishimoto A., Kaminishi M., Esumi H. Biochem. Biophys. Res. Commun. 287:562-567(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors." Yang W., Hong Y.H., Shen X.Q., Frankowski C., Camp H.S., Leff T. J. Biol. Chem. 276:38341-38344(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF EP300.
[7]	"Role of AMP-activated protein kinase in mechanism of metformin action." Zhou G., Myers R., Li Y., Chen Y., Shen X., Fenyk-Melody J., Wu M., Ventre J., Doebber T., Fujii N., Musi N., Hirshman M.F., Goodyear L.J., Moller D.E. J. Clin. Invest. 108:1167-1174(2001) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[8]	"Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells." Hallows K.R., Kobinger G.P., Wilson J.M., Witters L.A., Foskett J.K. Am. J. Physiol. 284:C1297-C1308(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CFTR.
[9]	"TSC2 mediates cellular energy response to control cell growth and survival." Inoki K., Zhu T., Guan K.L. Cell 115:577-590(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF TSC2.
[10]	"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) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-172, ENZYME REGULATION.
[11]	"AMP-activated protein kinase induces a p53-dependent metabolic checkpoint." Jones R.G., Plas D.R., Kubek S., Buzzai M., Mu J., Xu Y., Birnbaum M.J., Thompson C.B. Mol. Cell 18:283-293(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[12]	"The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor." Greer E.L., Oskoui P.R., Banko M.R., Maniar J.M., Gygi M.P., Gygi S.P., Brunet A. J. Biol. Chem. 282:30107-30119(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF FOXO3.
[13]	"Energy-dependent regulation of cell structure by AMP-activated protein kinase." Lee J.H., Koh H., Kim M., Kim Y., Lee S.Y., Karess R.E., Lee S.H., Shong M., Kim J.M., Kim J., Chung J. Nature 447:1017-1020(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN CELL POLARITY.
[14]	"AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5." McGee S.L., van Denderen B.J., Howlett K.F., Mollica J., Schertzer J.D., Kemp B.E., Hargreaves M. Diabetes 57:860-867(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HDAC5.
[15]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[16]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[17]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, MASS SPECTROMETRY.
[18]	"Cell-wide analysis of secretory granule dynamics in three dimensions in living pancreatic beta-cells: evidence against a role for AMPK-dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin granule movement." McDonald A., Fogarty S., Leclerc I., Hill E.V., Hardie D.G., Rutter G.A. Biochem. Soc. Trans. 38:205-208(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF KLC1.
[19]	"ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS." Alexander A., Cai S.L., Kim J., Nanez A., Sahin M., MacLean K.H., Inoki K., Guan K.L., Shen J., Person M.D., Kusewitt D., Mills G.B., Kastan M.B., Walker C.L. Proc. Natl. Acad. Sci. U.S.A. 107:4153-4158(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[20]	"Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory 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) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY ULK1.
[21]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[22]	"Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy." Egan D.F., Shackelford D.B., Mihaylova M.M., Gelino S., Kohnz R.A., Mair W., Vasquez D.S., Joshi A., Gwinn D.M., Taylor R., Asara J.M., Fitzpatrick J., Dillin A., Viollet B., Kundu M., Hansen M., Shaw R.J. Science 331:456-461(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF ULK1.
[23]	"AMP-activated protein kinase in metabolic control and insulin signaling." Towler M.C., Hardie D.G. Circ. Res. 100:328-341(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[24]	"AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy." Hardie D.G. Nat. Rev. Mol. Cell Biol. 8:774-785(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[25]	"The ancient drug salicylate directly activates AMP-activated protein kinase." Hawley S.A., Fullerton M.D., Ross F.A., Schertzer J.D., Chevtzoff C., Walker K.J., Peggie M.W., Zibrova D., Green K.A., Mustard K.J., Kemp B.E., Sakamoto K., Steinberg G.R., Hardie D.G. Science 336:918-922(2012) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION BY SALICYLATE.
[26]	"A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation." Littler D.R., Walker J.R., Davis T., Wybenga-Groot L.E., Finerty P.J. Jr., Newman E., Mackenzie F., Dhe-Paganon S. Acta Crystallogr. F 66:143-151(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 6-279.
[27]	"Structural basis for compound C inhibition of the human AMP-activated protein kinase alpha2 subunit kinase domain." Handa N., Takagi T., Saijo S., Kishishita S., Takaya D., Toyama M., Terada T., Shirouzu M., Suzuki A., Lee S., Yamauchi T., Okada-Iwabu M., Iwabu M., Kadowaki T., Minokoshi Y., Yokoyama S. Acta Crystallogr. D 67:480-487(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) OF 6-279 OF MUTANT THR-172 IN COMPLEX WITH COMPOUND C, ENZYME REGULATION.
[28]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-371 AND GLY-523.
[29]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-371 AND GLN-407.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U06454 mRNA. Translation: AAA64745.1.
AL035705 Genomic DNA. Translation: CAC17574.2.
BC069680 mRNA. Translation: AAH69680.1.
BC069740 mRNA. Translation: AAH69740.1.
BC069823 mRNA. Translation: AAH69823.1.

IPI

IPI00307755.

PIR

S51025.

RefSeq

NP_006243.2. NM_006252.3.

UniGene

Hs.437039.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2H6D	X-ray	1.85	A	6-279	[»]
2YZA	X-ray	3.02	A	6-279	[»]
3AQV	X-ray	2.08	A	6-279	[»]

ProteinModelPortal

P54646.

ModBase

Search...

Protein-protein interaction databases

IntAct

P54646. 31 interactions.

STRING

9606.ENSP00000360290.

PTM databases

PhosphoSite

P54646.

Polymorphism databases

DMDM

20178276.

Proteomic databases

PaxDb

P54646.

PRIDE

P54646.

Protocols and materials databases

DNASU

5563.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000371244; ENSP00000360290; ENSG00000162409.

GeneID

5563.

KEGG

hsa:5563.

UCSC

uc001cyk.4. human.

Organism-specific databases

CTD

5563.

GeneCards

GC01P057027.

HGNC

HGNC:9377. PRKAA2.

HPA

CAB013043.

MIM

600497. gene.

neXtProt

NX_P54646.

PharmGKB

PA33745.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233016.

HOVERGEN

HBG050432.

InParanoid

P54646.

KO

K07198.

OMA

TMHIPPG.

OrthoDB

EOG4XSKPM.

PhylomeDB

P54646.

Enzyme and pathway databases

BRENDA

2.7.11.1. 2681.

Reactome

REACT_111102. Signal Transduction.
REACT_111217. Metabolism.
REACT_11123. Membrane Trafficking.
REACT_11163. Activated AMPK stimulates fatty-acid oxidation in muscle.

Gene expression databases

Bgee

P54646.

CleanEx

HS_PRKAA2.

Genevestigator

P54646.

GermOnline

ENSG00000162409. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P54646.

ChEMBL

CHEMBL2116.

EvolutionaryTrace

P54646.

GenomeRNAi

5563.

NextBio

21552.

SOURCE

Search...

Entry information

Entry name

AAPK2_HUMAN

Accession

Primary (citable) accession number: P54646
Secondary accession number(s): Q9H1E8, Q9UD43

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	April 16, 2002
Last modified:	May 1, 2013
This is version 134 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.