Reviewed, UniProtKB/Swiss-Prot P54646 (AAPK2_HUMAN)

Names and origin

Protein names

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

Gene names

Name:	PRKAA2
Synonyms:	AMPK, AMPK2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	552 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Responsible for the regulation of fatty acid synthesis by phosphorylation of acetyl-CoA carboxylase. It also regulates cholesterol synthesis via phosphorylation and inactivation of hormone-sensitive lipase and hydroxymethylglutaryl-CoA reductase. Appears to act as a metabolic stress-sensing protein kinase switching off biosynthetic pathways when cellular ATP levels are depleted and when 5'-AMP rises in response to fuel limitation and/or hypoxia. This is a catalytic subunit. Ref.1
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Enzyme regulation	Binding of AMP results in allosteric activation, inducing phosphorylation on Thr-172 by STK11 in complex with STE20-related adapter-alpha (STRAD alpha) pseudo kinase and CAB39. Also activated by phosphorylation by CAMKK2 triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio By similarity.
Subunit structure	Heterotrimer of a catalytic subunit, a beta and a gamma non-catalytic subunits.
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	Cholesterol biosynthesis Fatty acid biosynthesis Lipid synthesis Steroid biosynthesis Sterol biosynthesis
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cholesterol biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW fatty acid biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW protein amino acid phosphorylation Ref.1 Traceable author statement. Source: ProtInc regulation of fatty acid oxidation Inferred from Experiment. Source: Reactome signal transduction Ref.1 Traceable author statement. Source: ProtInc
Cellular component	cytosol Inferred from Experiment. Source: Reactome nucleoplasm Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Ppard	P35396	1	EBI-1383852,EBI-1809541	From a different organism.

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

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 STK11 By similarity

Modified residue

173

1

Phosphoserine Ref.5

Modified residue

176

1

Phosphoserine Ref.5 Ref.6

Modified residue

258

1

Phosphothreonine By similarity

Modified residue

377

1

Phosphoserine Ref.6 Ref.7

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.9 Ref.10

VAR_035623

Natural variant

407

1

R → Q in a gastric adenocarcinoma sample; somatic mutation. Ref.10

VAR_040355

Natural variant

523

1

S → G in a breast cancer sample; somatic mutation. Ref.9

VAR_035624

Experimental info

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)
	P54646-1 [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

	« Hide 'large scale' referencesShow 'large scale' references »
[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: 7959015] [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: 7988703] [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: 16710414] [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis." Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-173 AND SER-176, MASS SPECTROMETRY.
[6]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-176 AND SER-377, MASS SPECTROMETRY.
[7]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, MASS SPECTROMETRY.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"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: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-371 AND GLY-523.
[10]	"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: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-371 AND GLN-407.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.

UniGene

Hs.437039

3D structure databases

PDBPDBe

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

ModBase

Search...

Protein-protein interaction databases

IntAct

P54646. 3 interactions.

PTM databases

PhosphoSite

P54646.

Proteomic databases

PRIDE

P54646.

Genome annotation databases

Ensembl

ENSG00000162409. Homo sapiens. [Contig view]

GeneID

5563.

KEGG

hsa:5563.

Organism-specific databases

GeneCards

GC01P056823.

H-InvDB

HIX0028788.

HGNC

HGNC:9377. PRKAA2.

HPA

CAB013043.

MIM

600497. gene.

PharmGKB

PA33745.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P54646.

HOVERGEN

P54646.

OMA

P54646. GVKPHPE.

Enzyme and pathway databases

BRENDA

2.7.11.1. 247.

Reactome

REACT_1505. Integration of energy metabolism.

Gene expression databases

ArrayExpress

P54646.

Bgee

P54646.

CleanEx

HS_PRKAA2.

GermOnline

ENSG00000162409. Homo sapiens.

Family and domain databases

InterPro

IPR015741. AMPK.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]

PANTHER

PTHR22982:SF61. AMPK. 1 hit.

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

PROSITE

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

ProtoNet

Search...

Other Resources

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:	June 16, 2009
This is version 90 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)