P54619 (AAKG1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
5'-AMP-activated protein kinase subunit gamma-1
Short name=AMPK gamma1
Short name=AMPK subunit gamma-1
Short name=AMPKg

Gene names

Name:

PRKAG1

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	331 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	AMP/ATP-binding 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. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive. Ref.11
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. Ref.5 Ref.7 Ref.11
Domain	The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1. Ref.4 Ref.6 Ref.11 The CBS domains mediate binding to AMP, ADP and ATP. 2 sites bind either AMP or ATP, whereas a third site contains a tightly bound AMP that does not exchange. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. Ref.4 Ref.6 Ref.11
Post-translational modification	Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK. Ref.9
Sequence similarities	Belongs to the 5'-AMP-activated protein kinase gamma subunit family. Contains 4 CBS domains.

Ontologies

Keywords
Biological process	Fatty acid biosynthesis Fatty acid metabolism Lipid biosynthesis Lipid metabolism
Coding sequence diversity	Polymorphism
Domain	CBS domain Repeat
Ligand	ATP-binding Nucleotide-binding
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cell cycle arrest Traceable author statement. Source: Reactome fatty acid biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW insulin receptor signaling pathway Traceable author statement. Source: Reactome positive regulation of gene expression Inferred from direct assay Ref.5. Source: UniProtKB positive regulation of protein kinase activity Traceable author statement PubMed 8663446. Source: BHF-UCL regulation of fatty acid oxidation Traceable author statement. Source: Reactome regulation of glycolysis Traceable author statement PubMed 8663446. Source: BHF-UCL spermatogenesis Traceable author statement PubMed 9598317. Source: ProtInc
Cellular_component	AMP-activated protein kinase complex Inferred from sequence or structural similarity. Source: UniProtKB cytosol Traceable author statement. Source: Reactome
Molecular_function	ADP binding Inferred from sequence or structural similarity. Source: UniProtKB AMP binding Inferred from sequence or structural similarity. Source: UniProtKB ATP binding Inferred from sequence or structural similarity. Source: UniProtKB cAMP-dependent protein kinase activity Traceable author statement PubMed 9598317. Source: ProtInc cAMP-dependent protein kinase regulator activity Traceable author statement PubMed 8663446. Source: BHF-UCL protein kinase binding Inferred from direct assay PubMed 10698692. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
PRKAB1	Q9Y478	3	EBI-1181439,EBI-719769
PRKAB2	O43741	3	EBI-1181439,EBI-1053424

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 331

331

5'-AMP-activated protein kinase subunit gamma-1

PRO_0000204377

Regions

Domain

43 – 103

61

CBS 1

Domain

125 – 187

63

CBS 2

Domain

198 – 260

63

CBS 3

Domain

272 – 329

58

CBS 4

Motif

138 – 159

22

AMPK pseudosubstrate

Sites

Binding site

70

1

AMP 1 By similarity

Binding site

70

1

ATP 1 By similarity

Binding site

151

1

AMP 2 By similarity

Binding site

151

1

AMP 3 By similarity

Binding site

151

1

ATP 2 By similarity

Binding site

152

1

ATP 1 By similarity

Binding site

152

1

ATP 2 By similarity

Binding site

170

1

AMP 1 By similarity

Binding site

170

1

ATP 1 By similarity

Binding site

298

1

AMP 3 By similarity

Binding site

299

1

AMP 1 By similarity

Binding site

299

1

ATP 1 By similarity

Amino acid modifications

Modified residue

261

1

Phosphoserine; by ULK1 By similarity

Modified residue

263

1

Phosphothreonine; by ULK1 By similarity

Modified residue

270

1

Phosphoserine; by ULK1 By similarity

Natural variations

Natural variant

89

1

T → S.
Corresponds to variant rs1126930 [ dbSNP | Ensembl ].

VAR_033453

Natural variant

329

1

K → N.
Corresponds to variant rs34210356 [ dbSNP | Ensembl ].

VAR_033454

Experimental info

Mutagenesis

90

1

D → A: Reduced AMP-activation of phosphorylation of PRKAA1 or PRKAA2. Reduced ADP activation of phosphorylation of PRKAA1 or PRKAA2. Ref.11

Mutagenesis

245

1

D → A: Reduced AMP-activation of phosphorylation of PRKAA1 or PRKAA2. Reduced ADP activation of phosphorylation of PRKAA1 or PRKAA2. Ref.11

Mutagenesis

317

1

D → A: Reduced AMP-activation of phosphorylation of PRKAA1 or PRKAA2. Does not affect ADP activation of phosphorylation of PRKAA1 or PRKAA2. Ref.11

Secondary structure

1

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331

Helix Strand Turn

Details...

Helix

186 – 189

4

Helix

193 – 196

4

Helix

213 – 223

11

Beta strand

226 – 231

6

Beta strand

235 – 242

8

Helix

243 – 251

9

Helix

262 – 267

6

Helix

271 – 274

4

Beta strand

277 – 279

3

Helix

285 – 295

11

Beta strand

298 – 303

6

Beta strand

307 – 314

8

Helix

315 – 322

8

Sequences

	Sequence		Length	Mass (Da)
	P54619 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 0F22B9CA1DBD87AE	FASTA	331	37,579
	10 20 30 40 50 60 METVISSDSS PAVENEHPQE TPESNNSVYT SFMKSHRCYD LIPTSSKLVV FDTSLQVKKA 70 80 90 100 110 120 FFALVTNGVR AAPLWDSKKQ SFVGMLTITD FINILHRYYK SALVQIYELE EHKIETWREV 130 140 150 160 170 180 YLQDSFKPLV CISPNASLFD AVSSLIRNKI HRLPVIDPES GNTLYILTHK RILKFLKLFI 190 200 210 220 230 240 TEFPKPEFMS KSLEELQIGT YANIAMVRTT TPVYVALGIF VQHRVSALPV VDEKGRVVDI 250 260 270 280 290 300 YSKFDVINLA AEKTYNNLDV SVTKALQHRS HYFEGVLKCY LHETLETIIN RLVEAEVHRL 310 320 330 VVVDENDVVK GIVSLSDILQ ALVLTGGEKK P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Non-catalytic beta- and gamma-subunit isoforms of the 5'-AMP-activated protein kinase." Gao G., Fernandez C.S., Stapleton D., Auster A.S., Widmer J., Dyck J.R.B., Kemp B.E., Witters L.A. J. Biol. Chem. 271:8675-8681(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE. Tissue: Fetal liver.
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"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]. Tissue: Muscle.
[4]	"CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations." Scott J.W., Hawley S.A., Green K.A., Anis M., Stewart G., Scullion G.A., Norman D.G., Hardie D.G. J. Clin. Invest. 113:274-284(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN CBS, AMP-BINDING, ATP-BINDING.
[5]	"Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling." Baba M., Hong S.-B., Sharma N., Warren M.B., Nickerson M.L., Iwamatsu A., Esposito D., Gillette W.K., Hopkins R.F. III, Hartley J.L., Furihata M., Oishi S., Zhen W., Burke T.R. Jr., Linehan W.M., Schmidt L.S., Zbar B. Proc. Natl. Acad. Sci. U.S.A. 103:15552-15557(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FNIP1, IDENTIFICATION BY MASS SPECTROMETRY.
[6]	"Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the gamma subunit." Scott J.W., Ross F.A., Liu J.K., Hardie D.G. EMBO J. 26:806-815(2007) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN AMPK PSEUDOSUBSTRATE.
[7]	"Identification and characterization of a novel folliculin-interacting protein FNIP2." Hasumi H., Baba M., Hong S.-B., Hasumi Y., Huang Y., Yao M., Valera V.A., Linehan W.M., Schmidt L.S. Gene 415:60-67(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FNIP2.
[8]	"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: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[9]	"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 AND ULK2.
[10]	"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].
[11]	"AMPK is a direct adenylate charge-regulated protein kinase." Oakhill J.S., Steel R., Chen Z.P., Scott J.W., Ling N., Tam S., Kemp B.E. Science 332:1433-1435(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PRKAA1 AND PRKAB1, DOMAIN CBS, ADP-BINDING, MUTAGENESIS OF ASP-90; ASP-245 AND ASP-317, FUNCTION.
[12]	"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.
[13]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U42412 mRNA. Translation: AAC50495.1.
BT007345 mRNA. Translation: AAP36009.1.
BC000358 mRNA. Translation: AAH00358.1.

IPI

IPI00473047.

RefSeq

NP_001193638.1. NM_001206709.1.
NP_001193639.1. NM_001206710.1.
NP_002724.1. NM_002733.4.

UniGene

Hs.530862.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2UV4	X-ray	1.33	A	182-325	[»]
2UV5	X-ray	1.69	A	182-325	[»]
2UV6	X-ray	2.00	A	182-325	[»]
2UV7	X-ray	2.00	A	182-325	[»]

ProteinModelPortal

P54619.

ModBase

Search...

Protein-protein interaction databases

IntAct

P54619. 17 interactions.

MINT

MINT-4649712.

STRING

9606.ENSP00000323867.

PTM databases

PhosphoSite

P54619.

Polymorphism databases

DMDM

1703037.

Proteomic databases

PaxDb

P54619.

PRIDE

P54619.

Protocols and materials databases

DNASU

5571.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000548065; ENSP00000447433; ENSG00000181929.

GeneID

5571.

KEGG

hsa:5571.

UCSC

uc001rsy.3. human.

Organism-specific databases

CTD

5571.

GeneCards

GC12M049396.

HGNC

HGNC:9385. PRKAG1.

MIM

602742. gene.

neXtProt

NX_P54619.

PharmGKB

PA33751.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0517.

HOVERGEN

HBG050431.

InParanoid

P54619.

KO

K07200.

OrthoDB

EOG45DWPQ.

PhylomeDB

P54619.

Enzyme and pathway databases

Reactome

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

Gene expression databases

ArrayExpress

P54619.

Bgee

P54619.

CleanEx

HS_PRKAG1.

Genevestigator

P54619.

GermOnline

ENSG00000181929. Homo sapiens.

Family and domain databases

InterPro

IPR000644. Cysta_beta_synth_core.
[Graphical view]

Pfam

PF00571. CBS. 3 hits.
[Graphical view]

SMART

SM00116. CBS. 4 hits.
[Graphical view]

PROSITE

PS51371. CBS. 4 hits.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P54619.

ChEMBL

CHEMBL2393.

ChiTaRS

PRKAG1. human.

EvolutionaryTrace

P54619.

GenomeRNAi

5571.

NextBio

21596.

SOURCE

Search...

Entry information

Entry name

AAKG1_HUMAN

Accession

Primary (citable) accession number: P54619

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 116 of the entry and version 1 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.