Q9UGI9 (AAKG3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
5'-AMP-activated protein kinase subunit gamma-3
Short name=AMPK gamma3
Short name=AMPK subunit gamma-3

Gene names

Name:	PRKAG3
Synonyms:	AMPKG3

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	489 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.4
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 By similarity.
Tissue specificity	Skeletal muscle, with weak expression in heart and pancreas.
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.5 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.5
Post-translational modification	Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Ref.8
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	Alternative splicing Polymorphism
Domain	CBS domain Repeat
Ligand	ATP-binding Nucleotide-binding
PTM	Phosphoprotein
Technical term	Complete proteome 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 glucose transport Inferred from electronic annotation. Source: Compara glycogen biosynthetic process Inferred from electronic annotation. Source: Compara insulin receptor signaling pathway Traceable author statement. Source: Reactome intracellular protein kinase cascade Traceable author statement Ref.1. Source: ProtInc regulation of fatty acid oxidation Traceable author statement. Source: Reactome
Cellular_component	AMP-activated protein kinase complex Inferred from electronic annotation. Source: Compara cytosol Traceable author statement. Source: Reactome
Molecular_function	AMP-activated protein kinase activity Traceable author statement Ref.1. Source: ProtInc ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein kinase binding Inferred from direct assay Ref.1. Source: BHF-UCL
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9UGI9-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9UGI9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-25: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 489	489	5'-AMP-activated protein kinase subunit gamma-3		PRO_0000204384
Regions
	Domain	197 – 258	62	CBS 1
	Domain	280 – 340	61	CBS 2
	Domain	355 – 415	61	CBS 3
	Domain	427 – 486	60	CBS 4
	Motif	293 – 314	22	AMPK pseudosubstrate
Sites
	Binding site	225	1	AMP 1 By similarity
	Binding site	225	1	ATP 1 By similarity
	Binding site	306	1	AMP 2 By similarity
	Binding site	306	1	AMP 3 By similarity
	Binding site	306	1	ATP 2 By similarity
	Binding site	307	1	ATP 1 By similarity
	Binding site	307	1	ATP 2 By similarity
	Binding site	325	1	AMP 1 By similarity
	Binding site	325	1	ATP 1 By similarity
	Binding site	453	1	AMP 3 By similarity
	Binding site	454	1	AMP 1 By similarity
	Binding site	454	1	ATP 1 By similarity
Natural variations
	Alternative sequence	1 – 25	25	Missing in isoform 2.		VSP_015587
	Natural variant	71	1	P → A. Ref.3 Corresponds to variant rs692243 [ dbSNP | Ensembl ].		VAR_023484
	Natural variant	153	1	L → V. Corresponds to variant rs35050588 [ dbSNP | Ensembl ].		VAR_048251
	Natural variant	340	1	R → W. Corresponds to variant rs33985460 [ dbSNP | Ensembl ].		VAR_048252
Experimental info
	Sequence conflict	83	1	A → T in AAF73987. Ref.2
	Sequence conflict	188 – 189	2	MQ → IE in CAB65117. Ref.1
	Sequence conflict	423	1	Q → K in CAB65117. Ref.1
	Sequence conflict	486 – 489	4	ALGA → PSGPEKI in CAB65117. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified September 13, 2005. Version 3. Checksum: 0E93E2B5117B328D	FASTA	489	54,258
	10 20 30 40 50 60 MEPGLEHALR RTPSWSSLGG SEHQEMSFLE QENSSSWPSP AVTSSSERIR GKRRAKALRW 70 80 90 100 110 120 TRQKSVEEGE PPGQGEGPRS RPAAESTGLE ATFPKTTPLA QADPAGVGTP PTGWDCLPSD 130 140 150 160 170 180 CTASAAGSST DDVELATEFP ATEAWECELE GLLEERPALC LSPQAPFPKL GWDDELRKPG 190 200 210 220 230 240 AQIYMRFMQE HTCYDAMATS SKLVIFDTML EIKKAFFALV ANGVRAAPLW DSKKQSFVGM 250 260 270 280 290 300 LTITDFILVL HRYYRSPLVQ IYEIEQHKIE TWREIYLQGC FKPLVSISPN DSLFEAVYTL 310 320 330 340 350 360 IKNRIHRLPV LDPVSGNVLH ILTHKRLLKF LHIFGSLLPR PSFLYRTIQD LGIGTFRDLA 370 380 390 400 410 420 VVLETAPILT ALDIFVDRRV SALPVVNECG QVVGLYSRFD VIHLAAQQTY NHLDMSVGEA 430 440 450 460 470 480 LRQRTLCLEG VLSCQPHESL GEVIDRIARE QVHRLVLVDE TQHLLGVVSL SDILQALVLS PAGIDALGA
	Isoform 2 [UniParc]. Checksum: 6404770D3EA7E2E4	FASTA	464	51,484
	10 20 30 40 50 60 MSFLEQENSS SWPSPAVTSS SERIRGKRRA KALRWTRQKS VEEGEPPGQG EGPRSRPAAE 70 80 90 100 110 120 STGLEATFPK TTPLAQADPA GVGTPPTGWD CLPSDCTASA AGSSTDDVEL ATEFPATEAW 130 140 150 160 170 180 ECELEGLLEE RPALCLSPQA PFPKLGWDDE LRKPGAQIYM RFMQEHTCYD AMATSSKLVI 190 200 210 220 230 240 FDTMLEIKKA FFALVANGVR AAPLWDSKKQ SFVGMLTITD FILVLHRYYR SPLVQIYEIE 250 260 270 280 290 300 QHKIETWREI YLQGCFKPLV SISPNDSLFE AVYTLIKNRI HRLPVLDPVS GNVLHILTHK 310 320 330 340 350 360 RLLKFLHIFG SLLPRPSFLY RTIQDLGIGT FRDLAVVLET APILTALDIF VDRRVSALPV 370 380 390 400 410 420 VNECGQVVGL YSRFDVIHLA AQQTYNHLDM SVGEALRQRT LCLEGVLSCQ PHESLGEVID 430 440 450 460 RIAREQVHRL VLVDETQHLL GVVSLSDILQ ALVLSPAGID ALGA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding." Cheung P.C.F., Salt I.P., Davies S.P., Hardie D.G., Carling D. Biochem. J. 346:659-669(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle." Milan D., Jeon J.-T., Looft C., Amarger V., Robic A., Thelander M., Rogel-Gaillard C., Paul S., Iannuccelli N., Rask L., Ronne H., Lundstroem K., Reinsch N., Gellin J., Kalm E., Le Roy P., Chardon P., Andersson L. Science 288:1248-1251(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Skeletal muscle.
[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] (ISOFORM 1), VARIANT ALA-71.
[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, FUNCTION.
[5]	"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.
[6]	"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.
[7]	"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.
[8]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ249977 mRNA. Translation: CAB65117.1. AF214519 mRNA. Translation: AAF73987.1. BC098102 mRNA. Translation: AAH98102.1. BC098255 mRNA. Translation: AAH98255.1. BC098277 mRNA. Translation: AAH98277.1. BC098306 mRNA. Translation: AAH98306.1.
IPI	IPI00220340. IPI00644202.
RefSeq	NP_059127.2. NM_017431.2.
UniGene	Hs.591634.
3D structure databases
ProteinModelPortal	Q9UGI9.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000233944.
PTM databases
PhosphoSite	Q9UGI9.
Polymorphism databases
DMDM	85681287.
Proteomic databases
PaxDb	Q9UGI9.
PRIDE	Q9UGI9.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000233944; ENSP00000233944; ENSG00000115592. ENST00000439262; ENSP00000397133; ENSG00000115592. ENST00000529249; ENSP00000436068; ENSG00000115592.
GeneID	53632.
KEGG	hsa:53632.
UCSC	uc002vjb.1. human.
Organism-specific databases
CTD	53632.
GeneCards	GC02M219651.
HGNC	HGNC:9387. PRKAG3.
HPA	HPA004909.
MIM	604976. gene.
neXtProt	NX_Q9UGI9.
PharmGKB	PA33753.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0517.
HOGENOM	HOG000176880.
HOVERGEN	HBG050431.
InParanoid	Q9UGI9.
KO	K07200.
OMA	YMRFMQE.
OrthoDB	EOG47H5PV.
PhylomeDB	Q9UGI9.
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	Q9UGI9.
Bgee	Q9UGI9.
CleanEx	HS_PRKAG3.
Genevestigator	Q9UGI9.
GermOnline	ENSG00000115592. 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
GenomeRNAi	53632.
NextBio	56112.
SOURCE	Search...

Entry information

Entry name

AAKG3_HUMAN

Accession

Primary (citable) accession number: Q9UGI9
Secondary accession number(s): Q4QQG8, Q4V779, Q9NRL1

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 2001
Last sequence update:	September 13, 2005
Last modified:	May 1, 2013
This is version 94 of the entry and version 3 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.