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Q9UGI9 (AAKG3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 104. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length489 AA.
Sequence statusComplete.
Protein existenceEvidence 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

Polymorphism

PRKAG3 genetic variants can be associated with increased glycogen content in skeletal muscle [MIM:604976]. Muscle fibers from carriers of variant Trp-225 have approximately 90% more muscle glycogen content than controls and decreased levels of intramuscular triglyceride.

Sequence similarities

Belongs to the 5'-AMP-activated protein kinase gamma subunit family.

Contains 4 CBS domains.

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 4894895'-AMP-activated protein kinase subunit gamma-3
PRO_0000204384

Regions

Domain197 – 25862CBS 1
Domain280 – 34061CBS 2
Domain355 – 41561CBS 3
Domain427 – 48660CBS 4
Motif293 – 31422AMPK pseudosubstrate

Sites

Binding site2251AMP 1 By similarity
Binding site2251ATP 1 By similarity
Binding site3061AMP 2 By similarity
Binding site3061AMP 3 By similarity
Binding site3061ATP 2 By similarity
Binding site3071ATP 1 By similarity
Binding site3071ATP 2 By similarity
Binding site3251AMP 1 By similarity
Binding site3251ATP 1 By similarity
Binding site4531AMP 3 By similarity
Binding site4541AMP 1 By similarity
Binding site4541ATP 1 By similarity

Natural variations

Alternative sequence1 – 2525Missing in isoform 2.
VSP_015587
Natural variant711P → A. Ref.3 Ref.9
Corresponds to variant rs692243 [ dbSNP | Ensembl ].
VAR_023484
Natural variant761E → Q. Ref.9
VAR_069470
Natural variant1031D → G. Ref.9
VAR_069471
Natural variant1131G → V. Ref.9
VAR_069472
Natural variant1531L → V. Ref.9
Corresponds to variant rs35050588 [ dbSNP | Ensembl ].
VAR_048251
Natural variant1611L → P. Ref.9
VAR_069473
Natural variant1711G → S. Ref.9
Corresponds to variant rs200004875 [ dbSNP | Ensembl ].
VAR_069474
Natural variant1801G → S. Ref.9
VAR_069475
Natural variant1971M → T. Ref.9
VAR_069476
Natural variant2111E → Q. Ref.9
VAR_069477
Natural variant2251R → Q. Ref.9
VAR_069478
Natural variant2251R → W. Ref.9
Corresponds to variant rs138130157 [ dbSNP | Ensembl ].
VAR_069479
Natural variant2601Q → R. Ref.9
Corresponds to variant rs41272689 [ dbSNP | Ensembl ].
VAR_069480
Natural variant2691I → T. Ref.9
VAR_069481
Natural variant3071R → C. Ref.9
VAR_069482
Natural variant3401R → Q. Ref.9
VAR_069483
Natural variant3401R → W. Ref.9
Corresponds to variant rs33985460 [ dbSNP | Ensembl ].
VAR_048252
Natural variant4461R → M. Ref.9
Corresponds to variant rs200750014 [ dbSNP | Ensembl ].
VAR_069484
Natural variant4821A → V. Ref.9
Corresponds to variant rs34720726 [ dbSNP | Ensembl ].
VAR_069485
Natural variant4851D → N. Ref.9
Corresponds to variant rs149508864 [ dbSNP | Ensembl ].
VAR_069486

Experimental info

Sequence conflict831A → T in AAF73987. Ref.2
Sequence conflict188 – 1892MQ → IE in CAB65117. Ref.1
Sequence conflict4231Q → K in CAB65117. Ref.1
Sequence conflict486 – 4894ALGA → PSGPEKI in CAB65117. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified September 13, 2005. Version 3.
Checksum: 0E93E2B5117B328D

FASTA48954,258
        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 

« Hide

Isoform 2 [UniParc].

Checksum: 6404770D3EA7E2E4
Show »

FASTA46451,484

References

« Hide '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.
[9]"Gain-of-function R225W mutation in human AMPKgamma(3) causing increased glycogen and decreased triglyceride in skeletal muscle."
Costford S.R., Kavaslar N., Ahituv N., Chaudhry S.N., Schackwitz W.S., Dent R., Pennacchio L.A., McPherson R., Harper M.E.
PLoS ONE 2:E903-E903(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS ALA-71; GLN-76; GLY-103; VAL-113; VAL-153; PRO-161; SER-171; SER-180; THR-197; GLN-211; GLN-225; TRP-225; ARG-260; THR-269; CYS-307; GLN-340; TRP-340; MET-446; VAL-482 AND ASN-485, POLYMORPHISM.
+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.
RefSeqNP_059127.2. NM_017431.2.
UniGeneHs.591634.

3D structure databases

ProteinModelPortalQ9UGI9.
SMRQ9UGI9. Positions 181-480.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid119791. 7 interactions.
IntActQ9UGI9. 2 interactions.
MINTMINT-8343007.
STRING9606.ENSP00000233944.

Chemistry

ChEMBLCHEMBL2096907.

PTM databases

PhosphoSiteQ9UGI9.

Polymorphism databases

DMDM85681287.

Proteomic databases

PaxDbQ9UGI9.
PRIDEQ9UGI9.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000233944; ENSP00000233944; ENSG00000115592. [Q9UGI9-1]
ENST00000439262; ENSP00000397133; ENSG00000115592. [Q9UGI9-2]
ENST00000529249; ENSP00000436068; ENSG00000115592. [Q9UGI9-1]
GeneID53632.
KEGGhsa:53632.
UCSCuc002vjb.1. human. [Q9UGI9-1]

Organism-specific databases

CTD53632.
GeneCardsGC02M219651.
HGNCHGNC:9387. PRKAG3.
HPAHPA004909.
MIM604976. gene+phenotype.
neXtProtNX_Q9UGI9.
PharmGKBPA33753.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0517.
HOGENOMHOG000176880.
HOVERGENHBG050431.
InParanoidQ9UGI9.
KOK07200.
OMAAKASRWT.
OrthoDBEOG74FF0W.
PhylomeDBQ9UGI9.
TreeFamTF313247.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_11123. Membrane Trafficking.

Gene expression databases

ArrayExpressQ9UGI9.
BgeeQ9UGI9.
CleanExHS_PRKAG3.
GenevestigatorQ9UGI9.

Family and domain databases

InterProIPR000644. CBS_dom.
[Graphical view]
PfamPF00571. CBS. 3 hits.
[Graphical view]
SMARTSM00116. CBS. 4 hits.
[Graphical view]
PROSITEPS51371. CBS. 4 hits.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiPRKAG3.
GenomeRNAi53632.
NextBio56112.
PROQ9UGI9.
SOURCESearch...

Entry information

Entry nameAAKG3_HUMAN
AccessionPrimary (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: April 16, 2014
This is version 104 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM