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Q9UGI9

- AAKG3_HUMAN

UniProt

Q9UGI9 - AAKG3_HUMAN

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Protein

5'-AMP-activated protein kinase subunit gamma-3

Gene

PRKAG3

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei225 – 2251AMP 1By similarity
Binding sitei225 – 2251ATP 1By similarity
Binding sitei306 – 3061AMP 2By similarity
Binding sitei306 – 3061AMP 3By similarity
Binding sitei306 – 3061ATP 2By similarity
Binding sitei307 – 3071ATP 1By similarity
Binding sitei307 – 3071ATP 2By similarity
Binding sitei325 – 3251AMP 1By similarity
Binding sitei325 – 3251ATP 1By similarity
Binding sitei453 – 4531AMP 3By similarity
Binding sitei454 – 4541AMP 1By similarity
Binding sitei454 – 4541ATP 1By similarity

GO - Molecular functioni

  1. AMP-activated protein kinase activity Source: ProtInc
  2. ATP binding Source: UniProtKB-KW
  3. protein kinase binding Source: BHF-UCL

GO - Biological processi

  1. cell cycle arrest Source: Reactome
  2. fatty acid biosynthetic process Source: UniProtKB-KW
  3. glucose transport Source: Ensembl
  4. glycogen biosynthetic process Source: Ensembl
  5. insulin receptor signaling pathway Source: Reactome
  6. intracellular signal transduction Source: ProtInc
  7. membrane organization Source: Reactome
  8. protein phosphorylation Source: GOC
Complete GO annotation...

Keywords - Biological processi

Fatty acid biosynthesis, Fatty acid metabolism, Lipid biosynthesis, Lipid metabolism

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_147867. Translocation of GLUT4 to the plasma membrane.
REACT_200686. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.
REACT_21285. Regulation of AMPK activity via LKB1.
REACT_21393. Regulation of Rheb GTPase activity by AMPK.

Names & Taxonomyi

Protein namesi
Recommended name:
5'-AMP-activated protein kinase subunit gamma-3
Short name:
AMPK gamma3
Short name:
AMPK subunit gamma-3
Gene namesi
Name:PRKAG3
Synonyms:AMPKG3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 2

Organism-specific databases

HGNCiHGNC:9387. PRKAG3.

Subcellular locationi

GO - Cellular componenti

  1. AMP-activated protein kinase complex Source: Ensembl
  2. cytosol Source: Reactome
  3. extracellular space Source: UniProt
Complete GO annotation...

Pathology & Biotechi

Organism-specific databases

MIMi604976. gene+phenotype.
PharmGKBiPA33753.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 4894895'-AMP-activated protein kinase subunit gamma-3PRO_0000204384Add
BLAST

Post-translational modificationi

Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ9UGI9.
PRIDEiQ9UGI9.

PTM databases

PhosphoSiteiQ9UGI9.

Expressioni

Tissue specificityi

Skeletal muscle, with weak expression in heart and pancreas.

Gene expression databases

BgeeiQ9UGI9.
CleanExiHS_PRKAG3.
ExpressionAtlasiQ9UGI9. baseline.
GenevestigatoriQ9UGI9.

Organism-specific databases

HPAiHPA004909.

Interactioni

Subunit structurei

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).By similarity

Protein-protein interaction databases

BioGridi119791. 7 interactions.
IntActiQ9UGI9. 2 interactions.
MINTiMINT-8343007.
STRINGi9606.ENSP00000233944.

Structurei

3D structure databases

ProteinModelPortaliQ9UGI9.
SMRiQ9UGI9. Positions 181-480.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini197 – 25862CBS 1PROSITE-ProRule annotationAdd
BLAST
Domaini280 – 34061CBS 2PROSITE-ProRule annotationAdd
BLAST
Domaini355 – 41561CBS 3PROSITE-ProRule annotationAdd
BLAST
Domaini427 – 48660CBS 4PROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi293 – 31422AMPK pseudosubstrateAdd
BLAST

Domaini

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.
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.

Sequence similaritiesi

Contains 4 CBS domains.PROSITE-ProRule annotation

Keywords - Domaini

CBS domain, Repeat

Phylogenomic databases

eggNOGiCOG0517.
GeneTreeiENSGT00390000009849.
HOGENOMiHOG000176880.
HOVERGENiHBG050431.
KOiK07200.
OMAiAKASRWT.
OrthoDBiEOG74FF0W.
PhylomeDBiQ9UGI9.
TreeFamiTF313247.

Family and domain databases

InterProiIPR000644. CBS_dom.
[Graphical view]
PfamiPF00571. CBS. 3 hits.
[Graphical view]
SMARTiSM00116. CBS. 4 hits.
[Graphical view]
PROSITEiPS51371. CBS. 4 hits.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: Q9UGI9-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MEPGLEHALR RTPSWSSLGG SEHQEMSFLE QENSSSWPSP AVTSSSERIR
60 70 80 90 100
GKRRAKALRW TRQKSVEEGE PPGQGEGPRS RPAAESTGLE ATFPKTTPLA
110 120 130 140 150
QADPAGVGTP PTGWDCLPSD CTASAAGSST DDVELATEFP ATEAWECELE
160 170 180 190 200
GLLEERPALC LSPQAPFPKL GWDDELRKPG AQIYMRFMQE HTCYDAMATS
210 220 230 240 250
SKLVIFDTML EIKKAFFALV ANGVRAAPLW DSKKQSFVGM LTITDFILVL
260 270 280 290 300
HRYYRSPLVQ IYEIEQHKIE TWREIYLQGC FKPLVSISPN DSLFEAVYTL
310 320 330 340 350
IKNRIHRLPV LDPVSGNVLH ILTHKRLLKF LHIFGSLLPR PSFLYRTIQD
360 370 380 390 400
LGIGTFRDLA VVLETAPILT ALDIFVDRRV SALPVVNECG QVVGLYSRFD
410 420 430 440 450
VIHLAAQQTY NHLDMSVGEA LRQRTLCLEG VLSCQPHESL GEVIDRIARE
460 470 480
QVHRLVLVDE TQHLLGVVSL SDILQALVLS PAGIDALGA
Length:489
Mass (Da):54,258
Last modified:September 13, 2005 - v3
Checksum:i0E93E2B5117B328D
GO
Isoform 2 (identifier: Q9UGI9-2) [UniParc]FASTAAdd to Basket

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

Show »
Length:464
Mass (Da):51,484
Checksum:i6404770D3EA7E2E4
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti83 – 831A → T in AAF73987. (PubMed:10818001)Curated
Sequence conflicti188 – 1892MQ → IE in CAB65117. (PubMed:10698692)Curated
Sequence conflicti423 – 4231Q → K in CAB65117. (PubMed:10698692)Curated
Sequence conflicti486 – 4894ALGA → PSGPEKI in CAB65117. (PubMed:10698692)Curated

Polymorphismi

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

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti71 – 711P → A.2 Publications
Corresponds to variant rs692243 [ dbSNP | Ensembl ].
VAR_023484
Natural varianti76 – 761E → Q.1 Publication
VAR_069470
Natural varianti103 – 1031D → G.1 Publication
VAR_069471
Natural varianti113 – 1131G → V.1 Publication
VAR_069472
Natural varianti153 – 1531L → V.1 Publication
Corresponds to variant rs35050588 [ dbSNP | Ensembl ].
VAR_048251
Natural varianti161 – 1611L → P.1 Publication
VAR_069473
Natural varianti171 – 1711G → S.1 Publication
Corresponds to variant rs200004875 [ dbSNP | Ensembl ].
VAR_069474
Natural varianti180 – 1801G → S.1 Publication
VAR_069475
Natural varianti197 – 1971M → T.1 Publication
VAR_069476
Natural varianti211 – 2111E → Q.1 Publication
VAR_069477
Natural varianti225 – 2251R → Q.1 Publication
VAR_069478
Natural varianti225 – 2251R → W.1 Publication
Corresponds to variant rs138130157 [ dbSNP | Ensembl ].
VAR_069479
Natural varianti260 – 2601Q → R.1 Publication
Corresponds to variant rs41272689 [ dbSNP | Ensembl ].
VAR_069480
Natural varianti269 – 2691I → T.1 Publication
VAR_069481
Natural varianti307 – 3071R → C.1 Publication
VAR_069482
Natural varianti340 – 3401R → Q.1 Publication
VAR_069483
Natural varianti340 – 3401R → W.1 Publication
Corresponds to variant rs33985460 [ dbSNP | Ensembl ].
VAR_048252
Natural varianti446 – 4461R → M.1 Publication
Corresponds to variant rs200750014 [ dbSNP | Ensembl ].
VAR_069484
Natural varianti482 – 4821A → V.1 Publication
Corresponds to variant rs34720726 [ dbSNP | Ensembl ].
VAR_069485
Natural varianti485 – 4851D → N.1 Publication
Corresponds to variant rs149508864 [ dbSNP | Ensembl ].
VAR_069486

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 2525Missing in isoform 2. 1 PublicationVSP_015587Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS2424.1. [Q9UGI9-1]
RefSeqiNP_059127.2. NM_017431.2. [Q9UGI9-1]
UniGeneiHs.591634.

Genome annotation databases

EnsembliENST00000233944; ENSP00000233944; ENSG00000115592. [Q9UGI9-1]
ENST00000439262; ENSP00000397133; ENSG00000115592. [Q9UGI9-1]
ENST00000529249; ENSP00000436068; ENSG00000115592. [Q9UGI9-1]
GeneIDi53632.
KEGGihsa:53632.
UCSCiuc002vjb.1. human. [Q9UGI9-1]

Polymorphism databases

DMDMi85681287.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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 .
CCDSi CCDS2424.1. [Q9UGI9-1 ]
RefSeqi NP_059127.2. NM_017431.2. [Q9UGI9-1 ]
UniGenei Hs.591634.

3D structure databases

ProteinModelPortali Q9UGI9.
SMRi Q9UGI9. Positions 181-480.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 119791. 7 interactions.
IntActi Q9UGI9. 2 interactions.
MINTi MINT-8343007.
STRINGi 9606.ENSP00000233944.

Chemistry

ChEMBLi CHEMBL3038457.
DrugBanki DB00945. Acetylsalicylic acid.

PTM databases

PhosphoSitei Q9UGI9.

Polymorphism databases

DMDMi 85681287.

Proteomic databases

PaxDbi Q9UGI9.
PRIDEi Q9UGI9.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000233944 ; ENSP00000233944 ; ENSG00000115592 . [Q9UGI9-1 ]
ENST00000439262 ; ENSP00000397133 ; ENSG00000115592 . [Q9UGI9-1 ]
ENST00000529249 ; ENSP00000436068 ; ENSG00000115592 . [Q9UGI9-1 ]
GeneIDi 53632.
KEGGi hsa:53632.
UCSCi uc002vjb.1. human. [Q9UGI9-1 ]

Organism-specific databases

CTDi 53632.
GeneCardsi GC02M219651.
HGNCi HGNC:9387. PRKAG3.
HPAi HPA004909.
MIMi 604976. gene+phenotype.
neXtProti NX_Q9UGI9.
PharmGKBi PA33753.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG0517.
GeneTreei ENSGT00390000009849.
HOGENOMi HOG000176880.
HOVERGENi HBG050431.
KOi K07200.
OMAi AKASRWT.
OrthoDBi EOG74FF0W.
PhylomeDBi Q9UGI9.
TreeFami TF313247.

Enzyme and pathway databases

Reactomei REACT_147867. Translocation of GLUT4 to the plasma membrane.
REACT_200686. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.
REACT_21285. Regulation of AMPK activity via LKB1.
REACT_21393. Regulation of Rheb GTPase activity by AMPK.

Miscellaneous databases

GeneWikii PRKAG3.
GenomeRNAii 53632.
NextBioi 56112.
PROi Q9UGI9.
SOURCEi Search...

Gene expression databases

Bgeei Q9UGI9.
CleanExi HS_PRKAG3.
ExpressionAtlasi Q9UGI9. baseline.
Genevestigatori Q9UGI9.

Family and domain databases

InterProi IPR000644. CBS_dom.
[Graphical view ]
Pfami PF00571. CBS. 3 hits.
[Graphical view ]
SMARTi SM00116. CBS. 4 hits.
[Graphical view ]
PROSITEi PS51371. CBS. 4 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. 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.

Entry informationi

Entry nameiAAKG3_HUMAN
AccessioniPrimary (citable) accession number: Q9UGI9
Secondary accession number(s): Q4QQG8, Q4V779, Q9NRL1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 2001
Last sequence update: September 13, 2005
Last modified: October 29, 2014
This is version 109 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3