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Q9UGI9

- AAKG3_HUMAN

UniProt

Q9UGI9 - AAKG3_HUMAN

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
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    • History
      Entry version 108 (01 Oct 2014)
      Sequence version 3 (13 Sep 2005)
      Previous versions | rss
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    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

    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

    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

    ArrayExpressiQ9UGI9.
    BgeeiQ9UGI9.
    CleanExiHS_PRKAG3.
    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.
    HOGENOMiHOG000176880.
    HOVERGENiHBG050431.
    InParanoidiQ9UGI9.
    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

    MEPGLEHALR RTPSWSSLGG SEHQEMSFLE QENSSSWPSP AVTSSSERIR    50
    GKRRAKALRW TRQKSVEEGE PPGQGEGPRS RPAAESTGLE ATFPKTTPLA 100
    QADPAGVGTP PTGWDCLPSD CTASAAGSST DDVELATEFP ATEAWECELE 150
    GLLEERPALC LSPQAPFPKL GWDDELRKPG AQIYMRFMQE HTCYDAMATS 200
    SKLVIFDTML EIKKAFFALV ANGVRAAPLW DSKKQSFVGM LTITDFILVL 250
    HRYYRSPLVQ IYEIEQHKIE TWREIYLQGC FKPLVSISPN DSLFEAVYTL 300
    IKNRIHRLPV LDPVSGNVLH ILTHKRLLKF LHIFGSLLPR PSFLYRTIQD 350
    LGIGTFRDLA VVLETAPILT ALDIFVDRRV SALPVVNECG QVVGLYSRFD 400
    VIHLAAQQTY NHLDMSVGEA LRQRTLCLEG VLSCQPHESL GEVIDRIARE 450
    QVHRLVLVDE TQHLLGVVSL SDILQALVLS PAGIDALGA 489
    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:
    EMBL
    GenBank
    DDBJ
    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. [Q9UGI9-2]
    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:
    EMBL
    GenBank
    DDBJ
    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 CHEMBL2096907.
    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 . [Q9UGI9-2 ]
    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.
    HOGENOMi HOG000176880.
    HOVERGENi HBG050431.
    InParanoidi Q9UGI9.
    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

    ArrayExpressi Q9UGI9.
    Bgeei Q9UGI9.
    CleanExi HS_PRKAG3.
    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

    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 1, 2014
    This is version 108 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