Full text data of PRKAG1
PRKAG1
[Confidence: low (only semi-automatic identification from reviews)]
5'-AMP-activated protein kinase subunit gamma-1; AMPK gamma1; AMPK subunit gamma-1; AMPKg
Note: presumably soluble (membrane word is not in UniProt keywords or features)
5'-AMP-activated protein kinase subunit gamma-1; AMPK gamma1; AMPK subunit gamma-1; AMPKg
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P54619
ID AAKG1_HUMAN Reviewed; 331 AA.
AC P54619; B4DDT7; Q8N7V9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=5'-AMP-activated protein kinase subunit gamma-1;
DE Short=AMPK gamma1;
DE Short=AMPK subunit gamma-1;
DE Short=AMPKg;
GN Name=PRKAG1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Fetal liver;
RX PubMed=8621499; DOI=10.1074/jbc.271.15.8675;
RA Gao G., Fernandez C.S., Stapleton D., Auster A.S., Widmer J.,
RA Dyck J.R.B., Kemp B.E., Witters L.A.;
RT "Non-catalytic beta- and gamma-subunit isoforms of the 5'-AMP-
RT activated protein kinase.";
RL J. Biol. Chem. 271:8675-8681(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Glial tumor, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP DOMAIN CBS, AMP-BINDING, AND ATP-BINDING.
RX PubMed=14722619; DOI=10.1172/JCI19874;
RA Scott J.W., Hawley S.A., Green K.A., Anis M., Stewart G.,
RA Scullion G.A., Norman D.G., Hardie D.G.;
RT "CBS domains form energy-sensing modules whose binding of adenosine
RT ligands is disrupted by disease mutations.";
RL J. Clin. Invest. 113:274-284(2004).
RN [7]
RP INTERACTION WITH FNIP1, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=17028174; DOI=10.1073/pnas.0603781103;
RA Baba M., Hong S.-B., Sharma N., Warren M.B., Nickerson M.L.,
RA Iwamatsu A., Esposito D., Gillette W.K., Hopkins R.F. III,
RA Hartley J.L., Furihata M., Oishi S., Zhen W., Burke T.R. Jr.,
RA Linehan W.M., Schmidt L.S., Zbar B.;
RT "Folliculin encoded by the BHD gene interacts with a binding protein,
RT FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:15552-15557(2006).
RN [8]
RP DOMAIN AMPK PSEUDOSUBSTRATE.
RX PubMed=17255938; DOI=10.1038/sj.emboj.7601542;
RA Scott J.W., Ross F.A., Liu J.K., Hardie D.G.;
RT "Regulation of AMP-activated protein kinase by a pseudosubstrate
RT sequence on the gamma subunit.";
RL EMBO J. 26:806-815(2007).
RN [9]
RP INTERACTION WITH FNIP2.
RX PubMed=18403135; DOI=10.1016/j.gene.2008.02.022;
RA Hasumi H., Baba M., Hong S.-B., Hasumi Y., Huang Y., Yao M.,
RA Valera V.A., Linehan W.M., Schmidt L.S.;
RT "Identification and characterization of a novel folliculin-interacting
RT protein FNIP2.";
RL Gene 415:60-67(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION BY ULK1 AND ULK2.
RX PubMed=21460634; DOI=10.4161/auto.7.7.15451;
RA Loffler A.S., Alers S., Dieterle A.M., Keppeler H., Franz-Wachtel M.,
RA Kundu M., Campbell D.G., Wesselborg S., Alessi D.R., Stork B.;
RT "Ulk1-mediated phosphorylation of AMPK constitutes a negative
RT regulatory feedback loop.";
RL Autophagy 7:696-706(2011).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP INTERACTION WITH PRKAA1 AND PRKAB1, DOMAIN CBS, ADP-BINDING,
RP MUTAGENESIS OF ASP-90; ASP-245 AND ASP-317, AND FUNCTION.
RX PubMed=21680840; DOI=10.1126/science.1200094;
RA Oakhill J.S., Steel R., Chen Z.P., Scott J.W., Ling N., Tam S.,
RA Kemp B.E.;
RT "AMPK is a direct adenylate charge-regulated protein kinase.";
RL Science 332:1433-1435(2011).
RN [14]
RP REVIEW ON FUNCTION.
RX PubMed=17307971; DOI=10.1161/01.RES.0000256090.42690.05;
RA Towler M.C., Hardie D.G.;
RT "AMP-activated protein kinase in metabolic control and insulin
RT signaling.";
RL Circ. Res. 100:328-341(2007).
RN [15]
RP REVIEW ON FUNCTION.
RX PubMed=17712357; DOI=10.1038/nrm2249;
RA Hardie D.G.;
RT "AMP-activated/SNF1 protein kinases: conserved guardians of cellular
RT energy.";
RL Nat. Rev. Mol. Cell Biol. 8:774-785(2007).
CC -!- FUNCTION: AMP/ATP-binding subunit of AMP-activated protein kinase
CC (AMPK), an energy sensor protein kinase that plays a key role in
CC regulating cellular energy metabolism. In response to reduction of
CC intracellular ATP levels, AMPK activates energy-producing pathways
CC and inhibits energy-consuming processes: inhibits protein,
CC carbohydrate and lipid biosynthesis, as well as cell growth and
CC proliferation. AMPK acts via direct phosphorylation of metabolic
CC enzymes, and by longer-term effects via phosphorylation of
CC transcription regulators. Also acts as a regulator of cellular
CC polarity by remodeling the actin cytoskeleton; probably by
CC indirectly activating myosin. Gamma non-catalytic subunit mediates
CC binding to AMP, ADP and ATP, leading to activate or inhibit AMPK:
CC AMP-binding results in allosteric activation of alpha catalytic
CC subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and
CC preventing dephosphorylation of catalytic subunits. ADP also
CC stimulates phosphorylation, without stimulating already
CC phosphorylated catalytic subunit. ATP promotes dephosphorylation
CC of catalytic subunit, rendering the AMPK enzyme inactive.
CC -!- SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit
CC (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-
CC catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with
CC FNIP1 and FNIP2.
CC -!- INTERACTION:
CC Q9Y478:PRKAB1; NbExp=4; IntAct=EBI-1181439, EBI-719769;
CC O43741:PRKAB2; NbExp=3; IntAct=EBI-1181439, EBI-1053424;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P54619-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P54619-2; Sequence=VSP_046711;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P54619-3; Sequence=VSP_046712;
CC Note=No experimental confirmation available. May be due to
CC competing acceptor splice site;
CC -!- DOMAIN: The AMPK pseudosubstrate motif resembles the sequence
CC around sites phosphorylated on target proteins of AMPK, except the
CC presence of a non-phosphorylatable residue in place of Ser. In the
CC absence of AMP this pseudosubstrate sequence may bind to the
CC active site groove on the alpha subunit (PRKAA1 or PRKAA2),
CC preventing phosphorylation by the upstream activating kinase
CC STK11/LKB1.
CC -!- DOMAIN: The CBS domains mediate binding to AMP, ADP and ATP. 2
CC sites bind either AMP or ATP, whereas a third site contains a
CC tightly bound AMP that does not exchange. Under physiological
CC conditions AMPK mainly exists in its inactive form in complex with
CC ATP, which is much more abundant than AMP.
CC -!- PTM: Phosphorylated by ULK1 and ULK2; leading to negatively
CC regulate AMPK activity and suggesting the existence of a
CC regulatory feedback loop between ULK1, ULK2 and AMPK.
CC -!- SIMILARITY: Belongs to the 5'-AMP-activated protein kinase gamma
CC subunit family.
CC -!- SIMILARITY: Contains 4 CBS domains.
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DR EMBL; U42412; AAC50495.1; -; mRNA.
DR EMBL; BT007345; AAP36009.1; -; mRNA.
DR EMBL; AK097606; BAC05117.1; -; mRNA.
DR EMBL; AK293332; BAG56848.1; -; mRNA.
DR EMBL; AC011603; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000358; AAH00358.1; -; mRNA.
DR RefSeq; NP_001193638.1; NM_001206709.1.
DR RefSeq; NP_001193639.1; NM_001206710.1.
DR RefSeq; NP_002724.1; NM_002733.4.
DR UniGene; Hs.530862; -.
DR PDB; 2UV4; X-ray; 1.33 A; A=182-325.
DR PDB; 2UV5; X-ray; 1.69 A; A=182-325.
DR PDB; 2UV6; X-ray; 2.00 A; A=182-325.
DR PDB; 2UV7; X-ray; 2.00 A; A=182-325.
DR PDBsum; 2UV4; -.
DR PDBsum; 2UV5; -.
DR PDBsum; 2UV6; -.
DR PDBsum; 2UV7; -.
DR ProteinModelPortal; P54619; -.
DR SMR; P54619; 24-327.
DR IntAct; P54619; 19.
DR MINT; MINT-4649712; -.
DR STRING; 9606.ENSP00000323867; -.
DR BindingDB; P54619; -.
DR ChEMBL; CHEMBL2096907; -.
DR PhosphoSite; P54619; -.
DR DMDM; 1703037; -.
DR PaxDb; P54619; -.
DR PRIDE; P54619; -.
DR DNASU; 5571; -.
DR Ensembl; ENST00000316299; ENSP00000323867; ENSG00000181929.
DR Ensembl; ENST00000548065; ENSP00000447433; ENSG00000181929.
DR Ensembl; ENST00000552212; ENSP00000448972; ENSG00000181929.
DR GeneID; 5571; -.
DR KEGG; hsa:5571; -.
DR UCSC; uc001rsy.3; human.
DR CTD; 5571; -.
DR GeneCards; GC12M049396; -.
DR HGNC; HGNC:9385; PRKAG1.
DR MIM; 602742; gene.
DR neXtProt; NX_P54619; -.
DR PharmGKB; PA33751; -.
DR eggNOG; COG0517; -.
DR HOVERGEN; HBG050431; -.
DR InParanoid; P54619; -.
DR KO; K07200; -.
DR OMA; KGGAYDE; -.
DR PhylomeDB; P54619; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_11123; Membrane Trafficking.
DR SignaLink; P54619; -.
DR ChiTaRS; PRKAG1; human.
DR EvolutionaryTrace; P54619; -.
DR GeneWiki; PRKAG1; -.
DR GenomeRNAi; 5571; -.
DR NextBio; 21596; -.
DR PRO; PR:P54619; -.
DR ArrayExpress; P54619; -.
DR Bgee; P54619; -.
DR CleanEx; HS_PRKAG1; -.
DR Genevestigator; P54619; -.
DR GO; GO:0031588; C:AMP-activated protein kinase complex; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0043531; F:ADP binding; ISS:UniProtKB.
DR GO; GO:0016208; F:AMP binding; ISS:UniProtKB.
DR GO; GO:0004679; F:AMP-activated protein kinase activity; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0004691; F:cAMP-dependent protein kinase activity; TAS:ProtInc.
DR GO; GO:0008603; F:cAMP-dependent protein kinase regulator activity; TAS:BHF-UCL.
DR GO; GO:0019901; F:protein kinase binding; IDA:BHF-UCL.
DR GO; GO:0007050; P:cell cycle arrest; TAS:Reactome.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; TAS:BHF-UCL.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0006110; P:regulation of glycolysis; TAS:BHF-UCL.
DR GO; GO:0007283; P:spermatogenesis; TAS:ProtInc.
DR InterPro; IPR000644; CBS_dom.
DR Pfam; PF00571; CBS; 4.
DR SMART; SM00116; CBS; 4.
DR PROSITE; PS51371; CBS; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; CBS domain;
KW Complete proteome; Direct protein sequencing; Fatty acid biosynthesis;
KW Fatty acid metabolism; Lipid biosynthesis; Lipid metabolism;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat.
FT CHAIN 1 331 5'-AMP-activated protein kinase subunit
FT gamma-1.
FT /FTId=PRO_0000204377.
FT DOMAIN 43 103 CBS 1.
FT DOMAIN 125 187 CBS 2.
FT DOMAIN 198 260 CBS 3.
FT DOMAIN 272 329 CBS 4.
FT MOTIF 138 159 AMPK pseudosubstrate.
FT BINDING 70 70 AMP 1 (By similarity).
FT BINDING 70 70 ATP 1 (By similarity).
FT BINDING 151 151 AMP 2 (By similarity).
FT BINDING 151 151 AMP 3 (By similarity).
FT BINDING 151 151 ATP 2 (By similarity).
FT BINDING 152 152 ATP 1 (By similarity).
FT BINDING 152 152 ATP 2 (By similarity).
FT BINDING 170 170 AMP 1 (By similarity).
FT BINDING 170 170 ATP 1 (By similarity).
FT BINDING 298 298 AMP 3 (By similarity).
FT BINDING 299 299 AMP 1 (By similarity).
FT BINDING 299 299 ATP 1 (By similarity).
FT MOD_RES 261 261 Phosphoserine; by ULK1 (By similarity).
FT MOD_RES 263 263 Phosphothreonine; by ULK1 (By
FT similarity).
FT MOD_RES 270 270 Phosphoserine; by ULK1 (By similarity).
FT VAR_SEQ 1 32 Missing (in isoform 2).
FT /FTId=VSP_046711.
FT VAR_SEQ 83 83 V -> VVLRALSCPL (in isoform 3).
FT /FTId=VSP_046712.
FT VARIANT 89 89 T -> S (in dbSNP:rs1126930).
FT /FTId=VAR_033453.
FT VARIANT 329 329 K -> N (in dbSNP:rs34210356).
FT /FTId=VAR_033454.
FT MUTAGEN 90 90 D->A: Reduced AMP-activation of
FT phosphorylation of PRKAA1 or PRKAA2.
FT Reduced ADP activation of phosphorylation
FT of PRKAA1 or PRKAA2.
FT MUTAGEN 245 245 D->A: Reduced AMP-activation of
FT phosphorylation of PRKAA1 or PRKAA2.
FT Reduced ADP activation of phosphorylation
FT of PRKAA1 or PRKAA2.
FT MUTAGEN 317 317 D->A: Reduced AMP-activation of
FT phosphorylation of PRKAA1 or PRKAA2. Does
FT not affect ADP activation of
FT phosphorylation of PRKAA1 or PRKAA2.
FT HELIX 186 189
FT HELIX 193 196
FT HELIX 213 223
FT STRAND 226 231
FT STRAND 235 242
FT HELIX 243 251
FT HELIX 262 267
FT HELIX 271 274
FT STRAND 277 279
FT HELIX 285 295
FT STRAND 298 303
FT STRAND 307 314
FT HELIX 315 322
SQ SEQUENCE 331 AA; 37579 MW; 0F22B9CA1DBD87AE CRC64;
METVISSDSS PAVENEHPQE TPESNNSVYT SFMKSHRCYD LIPTSSKLVV FDTSLQVKKA
FFALVTNGVR AAPLWDSKKQ SFVGMLTITD FINILHRYYK SALVQIYELE EHKIETWREV
YLQDSFKPLV CISPNASLFD AVSSLIRNKI HRLPVIDPES GNTLYILTHK RILKFLKLFI
TEFPKPEFMS KSLEELQIGT YANIAMVRTT TPVYVALGIF VQHRVSALPV VDEKGRVVDI
YSKFDVINLA AEKTYNNLDV SVTKALQHRS HYFEGVLKCY LHETLETIIN RLVEAEVHRL
VVVDENDVVK GIVSLSDILQ ALVLTGGEKK P
//
ID AAKG1_HUMAN Reviewed; 331 AA.
AC P54619; B4DDT7; Q8N7V9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=5'-AMP-activated protein kinase subunit gamma-1;
DE Short=AMPK gamma1;
DE Short=AMPK subunit gamma-1;
DE Short=AMPKg;
GN Name=PRKAG1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Fetal liver;
RX PubMed=8621499; DOI=10.1074/jbc.271.15.8675;
RA Gao G., Fernandez C.S., Stapleton D., Auster A.S., Widmer J.,
RA Dyck J.R.B., Kemp B.E., Witters L.A.;
RT "Non-catalytic beta- and gamma-subunit isoforms of the 5'-AMP-
RT activated protein kinase.";
RL J. Biol. Chem. 271:8675-8681(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Glial tumor, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP DOMAIN CBS, AMP-BINDING, AND ATP-BINDING.
RX PubMed=14722619; DOI=10.1172/JCI19874;
RA Scott J.W., Hawley S.A., Green K.A., Anis M., Stewart G.,
RA Scullion G.A., Norman D.G., Hardie D.G.;
RT "CBS domains form energy-sensing modules whose binding of adenosine
RT ligands is disrupted by disease mutations.";
RL J. Clin. Invest. 113:274-284(2004).
RN [7]
RP INTERACTION WITH FNIP1, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=17028174; DOI=10.1073/pnas.0603781103;
RA Baba M., Hong S.-B., Sharma N., Warren M.B., Nickerson M.L.,
RA Iwamatsu A., Esposito D., Gillette W.K., Hopkins R.F. III,
RA Hartley J.L., Furihata M., Oishi S., Zhen W., Burke T.R. Jr.,
RA Linehan W.M., Schmidt L.S., Zbar B.;
RT "Folliculin encoded by the BHD gene interacts with a binding protein,
RT FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:15552-15557(2006).
RN [8]
RP DOMAIN AMPK PSEUDOSUBSTRATE.
RX PubMed=17255938; DOI=10.1038/sj.emboj.7601542;
RA Scott J.W., Ross F.A., Liu J.K., Hardie D.G.;
RT "Regulation of AMP-activated protein kinase by a pseudosubstrate
RT sequence on the gamma subunit.";
RL EMBO J. 26:806-815(2007).
RN [9]
RP INTERACTION WITH FNIP2.
RX PubMed=18403135; DOI=10.1016/j.gene.2008.02.022;
RA Hasumi H., Baba M., Hong S.-B., Hasumi Y., Huang Y., Yao M.,
RA Valera V.A., Linehan W.M., Schmidt L.S.;
RT "Identification and characterization of a novel folliculin-interacting
RT protein FNIP2.";
RL Gene 415:60-67(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION BY ULK1 AND ULK2.
RX PubMed=21460634; DOI=10.4161/auto.7.7.15451;
RA Loffler A.S., Alers S., Dieterle A.M., Keppeler H., Franz-Wachtel M.,
RA Kundu M., Campbell D.G., Wesselborg S., Alessi D.R., Stork B.;
RT "Ulk1-mediated phosphorylation of AMPK constitutes a negative
RT regulatory feedback loop.";
RL Autophagy 7:696-706(2011).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP INTERACTION WITH PRKAA1 AND PRKAB1, DOMAIN CBS, ADP-BINDING,
RP MUTAGENESIS OF ASP-90; ASP-245 AND ASP-317, AND FUNCTION.
RX PubMed=21680840; DOI=10.1126/science.1200094;
RA Oakhill J.S., Steel R., Chen Z.P., Scott J.W., Ling N., Tam S.,
RA Kemp B.E.;
RT "AMPK is a direct adenylate charge-regulated protein kinase.";
RL Science 332:1433-1435(2011).
RN [14]
RP REVIEW ON FUNCTION.
RX PubMed=17307971; DOI=10.1161/01.RES.0000256090.42690.05;
RA Towler M.C., Hardie D.G.;
RT "AMP-activated protein kinase in metabolic control and insulin
RT signaling.";
RL Circ. Res. 100:328-341(2007).
RN [15]
RP REVIEW ON FUNCTION.
RX PubMed=17712357; DOI=10.1038/nrm2249;
RA Hardie D.G.;
RT "AMP-activated/SNF1 protein kinases: conserved guardians of cellular
RT energy.";
RL Nat. Rev. Mol. Cell Biol. 8:774-785(2007).
CC -!- FUNCTION: AMP/ATP-binding subunit of AMP-activated protein kinase
CC (AMPK), an energy sensor protein kinase that plays a key role in
CC regulating cellular energy metabolism. In response to reduction of
CC intracellular ATP levels, AMPK activates energy-producing pathways
CC and inhibits energy-consuming processes: inhibits protein,
CC carbohydrate and lipid biosynthesis, as well as cell growth and
CC proliferation. AMPK acts via direct phosphorylation of metabolic
CC enzymes, and by longer-term effects via phosphorylation of
CC transcription regulators. Also acts as a regulator of cellular
CC polarity by remodeling the actin cytoskeleton; probably by
CC indirectly activating myosin. Gamma non-catalytic subunit mediates
CC binding to AMP, ADP and ATP, leading to activate or inhibit AMPK:
CC AMP-binding results in allosteric activation of alpha catalytic
CC subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and
CC preventing dephosphorylation of catalytic subunits. ADP also
CC stimulates phosphorylation, without stimulating already
CC phosphorylated catalytic subunit. ATP promotes dephosphorylation
CC of catalytic subunit, rendering the AMPK enzyme inactive.
CC -!- SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit
CC (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-
CC catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with
CC FNIP1 and FNIP2.
CC -!- INTERACTION:
CC Q9Y478:PRKAB1; NbExp=4; IntAct=EBI-1181439, EBI-719769;
CC O43741:PRKAB2; NbExp=3; IntAct=EBI-1181439, EBI-1053424;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P54619-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P54619-2; Sequence=VSP_046711;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P54619-3; Sequence=VSP_046712;
CC Note=No experimental confirmation available. May be due to
CC competing acceptor splice site;
CC -!- DOMAIN: The AMPK pseudosubstrate motif resembles the sequence
CC around sites phosphorylated on target proteins of AMPK, except the
CC presence of a non-phosphorylatable residue in place of Ser. In the
CC absence of AMP this pseudosubstrate sequence may bind to the
CC active site groove on the alpha subunit (PRKAA1 or PRKAA2),
CC preventing phosphorylation by the upstream activating kinase
CC STK11/LKB1.
CC -!- DOMAIN: The CBS domains mediate binding to AMP, ADP and ATP. 2
CC sites bind either AMP or ATP, whereas a third site contains a
CC tightly bound AMP that does not exchange. Under physiological
CC conditions AMPK mainly exists in its inactive form in complex with
CC ATP, which is much more abundant than AMP.
CC -!- PTM: Phosphorylated by ULK1 and ULK2; leading to negatively
CC regulate AMPK activity and suggesting the existence of a
CC regulatory feedback loop between ULK1, ULK2 and AMPK.
CC -!- SIMILARITY: Belongs to the 5'-AMP-activated protein kinase gamma
CC subunit family.
CC -!- SIMILARITY: Contains 4 CBS domains.
CC -----------------------------------------------------------------------
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DR EMBL; U42412; AAC50495.1; -; mRNA.
DR EMBL; BT007345; AAP36009.1; -; mRNA.
DR EMBL; AK097606; BAC05117.1; -; mRNA.
DR EMBL; AK293332; BAG56848.1; -; mRNA.
DR EMBL; AC011603; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000358; AAH00358.1; -; mRNA.
DR RefSeq; NP_001193638.1; NM_001206709.1.
DR RefSeq; NP_001193639.1; NM_001206710.1.
DR RefSeq; NP_002724.1; NM_002733.4.
DR UniGene; Hs.530862; -.
DR PDB; 2UV4; X-ray; 1.33 A; A=182-325.
DR PDB; 2UV5; X-ray; 1.69 A; A=182-325.
DR PDB; 2UV6; X-ray; 2.00 A; A=182-325.
DR PDB; 2UV7; X-ray; 2.00 A; A=182-325.
DR PDBsum; 2UV4; -.
DR PDBsum; 2UV5; -.
DR PDBsum; 2UV6; -.
DR PDBsum; 2UV7; -.
DR ProteinModelPortal; P54619; -.
DR SMR; P54619; 24-327.
DR IntAct; P54619; 19.
DR MINT; MINT-4649712; -.
DR STRING; 9606.ENSP00000323867; -.
DR BindingDB; P54619; -.
DR ChEMBL; CHEMBL2096907; -.
DR PhosphoSite; P54619; -.
DR DMDM; 1703037; -.
DR PaxDb; P54619; -.
DR PRIDE; P54619; -.
DR DNASU; 5571; -.
DR Ensembl; ENST00000316299; ENSP00000323867; ENSG00000181929.
DR Ensembl; ENST00000548065; ENSP00000447433; ENSG00000181929.
DR Ensembl; ENST00000552212; ENSP00000448972; ENSG00000181929.
DR GeneID; 5571; -.
DR KEGG; hsa:5571; -.
DR UCSC; uc001rsy.3; human.
DR CTD; 5571; -.
DR GeneCards; GC12M049396; -.
DR HGNC; HGNC:9385; PRKAG1.
DR MIM; 602742; gene.
DR neXtProt; NX_P54619; -.
DR PharmGKB; PA33751; -.
DR eggNOG; COG0517; -.
DR HOVERGEN; HBG050431; -.
DR InParanoid; P54619; -.
DR KO; K07200; -.
DR OMA; KGGAYDE; -.
DR PhylomeDB; P54619; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_11123; Membrane Trafficking.
DR SignaLink; P54619; -.
DR ChiTaRS; PRKAG1; human.
DR EvolutionaryTrace; P54619; -.
DR GeneWiki; PRKAG1; -.
DR GenomeRNAi; 5571; -.
DR NextBio; 21596; -.
DR PRO; PR:P54619; -.
DR ArrayExpress; P54619; -.
DR Bgee; P54619; -.
DR CleanEx; HS_PRKAG1; -.
DR Genevestigator; P54619; -.
DR GO; GO:0031588; C:AMP-activated protein kinase complex; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0043531; F:ADP binding; ISS:UniProtKB.
DR GO; GO:0016208; F:AMP binding; ISS:UniProtKB.
DR GO; GO:0004679; F:AMP-activated protein kinase activity; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0004691; F:cAMP-dependent protein kinase activity; TAS:ProtInc.
DR GO; GO:0008603; F:cAMP-dependent protein kinase regulator activity; TAS:BHF-UCL.
DR GO; GO:0019901; F:protein kinase binding; IDA:BHF-UCL.
DR GO; GO:0007050; P:cell cycle arrest; TAS:Reactome.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; TAS:BHF-UCL.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0006110; P:regulation of glycolysis; TAS:BHF-UCL.
DR GO; GO:0007283; P:spermatogenesis; TAS:ProtInc.
DR InterPro; IPR000644; CBS_dom.
DR Pfam; PF00571; CBS; 4.
DR SMART; SM00116; CBS; 4.
DR PROSITE; PS51371; CBS; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; CBS domain;
KW Complete proteome; Direct protein sequencing; Fatty acid biosynthesis;
KW Fatty acid metabolism; Lipid biosynthesis; Lipid metabolism;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat.
FT CHAIN 1 331 5'-AMP-activated protein kinase subunit
FT gamma-1.
FT /FTId=PRO_0000204377.
FT DOMAIN 43 103 CBS 1.
FT DOMAIN 125 187 CBS 2.
FT DOMAIN 198 260 CBS 3.
FT DOMAIN 272 329 CBS 4.
FT MOTIF 138 159 AMPK pseudosubstrate.
FT BINDING 70 70 AMP 1 (By similarity).
FT BINDING 70 70 ATP 1 (By similarity).
FT BINDING 151 151 AMP 2 (By similarity).
FT BINDING 151 151 AMP 3 (By similarity).
FT BINDING 151 151 ATP 2 (By similarity).
FT BINDING 152 152 ATP 1 (By similarity).
FT BINDING 152 152 ATP 2 (By similarity).
FT BINDING 170 170 AMP 1 (By similarity).
FT BINDING 170 170 ATP 1 (By similarity).
FT BINDING 298 298 AMP 3 (By similarity).
FT BINDING 299 299 AMP 1 (By similarity).
FT BINDING 299 299 ATP 1 (By similarity).
FT MOD_RES 261 261 Phosphoserine; by ULK1 (By similarity).
FT MOD_RES 263 263 Phosphothreonine; by ULK1 (By
FT similarity).
FT MOD_RES 270 270 Phosphoserine; by ULK1 (By similarity).
FT VAR_SEQ 1 32 Missing (in isoform 2).
FT /FTId=VSP_046711.
FT VAR_SEQ 83 83 V -> VVLRALSCPL (in isoform 3).
FT /FTId=VSP_046712.
FT VARIANT 89 89 T -> S (in dbSNP:rs1126930).
FT /FTId=VAR_033453.
FT VARIANT 329 329 K -> N (in dbSNP:rs34210356).
FT /FTId=VAR_033454.
FT MUTAGEN 90 90 D->A: Reduced AMP-activation of
FT phosphorylation of PRKAA1 or PRKAA2.
FT Reduced ADP activation of phosphorylation
FT of PRKAA1 or PRKAA2.
FT MUTAGEN 245 245 D->A: Reduced AMP-activation of
FT phosphorylation of PRKAA1 or PRKAA2.
FT Reduced ADP activation of phosphorylation
FT of PRKAA1 or PRKAA2.
FT MUTAGEN 317 317 D->A: Reduced AMP-activation of
FT phosphorylation of PRKAA1 or PRKAA2. Does
FT not affect ADP activation of
FT phosphorylation of PRKAA1 or PRKAA2.
FT HELIX 186 189
FT HELIX 193 196
FT HELIX 213 223
FT STRAND 226 231
FT STRAND 235 242
FT HELIX 243 251
FT HELIX 262 267
FT HELIX 271 274
FT STRAND 277 279
FT HELIX 285 295
FT STRAND 298 303
FT STRAND 307 314
FT HELIX 315 322
SQ SEQUENCE 331 AA; 37579 MW; 0F22B9CA1DBD87AE CRC64;
METVISSDSS PAVENEHPQE TPESNNSVYT SFMKSHRCYD LIPTSSKLVV FDTSLQVKKA
FFALVTNGVR AAPLWDSKKQ SFVGMLTITD FINILHRYYK SALVQIYELE EHKIETWREV
YLQDSFKPLV CISPNASLFD AVSSLIRNKI HRLPVIDPES GNTLYILTHK RILKFLKLFI
TEFPKPEFMS KSLEELQIGT YANIAMVRTT TPVYVALGIF VQHRVSALPV VDEKGRVVDI
YSKFDVINLA AEKTYNNLDV SVTKALQHRS HYFEGVLKCY LHETLETIIN RLVEAEVHRL
VVVDENDVVK GIVSLSDILQ ALVLTGGEKK P
//
MIM
602742
*RECORD*
*FIELD* NO
602742
*FIELD* TI
*602742 PROTEIN KINASE, AMP-ACTIVATED, NONCATALYTIC, GAMMA-1; PRKAG1
;;AMP-ACTIVATED PROTEIN KINASE, NONCATALYTIC, GAMMA-1;;
read moreAMPK-GAMMA-1
*FIELD* TX
DESCRIPTION
The mammalian 5-prime-AMP-activated protein kinase (AMPK) appears to act
as a metabolic stress-sensing protein kinase. AMPK is a heterotrimeric
protein composed of a catalytic alpha subunit, a noncatalytic beta
subunit, and a noncatalytic gamma subunit. See PRKAA1 (602739) for
background.
CLONING
By PCR with degenerate oligonucleotides based on the rat Ampk-gamma-1
protein sequence, Woods et al. (1996) isolated rat liver cDNAs encoding
Ampk-gamma-1. Both the Ampk-gamma-1 mRNA and protein are widely
expressed in rat tissues. Gao et al. (1996) screened a human fetal liver
cDNA library with the rat Ampk-gamma-1 cDNA and isolated a cDNA encoding
AMPK-gamma-1. The predicted 331-amino acid human protein has a mass of
37.5 kD by SDS-PAGE.
GENE FUNCTION
By site-directed mutagenesis, Hamilton et al. (2001) introduced an
arg70-to-glu mutation into PRKAG1. The mutation caused a marked increase
in AMPK activity, and the activity was largely AMP-independent.
Activation was associated with increased threonine phosphorylation
within the activation loop of the alpha subunit, PRKAA1. There was also
increased phosphorylation of one of its major substrates, acetyl-CoA
carboxylase (200350).
Minokoshi et al. (2004) investigated the potential role of AMP-activated
protein kinase (AMPK) in the hypothalamus in the regulation of food
intake. Minokoshi et al. (2004) reported that AMPK activity is inhibited
in arcuate and paraventricular hypothalamus by the anorexigenic hormone
leptin (164160), and in multiple hypothalamic regions by insulin
(176730), high glucose, and refeeding. A melanocortin receptor (see
155555) agonist, a potent anorexigen, decreased AMPK activity in
paraventricular hypothalamus, whereas agouti-related protein (602311),
an orexigen, increased AMPK activity. Melanocortin receptor signaling is
required for leptin and refeeding effects of AMPK in the paraventricular
hypothalamus. Dominant-negative AMPK expression in the hypothalamus was
sufficient to reduce food intake and body weight, whereas constitutively
active AMPK increased both. Alterations of hypothalamic AMPK activity
augmented changes in arcuate neuropeptide expression induced by fasting
and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary
for leptin's effects on food intake and body weight, as constitutively
active AMPK blocks these effects. Thus, Minokoshi et al. (2004)
concluded that hypothalamic AMPK plays a critical role in hormonal and
nutrient-derived anorexigenic and orexigenic signals and in energy
balance.
Baba et al. (2006) showed that FNIP1 (610594) interacted with the alpha,
beta, and gamma subunits of AMPK. FNIP1 was phosphorylated by AMPK, and
its phosphorylation was inhibited in a dose-dependent manner by an AMPK
inhibitor, resulting in reduced FNIP1 expression. FLCN (607273)
phosphorylation was diminished by rapamycin and amino acid starvation
and facilitated by FNIP1 overexpression, suggesting that FLCN
phosphorylation may be regulated by mTOR (FRAP1; 601231) and AMPK
signaling. Baba et al. (2006) concluded that FLCN and FNIP1 may be
involved in energy and/or nutrient sensing through the AMPK and mTOR
signaling pathways.
AMPK is an alpha-beta-gamma heterotrimer activated by decreasing
concentrations of adenosine triphosphate (ATP) and increasing AMP
concentrations (summary by Oakhill et al., 2011). AMPK activation
depends on phosphorylation of the alpha catalytic subunit on thr172 by
kinases LKB1 (602216) or CaMKK-beta (CAMMK2; 615002), and this is
promoted by AMP binding to the gamma subunit. AMP sustains activity by
inhibiting dephosphorylation of alpha-thr172, whereas ATP promotes
dephosphorylation. Oakhill et al. (2011) found that adenosine
diphosphate (ADP), like AMP, bound to gamma sites 1 and 3 and stimulated
alpha-Thr172 phosphorylation. However, in contrast to AMP, ADP did not
directly activate phosphorylated AMPK. In this way, both ADP/ATP and
AMP/ATP ratios contribute to AMPK regulation.
MAPPING
Stapleton et al. (1997) mapped the human AMPK-gamma-1 gene to 12q13.1 by
fluorescence in situ hybridization.
BIOCHEMICAL FEATURES
- Crystal Structure
Xiao et al. (2007) reported the crystal structure of the regulatory
fragment of mammalian AMPK in complexes with AMP and ATP. The phosphate
groups of AMP/ATP lie in a groove on the surface of the gamma domain,
which is lined with basic residues, many of which are associated with
disease-causing mutations. Structural and solution studies revealed that
2 sites on the gamma domain bind either AMP or magnesium ATP, whereas a
third site contains a tightly bound AMP that does not exchange. Xiao et
al. (2007) stated that their binding studies indicated that under
physiologic conditions AMPK mainly exists in its inactive form in
complex with magnesium ATP, which is much more abundant than AMP. Their
modeling studies suggested how changes in the concentration of AMP
enhance AMPK activity levels. The structure also suggested a mechanism
for propagating AMP/ATP signaling whereby a phosphorylated residue from
the alpha and/or beta subunits binds to the gamma subunit in the
presence of AMP but not when ATP is bound.
*FIELD* RF
1. 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.: Folliculin encoded by the
BHD gene interacts with a binding protein, FNIP1, and AMPK, and is
involved in AMPK and mTOR signaling. Proc. Nat. Acad. Sci. 103:
15552-15557, 2006.
2. Gao, G.; Fernandez, C. S.; Stapleton, D.; Auster, A. S.; Widmer,
J.; Dyck, J. R. B.; Kemp, B. E.; Witters, L. A.: Non-catalytic beta-
and gamma-subunit isoforms of the 5-prime-AMP-activated protein kinase. J.
Biol. Chem. 271: 8675-8681, 1996.
3. Hamilton, S. R.; Stapleton, D.; O'Donnell, J. B., Jr.; Kung, J.
T.; Dalal, S. R.; Kemp, B. E.; Witters, L. A.: An activating mutation
in the gamma-1 subunit of the AMP-activated protein kinase. FEBS
Lett. 500: 163-168, 2001.
4. Minokoshi, Y.; Alquier, T.; Furukawa, N.; Kim, Y.-B.; Lee, A.;
Xue, B.; Mu, J.; Foufelle, F.; Ferre, P.; Birnbaum, M. J.; Stuck,
B. J.; Kahn, B. B.: AMP-kinase regulates food intake by responding
to hormonal and nutrient signals in the hypothalamus. Nature 428:
569-574, 2004.
5. Oakhill, J. S.; Steel, R.; Chen, Z.-P.; Scott, J. W.; Ling, N.;
Tam, S.; Kemp, B. E.: AMPK is a direct adenylate charge-regulated
protein kinase. Science 332: 1433-1435, 2011.
6. Stapleton, D.; Woollatt, E.; Mitchelhill, K. I.; Nicholl, J. K.;
Fernandez, C. S.; Michell, B. J.; Witters, L. A.; Power, D. A.; Sutherland,
G. R.; Kemp, B. E.: AMP-activated protein kinase isoenzyme family:
subunit structure and chromosomal location. FEBS Lett. 409: 452-456,
1997.
7. Woods, A.; Cheung, P. C. F.; Smith, F. C.; Davison, M. D.; Scott,
J.; Beri, R. K.; Carling, D.: Characterization of AMP-activated protein
kinase beta and gamma subunits: assembly of the heterotrimeric complex
in vitro. J. Biol. Chem. 271: 10282-10290, 1996.
8. Xiao, B.; Heath, R.; Saiu, P.; Leiper, F. C.; Leone, P.; Jing,
C.; Walker, P. A.; Haire, L.; Eccleston, J. F.; Davis, C. T.; Martin,
S. R.; Carling, D.; Gamblin, S. J.: Structural basis for AMP binding
to mammalian AMP-activated protein kinase. Nature 449: 496-500,
2007.
*FIELD* CN
Ada Hamosh - updated: 7/1/2011
Ada Hamosh - updated: 10/11/2007
Dorothy S. Reilly - updated: 11/27/2006
Ada Hamosh - updated: 4/7/2004
Patricia A. Hartz - updated: 1/21/2003
*FIELD* CD
Rebekah S. Rasooly: 6/22/1998
*FIELD* ED
carol: 12/20/2012
alopez: 7/7/2011
terry: 7/1/2011
alopez: 10/16/2007
terry: 10/11/2007
wwang: 11/27/2006
alopez: 4/8/2004
terry: 4/7/2004
mgross: 1/21/2003
terry: 1/21/2003
dkim: 9/22/1998
psherman: 6/24/1998
*RECORD*
*FIELD* NO
602742
*FIELD* TI
*602742 PROTEIN KINASE, AMP-ACTIVATED, NONCATALYTIC, GAMMA-1; PRKAG1
;;AMP-ACTIVATED PROTEIN KINASE, NONCATALYTIC, GAMMA-1;;
read moreAMPK-GAMMA-1
*FIELD* TX
DESCRIPTION
The mammalian 5-prime-AMP-activated protein kinase (AMPK) appears to act
as a metabolic stress-sensing protein kinase. AMPK is a heterotrimeric
protein composed of a catalytic alpha subunit, a noncatalytic beta
subunit, and a noncatalytic gamma subunit. See PRKAA1 (602739) for
background.
CLONING
By PCR with degenerate oligonucleotides based on the rat Ampk-gamma-1
protein sequence, Woods et al. (1996) isolated rat liver cDNAs encoding
Ampk-gamma-1. Both the Ampk-gamma-1 mRNA and protein are widely
expressed in rat tissues. Gao et al. (1996) screened a human fetal liver
cDNA library with the rat Ampk-gamma-1 cDNA and isolated a cDNA encoding
AMPK-gamma-1. The predicted 331-amino acid human protein has a mass of
37.5 kD by SDS-PAGE.
GENE FUNCTION
By site-directed mutagenesis, Hamilton et al. (2001) introduced an
arg70-to-glu mutation into PRKAG1. The mutation caused a marked increase
in AMPK activity, and the activity was largely AMP-independent.
Activation was associated with increased threonine phosphorylation
within the activation loop of the alpha subunit, PRKAA1. There was also
increased phosphorylation of one of its major substrates, acetyl-CoA
carboxylase (200350).
Minokoshi et al. (2004) investigated the potential role of AMP-activated
protein kinase (AMPK) in the hypothalamus in the regulation of food
intake. Minokoshi et al. (2004) reported that AMPK activity is inhibited
in arcuate and paraventricular hypothalamus by the anorexigenic hormone
leptin (164160), and in multiple hypothalamic regions by insulin
(176730), high glucose, and refeeding. A melanocortin receptor (see
155555) agonist, a potent anorexigen, decreased AMPK activity in
paraventricular hypothalamus, whereas agouti-related protein (602311),
an orexigen, increased AMPK activity. Melanocortin receptor signaling is
required for leptin and refeeding effects of AMPK in the paraventricular
hypothalamus. Dominant-negative AMPK expression in the hypothalamus was
sufficient to reduce food intake and body weight, whereas constitutively
active AMPK increased both. Alterations of hypothalamic AMPK activity
augmented changes in arcuate neuropeptide expression induced by fasting
and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary
for leptin's effects on food intake and body weight, as constitutively
active AMPK blocks these effects. Thus, Minokoshi et al. (2004)
concluded that hypothalamic AMPK plays a critical role in hormonal and
nutrient-derived anorexigenic and orexigenic signals and in energy
balance.
Baba et al. (2006) showed that FNIP1 (610594) interacted with the alpha,
beta, and gamma subunits of AMPK. FNIP1 was phosphorylated by AMPK, and
its phosphorylation was inhibited in a dose-dependent manner by an AMPK
inhibitor, resulting in reduced FNIP1 expression. FLCN (607273)
phosphorylation was diminished by rapamycin and amino acid starvation
and facilitated by FNIP1 overexpression, suggesting that FLCN
phosphorylation may be regulated by mTOR (FRAP1; 601231) and AMPK
signaling. Baba et al. (2006) concluded that FLCN and FNIP1 may be
involved in energy and/or nutrient sensing through the AMPK and mTOR
signaling pathways.
AMPK is an alpha-beta-gamma heterotrimer activated by decreasing
concentrations of adenosine triphosphate (ATP) and increasing AMP
concentrations (summary by Oakhill et al., 2011). AMPK activation
depends on phosphorylation of the alpha catalytic subunit on thr172 by
kinases LKB1 (602216) or CaMKK-beta (CAMMK2; 615002), and this is
promoted by AMP binding to the gamma subunit. AMP sustains activity by
inhibiting dephosphorylation of alpha-thr172, whereas ATP promotes
dephosphorylation. Oakhill et al. (2011) found that adenosine
diphosphate (ADP), like AMP, bound to gamma sites 1 and 3 and stimulated
alpha-Thr172 phosphorylation. However, in contrast to AMP, ADP did not
directly activate phosphorylated AMPK. In this way, both ADP/ATP and
AMP/ATP ratios contribute to AMPK regulation.
MAPPING
Stapleton et al. (1997) mapped the human AMPK-gamma-1 gene to 12q13.1 by
fluorescence in situ hybridization.
BIOCHEMICAL FEATURES
- Crystal Structure
Xiao et al. (2007) reported the crystal structure of the regulatory
fragment of mammalian AMPK in complexes with AMP and ATP. The phosphate
groups of AMP/ATP lie in a groove on the surface of the gamma domain,
which is lined with basic residues, many of which are associated with
disease-causing mutations. Structural and solution studies revealed that
2 sites on the gamma domain bind either AMP or magnesium ATP, whereas a
third site contains a tightly bound AMP that does not exchange. Xiao et
al. (2007) stated that their binding studies indicated that under
physiologic conditions AMPK mainly exists in its inactive form in
complex with magnesium ATP, which is much more abundant than AMP. Their
modeling studies suggested how changes in the concentration of AMP
enhance AMPK activity levels. The structure also suggested a mechanism
for propagating AMP/ATP signaling whereby a phosphorylated residue from
the alpha and/or beta subunits binds to the gamma subunit in the
presence of AMP but not when ATP is bound.
*FIELD* RF
1. 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.: Folliculin encoded by the
BHD gene interacts with a binding protein, FNIP1, and AMPK, and is
involved in AMPK and mTOR signaling. Proc. Nat. Acad. Sci. 103:
15552-15557, 2006.
2. Gao, G.; Fernandez, C. S.; Stapleton, D.; Auster, A. S.; Widmer,
J.; Dyck, J. R. B.; Kemp, B. E.; Witters, L. A.: Non-catalytic beta-
and gamma-subunit isoforms of the 5-prime-AMP-activated protein kinase. J.
Biol. Chem. 271: 8675-8681, 1996.
3. Hamilton, S. R.; Stapleton, D.; O'Donnell, J. B., Jr.; Kung, J.
T.; Dalal, S. R.; Kemp, B. E.; Witters, L. A.: An activating mutation
in the gamma-1 subunit of the AMP-activated protein kinase. FEBS
Lett. 500: 163-168, 2001.
4. Minokoshi, Y.; Alquier, T.; Furukawa, N.; Kim, Y.-B.; Lee, A.;
Xue, B.; Mu, J.; Foufelle, F.; Ferre, P.; Birnbaum, M. J.; Stuck,
B. J.; Kahn, B. B.: AMP-kinase regulates food intake by responding
to hormonal and nutrient signals in the hypothalamus. Nature 428:
569-574, 2004.
5. Oakhill, J. S.; Steel, R.; Chen, Z.-P.; Scott, J. W.; Ling, N.;
Tam, S.; Kemp, B. E.: AMPK is a direct adenylate charge-regulated
protein kinase. Science 332: 1433-1435, 2011.
6. Stapleton, D.; Woollatt, E.; Mitchelhill, K. I.; Nicholl, J. K.;
Fernandez, C. S.; Michell, B. J.; Witters, L. A.; Power, D. A.; Sutherland,
G. R.; Kemp, B. E.: AMP-activated protein kinase isoenzyme family:
subunit structure and chromosomal location. FEBS Lett. 409: 452-456,
1997.
7. Woods, A.; Cheung, P. C. F.; Smith, F. C.; Davison, M. D.; Scott,
J.; Beri, R. K.; Carling, D.: Characterization of AMP-activated protein
kinase beta and gamma subunits: assembly of the heterotrimeric complex
in vitro. J. Biol. Chem. 271: 10282-10290, 1996.
8. Xiao, B.; Heath, R.; Saiu, P.; Leiper, F. C.; Leone, P.; Jing,
C.; Walker, P. A.; Haire, L.; Eccleston, J. F.; Davis, C. T.; Martin,
S. R.; Carling, D.; Gamblin, S. J.: Structural basis for AMP binding
to mammalian AMP-activated protein kinase. Nature 449: 496-500,
2007.
*FIELD* CN
Ada Hamosh - updated: 7/1/2011
Ada Hamosh - updated: 10/11/2007
Dorothy S. Reilly - updated: 11/27/2006
Ada Hamosh - updated: 4/7/2004
Patricia A. Hartz - updated: 1/21/2003
*FIELD* CD
Rebekah S. Rasooly: 6/22/1998
*FIELD* ED
carol: 12/20/2012
alopez: 7/7/2011
terry: 7/1/2011
alopez: 10/16/2007
terry: 10/11/2007
wwang: 11/27/2006
alopez: 4/8/2004
terry: 4/7/2004
mgross: 1/21/2003
terry: 1/21/2003
dkim: 9/22/1998
psherman: 6/24/1998