UniProtKB - Q9UGJ0 (AAKG2_HUMAN)
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Protein
5'-AMP-activated protein kinase subunit gamma-2
Gene
PRKAG2
Organism
Homo sapiens (Human)
Status
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 key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Binding sitei | 302 | AMP, ADP or ATP 2By similarity | 1 | |
| Binding sitei | 362 | AMP, ADP or ATP 1; via amide nitrogen and carbonyl oxygenBy similarity | 1 | |
| Binding sitei | 383 | AMP 3By similarity | 1 | |
| Binding sitei | 402 | AMP, ADP or ATP 2By similarity | 1 | |
| Binding sitei | 432 | AMP 3By similarity | 1 | |
| Binding sitei | 437 | AMP 3; via amide nitrogen and carbonyl oxygenBy similarity | 1 | |
| Binding sitei | 501 | AMP, ADP or ATP 2By similarity | 1 | |
| Binding sitei | 509 | AMP, ADP or ATP 2; via amide nitrogen and carbonyl oxygenBy similarity | 1 | |
| Binding sitei | 530 | AMP 3By similarity | 1 |
Regions
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Nucleotide bindingi | 319 – 322 | AMP, ADP or ATP 1By similarity | 4 | |
| Nucleotide bindingi | 383 – 384 | AMP, ADP or ATP 1By similarity | 2 | |
| Nucleotide bindingi | 458 – 459 | AMP 3By similarity | 2 | |
| Nucleotide bindingi | 474 – 477 | AMP, ADP or ATP 2By similarity | 4 | |
| Nucleotide bindingi | 530 – 531 | AMP, ADP or ATP 2By similarity | 2 | |
| Nucleotide bindingi | 546 – 549 | AMP 3By similarity | 4 |
GO - Molecular functioni
- ADP binding Source: BHF-UCL
- AMP-activated protein kinase activity Source: Ensembl
- AMP binding Source: Ensembl
- ATP binding Source: BHF-UCL
- cAMP-dependent protein kinase inhibitor activity Source: BHF-UCL
- cAMP-dependent protein kinase regulator activity Source: BHF-UCL
- phosphorylase kinase regulator activity Source: BHF-UCL
- protein kinase activator activity Source: BHF-UCL
- protein kinase binding Source: BHF-UCL
GO - Biological processi
- ATP biosynthetic process Source: BHF-UCL
- carnitine shuttle Source: Reactome
- cell cycle arrest Source: Reactome
- fatty acid biosynthetic process Source: UniProtKB-KW
- glycogen metabolic process Source: BHF-UCL
- intracellular signal transduction Source: BHF-UCL
- macroautophagy Source: Reactome
- negative regulation of protein kinase activity Source: BHF-UCL
- positive regulation of peptidyl-threonine phosphorylation Source: BHF-UCL
- positive regulation of protein kinase activity Source: BHF-UCL
- regulation of fatty acid biosynthetic process Source: Reactome
- regulation of fatty acid metabolic process Source: BHF-UCL
- regulation of fatty acid oxidation Source: BHF-UCL
- regulation of glucose import Source: BHF-UCL
- regulation of glycolytic process Source: BHF-UCL
- regulation of macroautophagy Source: Reactome
- regulation of signal transduction by p53 class mediator Source: Reactome
- sterol biosynthetic process Source: BHF-UCL
Keywordsi
| Biological process | Fatty acid biosynthesis, Fatty acid metabolism, Lipid biosynthesis, Lipid metabolism |
| Ligand | ATP-binding, Nucleotide-binding |
Enzyme and pathway databases
| Reactomei | R-HSA-1445148. Translocation of GLUT4 to the plasma membrane. R-HSA-1632852. Macroautophagy. R-HSA-163680. AMPK inhibits chREBP transcriptional activation activity. R-HSA-200425. Import of palmitoyl-CoA into the mitochondrial matrix. R-HSA-2151209. Activation of PPARGC1A (PGC-1alpha) by phosphorylation. R-HSA-380972. Energy dependent regulation of mTOR by LKB1-AMPK. R-HSA-5628897. TP53 Regulates Metabolic Genes. R-HSA-6804756. Regulation of TP53 Activity through Phosphorylation. |
| SignaLinki | Q9UGJ0. |
| SIGNORi | Q9UGJ0. |
Names & Taxonomyi
| Protein namesi | Recommended name: 5'-AMP-activated protein kinase subunit gamma-2Short name: AMPK gamma2 Short name: AMPK subunit gamma-2 Alternative name(s): H91620p |
| Gene namesi | Name:PRKAG2 |
| Organismi | Homo sapiens (Human) |
| Taxonomic identifieri | 9606 [NCBI] |
| Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
| Proteomesi |
|
Organism-specific databases
| HGNCi | HGNC:9386. PRKAG2. |
Subcellular locationi
GO - Cellular componenti
- cytosol Source: Reactome
- extracellular space Source: UniProtKB
- nucleoplasm Source: Reactome
- nucleotide-activated protein kinase complex Source: BHF-UCL
Pathology & Biotechi
Involvement in diseasei
Wolff-Parkinson-White syndrome (WPWS)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA supernormal conduction disorder characterized by the presence of one or several accessory atrioventricular connections, which can lead to episodes of sporadic tachycardia.
See also OMIM:194200| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Natural variantiVAR_013264 | 302 | R → Q in WPWS and CMH6; impaired AMP- and ATP-binding. 3 PublicationsCorresponds to variant dbSNP:rs121908987Ensembl. | 1 | |
| Natural variantiVAR_032909 | 531 | R → G in WPWS; absence of cardiac hypertrophy; onset in childhood; impaired AMP- and ATP-binding. 2 PublicationsCorresponds to variant dbSNP:rs121908990Ensembl. | 1 |
Cardiomyopathy, familial hypertrophic 6 (CMH6)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. CMH6 patients present Wolff-Parkinson-White ventricular preexcitation, enlarged myocytes without myofiber disarray, and glycogen-containing cytosolic vacuoles within cardiomyocytes.
See also OMIM:600858| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Natural variantiVAR_013264 | 302 | R → Q in WPWS and CMH6; impaired AMP- and ATP-binding. 3 PublicationsCorresponds to variant dbSNP:rs121908987Ensembl. | 1 | |
| Natural variantiVAR_013265 | 350 | R → RL in CMH6; severe. 1 Publication | 1 | |
| Natural variantiVAR_013266 | 383 | H → R in CMH6; severe; impaired AMP- and ATP-binding. 2 PublicationsCorresponds to variant dbSNP:rs121908988Ensembl. | 1 | |
| Natural variantiVAR_013267 | 400 | T → N in CMH6; severe; impaired AMP- and ATP-binding. 2 PublicationsCorresponds to variant dbSNP:rs28938173Ensembl. | 1 | |
| Natural variantiVAR_013268 | 488 | N → I in CMH6; severe. 1 PublicationCorresponds to variant dbSNP:rs121908989Ensembl. | 1 |
Glycogen storage disease of heart lethal congenital (GSDH)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRare disease which leads to death within a few weeks to a few months after birth, through heart failure and respiratory compromise.
See also OMIM:261740| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Natural variantiVAR_013269 | 531 | R → Q in GSDH; reduction of binding affinities for AMP and ATP; loss of cooperative binding; enhanced basal activity; increased phosphorylation of the alpha-subunit. 1 PublicationCorresponds to variant dbSNP:rs121908991Ensembl. | 1 |
Mutagenesis
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Mutagenesisi | 387 | V → S: Induces phosphorylation by AMPK. 1 Publication | 1 |
Keywords - Diseasei
Cardiomyopathy, Disease mutation, Glycogen storage diseaseOrganism-specific databases
| DisGeNETi | 51422. |
| MalaCardsi | PRKAG2. |
| MIMi | 194200. phenotype. 261740. phenotype. 600858. phenotype. |
| OpenTargetsi | ENSG00000106617. |
| Orphaneti | 155. Familial isolated hypertrophic cardiomyopathy. 907. Wolff-Parkinson-White syndrome. |
| PharmGKBi | PA33752. |
Chemistry databases
| ChEMBLi | CHEMBL3038451. |
| DrugBanki | DB00945. Acetylsalicylic acid. |
Polymorphism and mutation databases
| BioMutai | PRKAG2. |
| DMDMi | 14285344. |
PTM / Processingi
Molecule processing
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| ChainiPRO_0000204381 | 1 – 569 | 5'-AMP-activated protein kinase subunit gamma-2Add BLAST | 569 |
Amino acid modifications
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Modified residuei | 65 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 71 | PhosphoserineCombined sources | 1 | |
| Modified residuei | 73 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 90 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 138 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 143 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 161 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 162 | PhosphoserineBy similarity | 1 | |
| Modified residuei | 165 | PhosphothreonineBy similarity | 1 | |
| Modified residuei | 196 | PhosphoserineBy similarity | 1 |
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
PhosphoproteinProteomic databases
| PaxDbi | Q9UGJ0. |
| PeptideAtlasi | Q9UGJ0. |
| PRIDEi | Q9UGJ0. |
PTM databases
| iPTMneti | Q9UGJ0. |
| PhosphoSitePlusi | Q9UGJ0. |
Expressioni
Tissue specificityi
Isoform B is ubiquitously expressed except in liver and thymus. The highest level is detected in heart with abundant expression in placenta and testis.
Gene expression databases
| Bgeei | ENSG00000106617. |
| CleanExi | HS_PRKAG2. |
| ExpressionAtlasi | Q9UGJ0. baseline and differential. |
| Genevisiblei | Q9UGJ0. HS. |
Organism-specific databases
| HPAi | CAB018641. HPA004246. |
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.
GO - Molecular functioni
- protein kinase binding Source: BHF-UCL
Protein-protein interaction databases
| BioGridi | 119531. 24 interactors. |
| IntActi | Q9UGJ0. 15 interactors. |
| MINTi | MINT-4831646. |
| STRINGi | 9606.ENSP00000287878. |
Structurei
3D structure databases
| ProteinModelPortali | Q9UGJ0. |
| SMRi | Q9UGJ0. |
| ModBasei | Search... |
| MobiDBi | Search... |
Family & Domainsi
Domains and Repeats
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Domaini | 275 – 335 | CBS 1PROSITE-ProRule annotationAdd BLAST | 61 | |
| Domaini | 357 – 415 | CBS 2PROSITE-ProRule annotationAdd BLAST | 59 | |
| Domaini | 430 – 492 | CBS 3PROSITE-ProRule annotationAdd BLAST | 63 | |
| Domaini | 504 – 562 | CBS 4PROSITE-ProRule annotationAdd BLAST | 59 |
Motif
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Motifi | 370 – 391 | AMPK pseudosubstrateAdd BLAST | 22 |
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 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.By similarity
Sequence similaritiesi
Belongs to the 5'-AMP-activated protein kinase gamma subunit family.Curated
Keywords - Domaini
CBS domain, RepeatPhylogenomic databases
| eggNOGi | KOG1764. Eukaryota. COG0517. LUCA. |
| GeneTreei | ENSGT00390000009849. |
| HOVERGENi | HBG050431. |
| KOi | K07200. |
| OMAi | XVQIYEL. |
| OrthoDBi | EOG091G0CZV. |
| PhylomeDBi | Q9UGJ0. |
| TreeFami | TF313247. |
Family and domain databases
| InterProi | View protein in InterPro IPR000644. CBS_dom. |
| Pfami | View protein in Pfam PF00571. CBS. 3 hits. |
| SMARTi | View protein in SMART SM00116. CBS. 4 hits. |
| PROSITEi | View protein in PROSITE PS51371. CBS. 4 hits. |
Sequences (3)i
Sequence statusi: Complete.
This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform A (identifier: Q9UGJ0-1) [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.
10 20 30 40 50
MGSAVMDTKK KKDVSSPGGS GGKKNASQKR RSLRVHIPDL SSFAMPLLDG
60 70 80 90 100
DLEGSGKHSS RKVDSPFGPG SPSKGFFSRG PQPRPSSPMS APVRPKTSPG
110 120 130 140 150
SPKTVFPFSY QESPPRSPRR MSFSGIFRSS SKESSPNSNP ATSPGGIRFF
160 170 180 190 200
SRSRKTSGLS SSPSTPTQVT KQHTFPLESY KHEPERLENR IYASSSPPDT
210 220 230 240 250
GQRFCPSSFQ SPTRPPLASP THYAPSKAAA LAAALGPAEA GMLEKLEFED
260 270 280 290 300
EAVEDSESGV YMRFMRSHKC YDIVPTSSKL VVFDTTLQVK KAFFALVANG
310 320 330 340 350
VRAAPLWESK KQSFVGMLTI TDFINILHRY YKSPMVQIYE LEEHKIETWR
360 370 380 390 400
ELYLQETFKP LVNISPDASL FDAVYSLIKN KIHRLPVIDP ISGNALYILT
410 420 430 440 450
HKRILKFLQL FMSDMPKPAF MKQNLDELGI GTYHNIAFIH PDTPIIKALN
460 470 480 490 500
IFVERRISAL PVVDESGKVV DIYSKFDVIN LAAEKTYNNL DITVTQALQH
510 520 530 540 550
RSQYFEGVVK CNKLEILETI VDRIVRAEVH RLVVVNEADS IVGIISLSDI
560
LQALILTPAG AKQKETETE
Sequence cautioni
The sequence AAH20540 differs from that shown. Reason: Erroneous initiation.Curated
The sequence AAS02032 differs from that shown. Reason: Erroneous gene model prediction.Curated
The sequence BAA84695 differs from that shown. Reason: Frameshift at positions 228 and 233. Frameshifts are upstream of the initiating Met of isoform B.Curated
Natural variant
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Natural variantiVAR_048250 | 6 | M → L. Corresponds to variant dbSNP:rs3207363Ensembl. | 1 | |
| Natural variantiVAR_013264 | 302 | R → Q in WPWS and CMH6; impaired AMP- and ATP-binding. 3 PublicationsCorresponds to variant dbSNP:rs121908987Ensembl. | 1 | |
| Natural variantiVAR_013265 | 350 | R → RL in CMH6; severe. 1 Publication | 1 | |
| Natural variantiVAR_013266 | 383 | H → R in CMH6; severe; impaired AMP- and ATP-binding. 2 PublicationsCorresponds to variant dbSNP:rs121908988Ensembl. | 1 | |
| Natural variantiVAR_013267 | 400 | T → N in CMH6; severe; impaired AMP- and ATP-binding. 2 PublicationsCorresponds to variant dbSNP:rs28938173Ensembl. | 1 | |
| Natural variantiVAR_013268 | 488 | N → I in CMH6; severe. 1 PublicationCorresponds to variant dbSNP:rs121908989Ensembl. | 1 | |
| Natural variantiVAR_032909 | 531 | R → G in WPWS; absence of cardiac hypertrophy; onset in childhood; impaired AMP- and ATP-binding. 2 PublicationsCorresponds to variant dbSNP:rs121908990Ensembl. | 1 | |
| Natural variantiVAR_013269 | 531 | R → Q in GSDH; reduction of binding affinities for AMP and ATP; loss of cooperative binding; enhanced basal activity; increased phosphorylation of the alpha-subunit. 1 PublicationCorresponds to variant dbSNP:rs121908991Ensembl. | 1 |
Alternative sequence
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Alternative sequenceiVSP_000261 | 1 – 241 | Missing in isoform B. 5 PublicationsAdd BLAST | 241 | |
| Alternative sequenceiVSP_015589 | 1 – 44 | Missing in isoform C. 1 PublicationAdd BLAST | 44 |
Sequence databases
| Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AB025580 mRNA. Translation: BAA84695.1. Frameshift. AJ249976 mRNA. Translation: CAB65116.1. AF087875 mRNA. Translation: AAK00413.1. AK001887 mRNA. Translation: BAA91962.1. BT007127 mRNA. Translation: AAP35791.1. AC006358 Genomic DNA. Translation: AAS02032.1. Sequence problems. AC006966 Genomic DNA. Translation: AAF03528.2. AC093583 Genomic DNA. No translation available. BC020540 mRNA. Translation: AAH20540.2. Different initiation. BC068598 mRNA. Translation: AAH68598.1. |
| CCDSi | CCDS43683.1. [Q9UGJ0-3] CCDS47752.1. [Q9UGJ0-2] CCDS5928.1. [Q9UGJ0-1] |
| RefSeqi | NP_001035723.1. NM_001040633.1. [Q9UGJ0-3] NP_001291456.1. NM_001304527.1. NP_001291460.1. NM_001304531.1. [Q9UGJ0-2] NP_057287.2. NM_016203.3. [Q9UGJ0-1] NP_077747.1. NM_024429.1. [Q9UGJ0-2] XP_016867759.1. XM_017012270.1. [Q9UGJ0-3] |
| UniGenei | Hs.647072. |
Genome annotation databases
| Ensembli | ENST00000287878; ENSP00000287878; ENSG00000106617. [Q9UGJ0-1] ENST00000392801; ENSP00000376549; ENSG00000106617. [Q9UGJ0-3] ENST00000418337; ENSP00000387386; ENSG00000106617. [Q9UGJ0-2] |
| GeneIDi | 51422. |
| KEGGi | hsa:51422. |
| UCSCi | uc003wki.4. human. [Q9UGJ0-1] |
Keywords - Coding sequence diversityi
Alternative splicing, PolymorphismSimilar proteinsi
Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:| 100% | UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry. |
| 90% | UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence). |
| 50% | UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster. |
Entry informationi
| Entry namei | AAKG2_HUMAN | |
| Accessioni | Q9UGJ0Primary (citable) accession number: Q9UGJ0 Secondary accession number(s): Q53Y07 Q9ULX8 | |
| Entry historyi | Integrated into UniProtKB/Swiss-Prot: | June 1, 2001 |
| Last sequence update: | May 1, 2000 | |
| Last modified: | July 5, 2017 | |
| This is version 159 of the entry and version 1 of the sequence. See complete history. | ||
| Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
| Annotation program | Chordata Protein Annotation Program | |
| Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. | |
Miscellaneousi
Keywords - Technical termi
Complete proteome, Reference proteomeDocuments
- Human chromosome 7
Human chromosome 7: entries, gene names and cross-references to MIM - Human entries with polymorphisms or disease mutations
List of human entries with polymorphisms or disease mutations - Human polymorphisms and disease mutations
Index of human polymorphisms and disease mutations - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - SIMILARITY comments
Index of protein domains and families
