Affinage

PRKAG1

5'-AMP-activated protein kinase subunit gamma-1 · UniProt P54619

Round 2 corrected
Length
331 aa
Mass
37.6 kDa
Annotated
2026-04-28
71 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKAG1 encodes the γ1 regulatory subunit of the AMP-activated protein kinase (AMPK) heterotrimer and is the predominant γ isoform in most mammalian tissues, directly participating in AMP binding and conferring intermediate AMP-dependence on the complex (PMID:10698692, PMID:8557660). PRKDC phosphorylates PRKAG1 at Ser192 and Thr284, priming the AMPK complex for lysosomal localization and starvation-induced activation by STK11/LKB1, thereby coupling DNA damage–responsive kinase signaling to AMPK-dependent autophagy (PMID:31983282). In erythrocytes, AMPK γ1 is required to maintain membrane deformability by restraining adducin phosphorylation; its loss causes regenerative hemolytic anemia with splenomegaly (PMID:20881209). Sustained AMPK γ1 expression in aged organisms opposes a fasting-like metabolic quiescence program in adipose tissue and extends healthy lifespan (PMID:37957359).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1996 High

    Establishing that PRKAG1 encodes a non-catalytic subunit of the heterotrimeric AMPK complex resolved the minimal composition required for AMP-stimulated kinase activity.

    Evidence Biochemical purification, immunoprecipitation, and kinase assays across rat tissues

    PMID:8557660

    Open questions at the time
    • Relative contribution of γ1 versus γ2/γ3 isoforms to tissue-specific AMPK activity was not resolved
    • No structural information on how γ1 binds AMP
  2. 2000 High

    Photoaffinity labelling demonstrated that the γ subunit itself is the AMP-binding component and that γ1-containing complexes exhibit intermediate AMP-dependence relative to γ2 and γ3, explaining isoform-specific allosteric tuning.

    Evidence 8-azido-[32P]AMP photoaffinity labelling and isoform-specific immunoprecipitation kinase assays

    PMID:10698692

    Open questions at the time
    • Atomic-level mechanism of differential AMP sensitivity among γ isoforms was unknown
    • Whether AMP-binding differences translate to distinct physiological outputs in vivo was untested
  3. 2010 High

    Mouse Prkag1 knockout revealed a non-redundant in vivo role for AMPKγ1 in erythrocyte membrane homeostasis, linking AMPK to adducin phosphorylation control and membrane deformability.

    Evidence Targeted gene knockout in mice with ektacytometry, osmotic fragility, phospho-adducin western blotting, and histology

    PMID:20881209

    Open questions at the time
    • Whether AMPK directly phosphorylates adducin or acts through an intermediate kinase was not determined
    • Contribution of γ2/γ3 compensation in non-erythroid lineages was not assessed
  4. 2020 High

    Discovery that PRKDC phosphorylates PRKAG1 at Ser192/Thr284 to enable lysosomal targeting and STK11-mediated AMPK activation established a previously unknown kinase-priming step upstream of canonical AMPK regulation.

    Evidence siRNA kinome screen, site-directed mutagenesis (S192A/T284A), co-immunoprecipitation with STK11, subcellular fractionation, proximity ligation assay

    PMID:31983282

    Open questions at the time
    • Whether PRKDC phosphorylation of γ1 occurs on lysosomes or prior to recruitment is unresolved
    • Structural basis for how Ser192/Thr284 phosphorylation promotes lysosomal targeting is unknown
    • Relevance of this priming mechanism under non-starvation AMPK-activating signals was not tested
  5. 2023 Medium

    Transgenic sustained expression of AMPKγ1 in aged killifish counteracted age-related metabolic quiescence and extended lifespan, establishing γ1 decline as a contributor to metabolic aging.

    Evidence Transgenic overexpression in Nothobranchius furzeri, lifespan measurement, transcriptomics, human tissue correlation

    PMID:37957359

    Open questions at the time
    • Causal role of PRKAG1 decline in human aging-associated multimorbidity is correlational only
    • Which downstream AMPK substrates mediate the longevity effect is not identified
    • Whether γ1-specific or total AMPK activity drives the phenotype is unclear
  6. 2025 Medium

    Knockdown and overexpression studies linked PRKAG1 to restraint of autophagy and promotion of JEV replication, connecting γ1 to antiviral innate defense via TP53 and GSK3B phosphorylation changes.

    Evidence RNA interference, overexpression, phosphoproteomics, JEV replication assay in cell culture

    PMID:41033165

    Open questions at the time
    • Whether autophagy modulation is a direct AMPK catalytic output or an indirect effect of γ1 scaffolding is unresolved
    • Single-lab study; independent replication in primary cells or in vivo not yet available
    • Specificity of the NTZ–PRKAG1 interaction versus other AMPK subunits is not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How γ1-specific post-translational modifications (e.g., PRKDC phosphorylation) integrate with nucleotide sensing to control AMPK substrate selectivity in different tissues remains an open question.
  • No high-resolution structure of full-length γ1 with Ser192/Thr284 phosphorylation exists
  • Tissue-specific phenotypes beyond erythrocytes in γ1 knockouts are underexplored
  • Functional interplay between γ1 and γ2/γ3 isoform switching during metabolic stress is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005829 cytosol 2 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 2
Partners
PRKAA1PRKAA2PRKAB1PRKDCSTK11
Complex memberships
AMPK heterotrimer (αβγ)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PRKAG1 (AMPKγ1) was characterized as a regulatory gamma subunit of the AMPK heterotrimer; γ1 mRNA is widely expressed in human tissues. Using isoform-specific antibodies, more than 80% of total AMPK activity in most tissues was found associated with the γ1 isoform. Labelling studies with 8-azido-[32P]AMP indicated that the gamma subunit participates directly in AMP binding within the complex. Complexes containing γ1 showed intermediate AMP-dependence compared with γ2 (greatest) and γ3 (lowest). Isoform-specific antibody immunoprecipitation, 8-azido-AMP photoaffinity labelling, kinase activity assays across rat tissues The Biochemical journal High 10698692
1996 PRKAG1 encodes the γ1 (non-catalytic) subunit of the mammalian AMPK heterotrimer. Both α1 and α2 catalytic isoforms associate with non-catalytic β and γ subunits (including γ1) to form the active kinase complex, and both α isoforms are stimulated by AMP. Biochemical purification, immunoprecipitation, kinase activity assays, Northern blotting across tissues The Journal of biological chemistry High 8557660
2010 Targeted disruption of mouse Prkag1 (AMPKγ1) causes regenerative hemolytic anemia with splenomegaly and iron accumulation due to compensatory splenic erythropoiesis. AMPKγ1-deficient erythrocytes were highly resistant to osmotic hemolysis, poorly deformable under shear stress (consistent with greater membrane rigidity), and displayed elevated phosphorylation of adducin (a protein that promotes spectrin-actin binding), without changes in cytoskeletal protein composition. Targeted gene knockout in mice, osmotic fragility assay, ektacytometry (deformability under shear stress), Western blotting of cytoskeletal proteins and phospho-adducin, histology FASEB journal High 20881209
2020 PRKDC (DNA-PKcs) phosphorylates PRKAG1 at Ser192 and Thr284 under basal conditions. These phosphorylation events are reduced upon AMPK complex activation. Alanine substitution of both sites (S192A/T284A) reduced AMPK complex activation and, critically, inhibited lysosomal localization of the AMPK complex and its starvation-induced association with STK11/LKB1, without affecting nucleotide-sensing capacity. Thus, PRKDC-mediated phosphorylation of PRKAG1 primes the AMPK complex for lysosomal activation by STK11. siRNA kinome screen, co-immunoprecipitation, site-directed mutagenesis (S192A/T284A alanine substitution), subcellular fractionation/confocal imaging for lysosomal localization, AMPK activity assays, proximity ligation assay Autophagy High 31983282
2015 A genome-wide RNAi screen in Drosophila cells identified SNF4Aγ (the Drosophila orthologue of PRKAG1/AMPKγ1) as a regulator of nuclear actin localization. Knockdown of SNF4Aγ/Prkag1 in both fly and mammalian cells reduced nuclear actin levels, linking the AMPKγ1 subunit to control of nuclear actin import. Genome-wide RNAi screen in Drosophila cells, validation by knockdown in mammalian cells, fluorescence microscopy for nuclear actin levels Journal of cell science Medium 26021350
2023 In the short-lived killifish Nothobranchius furzeri, Prkag1 (AMPKγ1) expression oscillates inversely with Prkag2 during the fasting-refeeding cycle in adipose tissue of young animals; aging blunts this regulation and reduces Prkag1 expression. Transgenic sustained expression of AMPKγ1 countered a fasting-like transcriptional program in aged fish, improved metabolic health markers, and extended longevity. In human tissues, PRKAG1 expression declines with age and is associated with multimorbidity risk. Transcriptomic analysis, transgenic overexpression in killifish, lifespan measurement, metabolic phenotyping Nature aging Medium 37957359
2019 TCDD-induced hypermethylation of PRKAG1 in human embryonic stem cells was maintained after pancreatic progenitor differentiation. Transient knockdown of Prkag1 in INS-1E insulinoma cells elevated glucose-stimulated insulin secretion (GSIS), possibly through mTOR signaling, indicating that PRKAG1 activity suppresses insulin secretion in pancreatic beta cells. DNA bisulfite sequencing (methylation validation), siRNA knockdown, GSIS assay in INS-1E cells, mTOR pathway analysis Environment international Medium 31195220
2025 PRKAG1 (AMPKγ1) interacts with Nitazoxanide (NTZ). Knockdown of PRKAG1 enhanced autophagy and inhibited Japanese encephalitis virus (JEV) replication synergistically with NTZ, while PRKAG1 overexpression reduced autophagy and promoted JEV replication. Phosphoproteomic analysis of PRKAG1-silenced cells showed increased phosphorylation of TP53 and GSK3B, suggesting PRKAG1 modulates multiple signaling pathways to restrain autophagy. Western blotting, solvent-induced protein precipitation profiling (SIP), RNA interference, overexpression, JEV replication assay, phosphorylation quantitative proteomics Veterinary microbiology Medium 41033165
2001 Mouse Prkag1 cDNA was cloned from testis (1623 nt, encoding 330 aa), shows ubiquitous expression as a 1.8-kb transcript, is highly conserved with human and rat PRKAG1 (96% protein identity), contains 12 exons with short introns, and maps to the distal region of mouse chromosome 15. cDNA cloning, Northern blotting, sequence comparison, interspecific backcross mapping Cytogenetics and cell genetics Medium 11306812
2005 The bovine PRKAG1 gene spans >14 kb on BTA 5q21-q22, consists of 12 exons (38–166 bp) and 11 introns, and encodes a protein 98% and 95% identical to human and rat AMPKγ1, respectively. The coding region shares 93% (human) and 90% (rat) nucleotide similarity. Genomic library isolation, sequencing, comparative sequence analysis, FISH/radiation hybrid mapping Mammalian genome Medium 15834636

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 TSC2 mediates cellular energy response to control cell growth and survival. Cell 3187 14651849
2008 AMPK phosphorylation of raptor mediates a metabolic checkpoint. Molecular cell 3139 18439900
2011 The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature cell biology 2435 21892142
2005 AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell metabolism 2232 16054041
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 1295 15058305
2010 Network organization of the human autophagy system. Nature 1286 20562859
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 Mammalian AMP-activated protein kinase subfamily. The Journal of biological chemistry 575 8557660
2000 Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. The Biochemical journal 489 10698692
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2010 The association of AMPK with ULK1 regulates autophagy. PloS one 397 21072212
2006 Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America 396 17028174
1998 AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. The Biochemical journal 380 9693118
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2015 Huntingtin functions as a scaffold for selective macroautophagy. Nature cell biology 330 25686248
2011 Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Molecular and cellular biology 311 21670147
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2018 Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. The Journal of biological chemistry 249 30232152
2007 New indicators of beef sensory quality revealed by expression of specific genes. Journal of agricultural and food chemistry 141 17547415
2015 The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML. Autophagy 88 26029847
2021 TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy. Autophagy 79 33779513
2006 Adenosine 5'-monophosphate kinase-activated protein kinase (PRKA) activators delay meiotic resumption in porcine oocytes. Biology of reproduction 49 17167165
2000 Molecular cloning, genomic organization, and mapping of PRKAG2, a heart abundant gamma2 subunit of 5'-AMP-activated protein kinase, to human chromosome 7q36. Genomics 47 11112354
2020 DNA-dependent protein kinase regulates lysosomal AMP-dependent protein kinase activation and autophagy. Autophagy 45 31983282
2015 Rare coding variants and X-linked loci associated with age at menarche. Nature communications 36 26239645
2015 Genome-wide RNAi screen for nuclear actin reveals a network of cofilin regulators. Journal of cell science 33 26021350
2010 The AMPKγ1 subunit plays an essential role in erythrocyte membrane elasticity, and its genetic inactivation induces splenomegaly and anemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 20881209
2010 Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry 31 20821366
2023 Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity. Nature aging 28 37957359
2018 Prolonged incubation with Metformin decreased angiogenic potential in human bone marrow mesenchymal stem cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 30372835
2019 Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the differentiation of embryonic stem cells towards pancreatic lineage and pancreatic beta cell function. Environment international 20 31195220
2018 DDN-AS1-miR-15a/16-TCF3 feedback loop regulates tumor progression in cervical cancer. Journal of cellular biochemistry 20 30582201
2003 The bovine 5' AMPK gene family: mapping and single nucleotide polymorphism detection. Mammalian genome : official journal of the International Mammalian Genome Society 16 14724738
2021 Whole-Genome Resequencing Points to Candidate DNA Loci Affecting Body Temperature under Cold Stress in Siberian Cattle Populations. Life (Basel, Switzerland) 14 34575108
2024 Evidence of a genetic background predisposing to complex regional pain syndrome type 1. Journal of medical genetics 13 37816627
2022 Effect of arginine supplementation on the production of milk fat in dairy cows. Journal of dairy science 13 35965125
2020 Amino acids regulate energy utilization through mammalian target of rapamycin complex 1 and adenosine monophosphate activated protein kinase pathway in porcine enterocytes. Animal nutrition (Zhongguo xu mu shou yi xue hui) 13 32211535
2023 Muscle transcriptome analysis provides new insights into the growth gap between fast- and slow-growing Sinocyclocheilus grahami. Frontiers in genetics 12 37538358
2020 Adiponectin enhances the bioenergetics of cardiac myocytes via an AMPK- and succinate dehydrogenase-dependent mechanism. Cellular signalling 10 33271223
2021 Effects of dietary l-carnitine supplementation on the response to an inflammatory challenge in mid-lactating dairy cows: Hepatic mRNA abundance of genes involved in fatty acid metabolism. Journal of dairy science 9 34253361
2004 Determination of PRKAG1 coding sequence and mapping of PRKAG1 and PRKAG2 relatively to porcine back fat thickness QTL. Animal genetics 9 15025572
2015 A SNP in the 3'-untranslated region of AMPKγ1 may associate with serum ketone body and milk production of Holstein dairy cows. Gene 5 26226224
2019 AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC and FIRE3. International journal of cancer 4 30856283
2005 Characterization of the bovine ampkgamma1 gene. Mammalian genome : official journal of the International Mammalian Genome Society 4 15834636
2025 Brain and blood transcriptome-wide association studies identify five novel genes associated with Alzheimer's disease. Journal of Alzheimer's disease : JAD 3 40111921
2024 Joint Screening and Identification of Potential Targets of Nitazoxanide by Affinity Chromatography and Label-Free Techniques. Current drug targets 2 39171461
2001 Cloning, organisation, chromosomal localization and expression analysis of the mouse Prkag1 gene. Cytogenetics and cell genetics 2 11306812
2025 Molecular mechanism of LncRNA MALAT1 in regulating hepatocellular carcinoma progression via the miR-383-5p/PRKAG1 axis and its role in the tumor immune microenvironment. Frontiers in oncology 1 40958861
2024 Brain and Blood Transcriptome-Wide Association Studies Identify Five Novel Genes Associated with Alzheimer's Disease. medRxiv : the preprint server for health sciences 1 38699333
2020 [Partial isoform-specific expression and function of AMPK in ovarian carcinoma]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 32727648
2026 PRKAB2 as a tumor suppressor in renal cell carcinoma: inhibiting mitophagy via the LRPPRC-PRKN/parkin interaction and cardiolipin biosynthesis. Autophagy 0 41612594
2026 Genome-wide association study identified genomic regions and putative candidate genes affecting different backfat layers in Landrace pigs. Animal : an international journal of animal bioscience 0 41666498
2026 Evaluating the Impact of Putative Metformin Targets on Cancer Outcomes: A Drug-Target Mendelian Randomization Study. Diabetes, obesity & metabolism 0 41755790
2026 HDAC3 Regulates Transcriptional Networks Governing Decidualization. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41984129
2025 PRKAG1 mediates the anti-Japanese encephalitis virus effect of Nitazoxanide through autophagy. Veterinary microbiology 0 41033165
2025 Whole Exome Sequencing in Children With Autoimmune Hepatitis Identified Mutations in Genes Involved in the mTORC1 Signaling Pathway. Gastro hep advances 0 41234702
2024 Positive-Unlabelled learning for identifying new candidate Dietary Restriction-related genes among ageing-related genes. Computers in biology and medicine 0 39137672
2023 Genome-Wide Analysis of MAMSTR Transcription Factor-Binding Sites via ChIP-Seq in Porcine Skeletal Muscle Fibroblasts. Animals : an open access journal from MDPI 0 37889674
2020 Effects of Single-Nucleotide Polymorphisms in Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2): A Comprehensive Study. Computational and mathematical methods in medicine 0 33082841