Affinage

WDR59

GATOR2 complex protein WDR59 · UniProt Q6PJI9

Length
974 aa
Mass
109.8 kDa
Annotated
2026-06-11
18 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WDR59 is a core subunit of the pentameric GATOR2 complex (with MIOS, WDR24, SEH1L, SEC13) that governs amino acid sensing upstream of mTORC1 (PMID:23723238). Within the 1.1 MDa cage-like GATOR2 architecture, WDR59 is present in two copies and contributes to the octagonal scaffold through non-catalytic RING domains and α-solenoids, while its WD40 β-propeller mediates interactions with the amino acid sensors SESN2 and CASTOR1 and with the downstream regulator GATOR1 (PMID:35831510). GATOR2 acts as a negative regulator of GATOR1 (DEPDC5), placing it upstream in the pathway, and amino acid sensor binding drives dynamic conformational changes in WDR59-containing GATOR2 that underlie its inhibitory regulation (PMID:23723238, PMID:40742811). WDR59 is structurally required to stabilize partner subunits MIOS and WDR24 against proteasomal degradation, such that its loss reduces mTORC1 activity in a manner rescued by proteasome inhibition (PMID:36577058). Beyond mTORC1, WDR59 serves as the essential molecular bridge linking GATOR2 to mTORC2, since its loss ablates Sestrin2-induced AKT activation (PMID:31915252). Proper lysosomal localization of WDR59/GATOR2 is required for nutrient-dependent mTORC1 suppression (PMID:28199315). Across organisms WDR59 has context-dependent roles, opposing or promoting TORC1 in a tissue-specific manner in Drosophila and functioning proximal to GATOR1 to attenuate TORC1 in fission yeast (PMID:33534698, PMID:36577058). Biallelic loss-of-function mutations in WDR59 cause autosomal recessive syndromic dilated cardiomyopathy, implicating dysregulated GATOR2-mTORC1 signaling in cardiomyocyte homeostasis (PMID:41715954).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2013 High

    Establishing WDR59 as a GATOR2 subunit answered where it sits in nutrient signaling, placing it upstream of GATOR1 as a positive regulator of mTORC1.

    Evidence RNAi knockdown, epistasis analysis, and Co-IP with mTORC1 activity assays

    PMID:23723238

    Open questions at the time
    • Molecular role of WDR59 within the complex not resolved
    • No structural basis for GATOR2-GATOR1 regulation
  2. 2017 Medium

    Lysosome-targeting experiments showed that subcellular localization of WDR59/GATOR2 is functionally required for nutrient-dependent mTORC1 suppression.

    Evidence Overexpression of lysosome-targeted WDR59 in SZT2-deficient cells with mTORC1 rescue assays

    PMID:28199315

    Open questions at the time
    • Endogenous trafficking of WDR59 not directly tracked
    • Single lab; mechanism of SOG-mediated recruitment of WDR59 not defined
  3. 2020 High

    Identifying WDR59 as the GATOR2 component required for mTORC2 engagement extended its role beyond mTORC1 to the Sestrin2→GATOR2→mTORC2→AKT axis.

    Evidence siRNA, CRISPR KO, Co-IP, in vitro kinase assay, and AKT phosphorylation assays

    PMID:31915252

    Open questions at the time
    • Structural basis of the WDR59-mTORC2 interface unknown
    • Whether GATOR2-mTORC2 coupling occurs at the lysosome not addressed
  4. 2021 Medium

    The fission yeast ortholog Sea3 revealed evolutionary divergence, functioning proximal to GATOR1 to attenuate TORC1 rather than acting through GATOR2.

    Evidence Genetic epistasis, Co-IP, and TORC1 activity assays in fission yeast

    PMID:33534698

    Open questions at the time
    • Relevance of GATOR1-proximal role to mammalian WDR59 unclear
    • Ortholog-based; not validated in human cells
  5. 2022 High

    Cryo-EM of human GATOR2 defined WDR59 stoichiometry and architecture, showing two copies contribute RING/α-solenoid scaffolding and a WD40 β-propeller that contacts SESN2, CASTOR1, and GATOR1.

    Evidence Cryo-electron microscopy structure with biochemical interaction mapping

    PMID:35831510

    Open questions at the time
    • Conformational dynamics upon sensor binding not captured
    • Functional consequence of two WDR59 copies not dissected
  6. 2022 High

    Dual-organism functional work showed WDR59 stabilizes MIOS and WDR24 against proteasomal degradation in mammalian cells and exerts tissue-dependent dual TORC1 regulation in Drosophila.

    Evidence Drosophila tissue-specific genetics, HeLa CRISPR KO, proteasome inhibitor rescue, and protein level measurements

    PMID:36577058

    Open questions at the time
    • Molecular determinant of the inhibitory versus activating switch unknown
    • Degradation pathway/E3 ligase acting on destabilized subunits not identified
  7. 2022 Medium

    Endogenous GFP-tagging validated that C-terminally tagged WDR59 retains GATOR2 association and signaling, enabling study of metabolically regulated interactions at native expression.

    Evidence CRISPR endogenous tagging with Co-IP and mTORC1 signaling assays

    PMID:36444289

    Open questions at the time
    • Methodological validation rather than new mechanism
    • Dynamics of interactions not quantified
  8. 2025 High

    Structures of sensor-bound GATOR2 plus HDX-MS demonstrated that WDR59-containing GATOR2 undergoes dynamic conformational changes upon amino acid sensor binding, clarifying the sensor-driven inhibitory mechanism.

    Evidence Cryo-EM structures of sensor-bound GATOR2 and hydrogen-deuterium exchange mass spectrometry

    PMID:40742811

    Open questions at the time
    • Direct allosteric coupling from sensor binding to GATOR1 not fully resolved
    • WDR59-specific conformational changes not isolated from whole-complex dynamics
  9. 2026 Medium

    Human biallelic loss-of-function variants tied WDR59 to autosomal recessive syndromic dilated cardiomyopathy, implicating GATOR2-mTORC1 signaling in cardiomyocyte homeostasis.

    Evidence Genetic mapping, whole-exome sequencing, RNA-seq splicing validation, and familial segregation

    PMID:41715954

    Open questions at the time
    • Direct functional rescue not yet demonstrated
    • Mechanism linking GATOR2 dysregulation to cardiomyocyte pathology unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular signal determines whether WDR59 promotes or inhibits TORC1 in a context-dependent manner and how this dual function relates to its mTORC2-bridging and disease roles.
  • No mechanism for the activating-versus-inhibitory switch
  • Tissue-specific GATOR2 composition not mapped
  • Functional model of cardiomyopathy-causing mutations not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CASTOR1DEPDC5MIOSSEC13SEH1LSESN2WDR24
Complex memberships
GATOR2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 WDR59 was identified as a subunit of the GATOR2 complex (along with Mios, WDR24, Seh1L, and Sec13). Inhibition of GATOR2 subunits including WDR59 suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates GATOR1 subunit DEPDC5, placing GATOR2 upstream of GATOR1 in the mTORC1 amino acid sensing pathway. RNAi knockdown, epistasis analysis, co-immunoprecipitation, mTORC1 activity assays Science High 23723238
2017 Lysosome-targeted WDR59 (a GATOR2 component) partially corrected hyperactivation of mTORC1 in SZT2-deficient cells under nutrient-deprived conditions, indicating that lysosomal localization of GATOR2 (via SZT2-orchestrated SOG complex) is required for proper mTORC1 suppression and that WDR59/GATOR2 at the lysosome functions to suppress mTORC1 signaling through SESN recruitment. Overexpression of lysosome-targeted WDR59 in SZT2-deficient cells, mTORC1 activity rescue assays Nature Medium 28199315
2020 WDR59 is the GATOR2 component essential for the GATOR2-mTORC2 interaction. Silencing or deleting WDR59 completely ablated Sestrin2-induced AKT activation, establishing WDR59 as the molecular bridge linking GATOR2 to mTORC2 in the Sestrin2→GATOR2→mTORC2→AKT signaling axis. siRNA knockdown, CRISPR knockout, co-immunoprecipitation, in vitro kinase assay for mTORC2 activity, AKT phosphorylation assays The Journal of biological chemistry High 31915252
2021 In fission yeast, the WDR59 ortholog Sea3 functions physically and functionally proximal to GATOR1 (rather than GATOR2), attenuating TORC1 activity. This is in contrast to the mammalian context, demonstrating that Sea3/WDR59 can function as part of a GATOR1-associated complex to suppress TORC1. Genetic epistasis, co-immunoprecipitation, TORC1 activity assays in fission yeast eLife Medium 33534698
2022 Cryo-EM structure of the human GATOR2 complex revealed that WDR59 is one of two WDR59 subunits in the 1.1 MDa cage-like architecture. WDR59 participates in the octagonal scaffold circularized via non-catalytic RING domains and α-solenoids, and its WD40 β-propeller mediates interactions with SESN2, CASTOR1, and GATOR1. Cryo-electron microscopy structure determination, biochemical interaction assays Nature High 35831510
2022 In Drosophila, Wdr59 has a dual context-dependent function: in the ovary and eye imaginal disc, Wdr59 inhibits TORC1 by opposing GATOR2-dependent inhibition of GATOR1; in the fat body, Wdr59 promotes accumulation of GATOR2 component Mio and is required for TORC1 activation. In mammalian HeLa cells, Wdr59 prevents proteasomal degradation of GATOR2 proteins Mio and Wdr24, and Wdr59 KO reduces TORC1 activity that is restored by proteasome inhibition. Drosophila genetics (tissue-specific analysis), CRISPR knockout in HeLa cells, proteasome inhibitor rescue, TORC1 activity assays, protein level measurements Proceedings of the National Academy of Sciences of the United States of America High 36577058
2022 Endogenous GFP-tagging of WDR59 in HeLa cells (using CRISPR) showed that GFP-WDR59 fusion retains proper GATOR2 complex association and downstream mTORC1 signaling, demonstrating that the WD-repeat region of WDR59 is not disrupted by C-terminal tagging and that WDR59 participates in metabolically regulated protein-protein interactions within the GATOR2 complex. CRISPR endogenous tagging, FACS/MACS selection, Co-IP, mTORC1 signaling assays MethodsX Medium 36444289
2025 Cryo-EM structures of GATOR2 bound to amino acid sensors showed that CASTOR1 (arginine sensor) engages the Mios WD40 β-propellers, while Sestrin2 (leucine sensor) interacts with the WDR24-Seh1L subcomplex. HDX-MS revealed that WDR59-containing GATOR2 undergoes dynamic conformational changes upon amino acid sensor binding. These structures clarify the inhibitory mechanism of GATOR2 by amino acid sensors. Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry (HDX-MS) Cell reports High 40742811
2026 Loss-of-function mutations in WDR59 (homozygous p.Gly963Arg founder variant or compound heterozygous splicing variants confirmed by RNA-seq) cause autosomal recessive syndromic dilated cardiomyopathy in humans, implicating dysregulated GATOR2-mTORC1 signaling in cardiomyocyte homeostasis. Genetic mapping, whole-exome sequencing, RNA-seq splicing validation, familial segregation analysis Clinical genetics Medium 41715954

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science (New York, N.Y.) 888 23723238
2017 SZT2 dictates GATOR control of mTORC1 signalling. Nature 159 28199315
2016 Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 140 27173016
2020 A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer. Journal of the National Cancer Institute 73 31917448
2022 Structure of the nutrient-sensing hub GATOR2. Nature 71 35831510
2020 The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation. The Journal of biological chemistry 52 31915252
2021 Tripartite suppression of fission yeast TORC1 signaling by the GATOR1-Sea3 complex, the TSC complex, and Gcn2 kinase. eLife 28 33534698
2022 The FACT complex facilitates expression of lysosomal and antioxidant genes through binding to TFEB and TFE3. Autophagy 23 35230915
2025 Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex. Cell reports 9 40742811
2021 Multiplexed suppression of TOR complex 1 induces autophagy during starvation. Autophagy 8 34085593
2024 New insights into GATOR2-dependent interactions and its conformational changes in amino acid sensing. Bioscience reports 7 38372438
2022 Wdr59 promotes or inhibits TORC1 activity depending on cellular context. Proceedings of the National Academy of Sciences of the United States of America 7 36577058
2023 Integration of GWAS and eGWAS to screen candidate genes underlying green head traits in male ducks. Animal genetics 4 37194451
2024 Unveiling GATOR2 Function: Novel Insights from Drosophila Research. Cells 3 39513902
2023 Interactions between genetic variants and environmental risk factors are associated with the severity of pelvic organ prolapse. Menopause (New York, N.Y.) 3 37040585
2026 WDR59 Is Mutated in Individuals With Autosomal Recessive Syndromic Dilated Cardiomyopathy. Clinical genetics 0 41715954
2025 Comparative genomics of two closely related Acropora coral species with different spawning seasons reveals genomic regions possibly associated with gametogenesis. BMC ecology and evolution 0 40887617
2022 Selection-free endogenous tagging of cell lines by bicistronic co-expression of the surface antigen NGFR. MethodsX 0 36444289

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