GO:0061700 GATOR2 complex: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0061700 (GATOR2 complex) is a multiprotein subcomplex of the GATOR complex that regulates TORC1 signaling by interacting with the Rag GTPase.
• In humans, GATOR2 comprises WDR24, WDR59, MIOS, SEH1L, and SEC13; in S. cerevisiae it is called SEACAT and contains Sea2p, Sea3p, Sea4p, Seh1p, and Sec13p.
• GATOR2 transmits amino acid availability signals to mTORC1, acting downstream of sensors such as Sestrin2 (leucine) and SAR1B (leucine).
• Structural studies have revealed how GATOR2 binds amino acid sensors and the Rag GTPase to control mTORC1.
• GATOR2 also maintains lysosomal-autophagic function by inhibiting degradation of MiT/TFE transcription factors.
• Dysregulation of GATOR2 is linked to myelination defects, cancer, and metabolic disorders.
Description
The GATOR2 complex (GO:0061700) is a conserved multiprotein assembly that serves as a central hub in the amino acid sensing branch of the mTORC1 pathway. It is defined as a subcomplex of the larger GATOR complex that regulates TORC1 signaling by interacting with the Rag GTPase. In humans, GATOR2 consists of WDR24, WDR59, MIOS, SEH1L, and SEC13, while in Saccharomyces cerevisiae the orthologous complex is known as SEACAT and contains Sea2p, Sea3p, Sea4p, Seh1p, and Sec13p. Because mTORC1 controls cell growth, proliferation, and autophagy in response to nutrients, understanding GATOR2 is essential for researchers studying metabolism, cancer, and neurobiology. Recent cryo-EM and biochemical studies have begun to reveal how GATOR2 engages amino acid sensors such as Sestrin2 and SAR1B, and how it transmits signals to the Rag GTPase to modulate mTORC1 activity. This article provides a research-grade overview of GATOR2, covering its structure, molecular mechanism, key genes, disease relevance, and experimental models for functional studies.
GATOR2 complex At A Glance
| GO ID | GO:0061700 |
|---|---|
| GO term | GATOR2 complex |
| Ontology | cellular_component |
| Synonym | SEACAT complex |
| Major function | Regulates TORC1 signaling by interacting with the Rag GTPase |
| Human subunits | WDR24, WDR59, MIOS, SEH1L, SEC13 |
| Yeast subunits | Sea2p, Sea3p, Sea4p, Seh1p, Sec13p |
| Associated sensors | Sestrin2 (leucine), SAR1B (leucine), CASTOR1 (arginine) |
| Disease links | Myelination defects, cancer, metabolic disorders |
What Is GO:0061700?
The GATOR2 complex is a multiprotein subcomplex of the GATOR complex that regulates TORC1 signaling by interacting with the Rag GTPase. In human cells, it is composed of WDR24, WDR59, MIOS, SEH1L, and SEC13. In S. cerevisiae, the equivalent complex is called SEACAT and contains Sea2p, Sea3p, Sea4p, Seh1p, and Sec13p.
Why Is GATOR2 complex Important in Cell Biology?
The GATOR2 complex is a critical node in nutrient sensing, acting as a positive regulator of mTORC1 in response to amino acids. Its dysfunction leads to altered mTORC1 signaling, which is implicated in a wide range of diseases including cancer, neurodegeneration, and metabolic syndromes. Understanding GATOR2 structure and regulation provides opportunities for therapeutic intervention and for dissecting fundamental growth control mechanisms.
• Central regulator of mTORC1 signaling in response to amino acid availability.
• Required for proper brain myelination; loss leads to myelination defects.
• Maintains lysosomal-autophagic function by inhibiting degradation of MiT/TFE factors.
• Integrates signals from leucine sensors Sestrin2 and SAR1B.
• Structural basis for amino acid sensor binding and Rag GTPase interaction.
• Implicated in cancer through dysregulated mTORC1 activity.
• Potential target for metabolic disorders and neurodegenerative diseases.
• Conserved from yeast to humans, enabling genetic studies in model organisms.
• Key for understanding how cells adapt to nutrient stress.
• Provides a paradigm for studying multiprotein complexes in signaling.
Structure and Composition of GATOR2 complex
Submit composition and architecture
In simple terms: GATOR2 is made of five proteins that fit together like a molecular machine.
In humans, the GATOR2 complex consists of WDR24, WDR59, MIOS, SEH1L, and SEC13. Structural studies using cryo-EM have revealed that these subunits assemble into a large, elongated complex with distinct domains for interacting with amino acid sensors and the Rag GTPase. The yeast ortholog, SEACAT, contains Sea2p, Sea3p, Sea4p, Seh1p, and Sec13p, and shares a similar overall architecture.
Interaction with amino acid sensors
In simple terms: GATOR2 directly binds sensor proteins that detect amino acids like leucine and arginine.
GATOR2 interacts with the leucine sensors Sestrin2 and SAR1B, as well as the arginine sensor CASTOR1. Cryo-EM structures of human GATOR2 bound to these sensors have elucidated the binding interfaces and conformational changes that occur upon amino acid availability. These interactions are critical for transmitting nutrient signals to mTORC1.
Assembly and stability
In simple terms: The complex must be properly assembled to function; missing parts can destabilize it.
The assembly of GATOR2 is thought to be coordinated, with subunits like WDR24 and MIOS playing key roles in maintaining complex integrity. Knockout of individual subunits can disrupt the entire complex, affecting mTORC1 signaling. The SEACAT complex in yeast similarly requires all subunits for stability and function.
Subcellular localization
In simple terms: GATOR2 works near the lysosome, where mTORC1 is activated.
GATOR2 localizes to the lysosomal membrane, where it interacts with the Rag GTPase and mTORC1. This localization is essential for its function in nutrient sensing and for maintaining lysosomal-autophagic function. The complex dynamically associates with the lysosome in response to amino acid levels.
Key Genes Involved in GO:0061700 GATOR2 complex
The following genes encode the core subunits and key interactors of the GATOR2 complex, representing primary targets for functional studies.
| Gene | Major Role | Research Relevance |
|---|---|---|
| WDR24 | Core subunit of GATOR2 | Essential for mTORC1 activation; knockout impairs signaling |
| WDR59 | Core subunit of GATOR2 | Required for complex integrity and nutrient sensing |
| MIOS | Core subunit of GATOR2 | Involved in GATOR2 assembly and function |
| SEH1L | Core subunit of GATOR2 | Scaffold protein; part of SEACAT in yeast |
| SEC13 | Core subunit of GATOR2 | Structural component; also in COPII |
| SESN2 | Leucine sensor | Binds GATOR2 to inhibit mTORC1 in leucine deprivation |
| SAR1B | Leucine sensor | Regulates mTORC1 via GATOR2 |
| CASTOR1 | Arginine sensor | Binds GATOR2 to modulate mTORC1 |
| RAGA | Rag GTPase | Interacts with GATOR2 to activate mTORC1 |
| RAGB | Rag GTPase | Interacts with GATOR2 to activate mTORC1 |
| RAGC | Rag GTPase | Interacts with GATOR2 to activate mTORC1 |
| RAGD | Rag GTPase | Interacts with GATOR2 to activate mTORC1 |
| MTOR | Kinase | Downstream effector of GATOR2 signaling |
| TFEB | Transcription factor | Regulated by GATOR2 via MiT/TFE degradation |
| TFE3 | Transcription factor | Regulated by GATOR2 via MiT/TFE degradation |
| LAMTOR1 | Scaffold for Rag GTPases | Required for GATOR2 function at lysosome |
| RRAGA | Rag GTPase | Interacts with GATOR2 |
| RRAGB | Rag GTPase | Interacts with GATOR2 |
How Is GATOR2 complex Regulated?
GATOR2 activity is regulated by amino acid availability. In leucine-rich conditions, Sestrin2 and SAR1B release GATOR2, allowing it to promote mTORC1 activation through the Rag GTPase. Conversely, leucine deprivation enhances Sestrin2 binding to GATOR2, inhibiting mTORC1. Arginine availability modulates the interaction between CASTOR1 and GATOR2. Additionally, GATOR2 is regulated by the GATOR1 complex, which acts as a GTPase-activating protein for RagA/B to inhibit mTORC1. Phosphorylation and other post-translational modifications may also influence GATOR2 function, though specific sites require further study.
GATOR2 complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| WDR24 | Myelination defects | Oligodendrocyte-specific knockout mouse |
| MIOS | Cancer | Cancer cell line knockout |
| SESN2 | Metabolic disorders | Sestrin2 knockout mouse |
| CASTOR1 | Arginine sensing disorders | Castor1 knockout cell line |
| TFEB | Lysosomal storage diseases | TFEB overexpression |
GATOR2 in myelination and neurological disorders
GATOR2 complex-mediated amino acid signaling is essential for brain myelination. Loss of GATOR2 subunits in oligodendrocytes leads to myelination defects, highlighting its role in white matter development and potential implications for demyelinating diseases.
GATOR2 in cancer
Dysregulation of mTORC1 signaling is a hallmark of cancer. GATOR2 subunits are frequently altered in cancers, and their loss can impair tumor growth due to defective nutrient sensing. Additionally, GATOR2 maintains lysosomal-autophagic function by inhibiting degradation of MiT/TFE transcription factors, which are implicated in cancer and lysosomal storage disorders.
GATOR2 in metabolic disorders
Given its central role in amino acid sensing, GATOR2 dysfunction may contribute to metabolic syndromes such as insulin resistance and obesity. Studies in model organisms have linked GATOR2 components to altered lipid metabolism and energy homeostasis.
From GATOR2 complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does GATOR2 subunit X regulate mTORC1 signaling? | Knockout cell line (e.g., HEK293T) |
| How does a point mutation in WDR24 affect complex assembly? | Point mutation knock-in via CRISPR |
| Can we tag GATOR2 subunits for imaging? | Knock-in of fluorescent tags (e.g., GFP) |
| What is the effect of GATOR2 overexpression? | Overexpression cell line |
| Which genes interact with GATOR2? | CRISPR library screening |
| How does GATOR2 respond to amino acid levels? | Live-cell imaging with tagged subunits |
How to Study the GATOR2 complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Gene function | Identify essential GATOR2 subunits |
| Cryo-EM | Protein structure | Determine GATOR2 architecture |
| Co-IP | Protein interactions | Study GATOR2-sensor binding |
| Live-cell imaging | Localization dynamics | Track GATOR2 at lysosome |
| RNA-seq | Transcriptional changes | Assess mTORC1 pathway output |
| Proteomics | Protein abundance | Quantify GATOR2 subunits |
| CRISPR library screening | Gene networks | Find modifiers of GATOR2 function |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify genes that modulate GATOR2 function or mTORC1 signaling. Such screens have revealed novel regulators and confirmed core subunits.
Structural biology (cryo-EM)
Cryo-EM structures of GATOR2 alone and in complex with amino acid sensors or Rag GTPase provide mechanistic insights into its function.
Biochemical assays
Co-immunoprecipitation and pull-down assays are used to study interactions between GATOR2 subunits and with sensors like Sestrin2.
Live-cell imaging
Fluorescently tagged GATOR2 subunits allow tracking of complex localization and dynamics in response to nutrients.
How CRISPR Can Be Used to Study GO:0061700 GATOR2 complex
Knockout
CRISPR knockout of GATOR2 subunits (e.g., WDR24, MIOS) in cell lines abolishes complex function, leading to impaired mTORC1 signaling and altered autophagy. These models are valuable for studying the role of GATOR2 in nutrient sensing.
Point Mutation
Introducing point mutations in GATOR2 subunits can dissect specific interaction interfaces or catalytic residues. For example, mutations in WDR24 that disrupt sensor binding help define its role in signal transmission.
Knock-in
Knock-in of epitope tags (e.g., HA, GFP) into endogenous GATOR2 genes enables precise localization and interaction studies without overexpression artifacts.
Overexpression
Overexpression of GATOR2 subunits or sensors can amplify signaling and is useful for biochemical purification and structural studies.
How EDITGENE Supports GATOR2 complex Research
Researchers studying GATOR2 complex-related genes often need to determine whether a candidate gene is causally involved in mTORC1 regulation, lysosomal function, or disease. EDITGENE provides a comprehensive suite of CRISPR services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for GATOR2 complex research.
Frequently Asked Questions About GATOR2 complex
What is the GATOR2 complex?
The GATOR2 complex is a multiprotein subcomplex of the GATOR complex that regulates TORC1 signaling by interacting with the Rag GTPase. In humans, it consists of WDR24, WDR59, MIOS, SEH1L, and SEC13.
What genes are involved in the GATOR2 complex?
The core genes in humans are WDR24, WDR59, MIOS, SEH1L, and SEC13. In yeast, they are Sea2p, Sea3p, Sea4p, Seh1p, and Sec13p.
What is the function of GATOR2 in mTORC1 signaling?
GATOR2 positively regulates mTORC1 in response to amino acids by interacting with the Rag GTPase and transmitting signals from sensors like Sestrin2 and SAR1B.
How is GATOR2 regulated by amino acids?
Amino acid availability modulates GATOR2 interactions with sensors. For example, leucine binding to Sestrin2 releases GATOR2 to activate mTORC1.
What diseases are associated with GATOR2 dysfunction?
GATOR2 dysfunction has been linked to myelination defects, cancer, and metabolic disorders.
What is the SEACAT complex?
SEACAT is the yeast ortholog of the GATOR2 complex, containing Sea2p, Sea3p, Sea4p, Seh1p, and Sec13p.
How can I study GATOR2 using CRISPR?
CRISPR knockout, point mutation, knock-in, and overexpression models can be used to dissect GATOR2 function in cell lines.
What are the subunits of GATOR2?
Human GATOR2 subunits are WDR24, WDR59, MIOS, SEH1L, and SEC13.
Does GATOR2 interact with Sestrin2?
Yes, Sestrin2 binds GATOR2 in the absence of leucine to inhibit mTORC1 signaling.
What is the role of GATOR2 in autophagy?
GATOR2 maintains lysosomal-autophagic function by inhibiting the degradation of MiT/TFE transcription factors.
Conclusion
The GATOR2 complex (GO:0061700) is a central regulator of mTORC1 signaling, integrating amino acid availability with cell growth and autophagy. Its structure, composition, and interactions with sensors and the Rag GTPase have been elucidated through recent structural and functional studies. Dysregulation of GATOR2 contributes to myelination defects, cancer, and metabolic disorders, making it a compelling target for therapeutic intervention. Researchers can leverage CRISPR-based models to further dissect its roles in health and disease.
References
- 1. Yu Z et al.. 2022. GATOR2 complex-mediated amino acid signaling regulates brain myelination.. Proc Natl Acad Sci U S A 119(3) PMID: 35022234
- 2. Valenstein ML et al.. 2022. Structure of the nutrient-sensing hub GATOR2.. Nature 607(7919):610-616 PMID: 35831510
- 3. Jansen RM et al.. 2025. Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.. Nat Struct Mol Biol 32(10):1980-1988 PMID: 40715445
- 4. Wolfson RL et al.. 2016. Sestrin2 is a leucine sensor for the mTORC1 pathway.. Science 351(6268):43-8 PMID: 26449471
- 6. Yang S et al.. 2024. The GATOR2 complex maintains lysosomal-autophagic function by inhibiting the protein degradation of MiT/TFEs.. Mol Cell 84(4):727-743.e8 PMID: 38325378
- 7. Su MY et al.. 2025. Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.. Cell Rep 44(8):116088 PMID: 40742811
- 8. Chen J et al.. 2021. SAR1B senses leucine levels to regulate mTORC1 signalling.. Nature 596(7871):281-284 PMID: 34290409
