Cellular nutrient sensing, the process by which cells detect nutrient availability like amino acids, is fundamental for their survival, growth, and proliferation. This allows cells to adapt their metabolic activities to environmental conditions. GATOR1 is a protein complex that acts as a brake on cell growth. It modulates a central cellular pathway that dictates whether a cell will grow or conserve resources.
Composition of the GATOR1 Complex
The GATOR1 complex is formed by the assembly of three protein subunits: DEPDC5, NPRL2, and NPRL3. DEPDC5 is the largest protein within this complex.
NPRL2 and NPRL3 are homologs of yeast proteins (npr2 and npr3) involved in nutrient sensing pathways. The GATOR1 complex possesses an unusual molecular architecture, differing from other known protein structures. This unique composition initially presented challenges in understanding its function.
Role in mTORC1 Pathway Regulation
The mTORC1 (mechanistic target of rapamycin complex 1) pathway coordinates cell growth, metabolism, and protein synthesis. This pathway integrates signals from nutrients, energy levels, and growth factors to govern cellular processes. GATOR1’s function is to act as a GTPase-Activating Protein (GAP) for Rag GTPases, such as RagA/B.
Rag GTPases transmit amino acid signals to mTORC1. When amino acid levels are low, GATOR1 activates and stimulates GTP hydrolysis on RagA/B. This action switches RagA/B to its inactive state, preventing mTORC1 from relocating to the lysosomal surface.
The lysosome is where mTORC1 is activated. By inhibiting mTORC1’s localization, GATOR1 applies a “brake” on cell growth and protein production. This mechanism ensures cells grow and divide only when sufficient resources are available.
Upstream Nutrient Sensing and GATOR1 Control
GATOR1’s activity is controlled by upstream nutrient-sensing mechanisms. The GATOR2 complex directly regulates GATOR1 by inhibiting its function. When amino acids are abundant, GATOR2 binds to GATOR1, inactivating it.
This inactivation “releases the brake” on mTORC1, allowing it to become active and promote growth. GATOR2 receives signals from various amino acid sensors. Sestrin2 senses leucine levels.
CASTOR1 detects arginine availability. SAMTOR monitors S-adenosyl methionine levels. These sensors transmit information about amino acid abundance to GATOR2, which then regulates GATOR1, aligning mTORC1 activity with the cell’s nutrient status.
GATOR1 Dysfunction in Human Disease
Mutations in GATOR1 subunit genes (DEPDC5, NPRL2, or NPRL3) can inactivate the complex. When the GATOR1 “brake” is compromised, the mTORC1 pathway becomes hyperactive. This uncontrolled activation of mTORC1 drives excessive cell growth and proliferation.
This dysregulation links to several human diseases, particularly neurological disorders. Focal cortical dysplasia (FCD) and forms of epilepsy, including sleep-related hypermotor epilepsy, are associated with GATOR1 gene mutations. Analysis of affected brain tissue in FCD reveals mTOR pathway overactivity.
Beyond neurological conditions, research indicates connections between GATOR1 pathway disruptions and cancer. The loss of GATOR1 function, leading to mTORC1 overactivity, contributes to the pathology observed in these conditions.