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Structure of the nutrient-sensing hub GATOR2
Max L Valenstein1,2, Kacper B Rogala3,4,5,6,7, Pranav V Lalgudi8,9
1Whitehead Institute for Biomedical Research, Cambridge, MA, USA. mvalenst@wi.mit.edu.
Nature
|July 13, 2022
Summary
The GATOR2 complex, crucial for nutrient sensing and mTORC1 activation, has been structurally elucidated. This reveals its cage-like architecture and evolutionary links, advancing our understanding of cellular growth regulation.
Area of Science:
- Cell Biology
- Structural Biology
- Biochemistry
Background:
- Mechanistic target of rapamycin complex 1 (mTORC1) regulates cellular growth in response to nutrients.
- Amino acid signaling to mTORC1 involves Rag GTPases, GATOR1, and GATOR2.
- GATOR2's structure and biochemical function were previously unknown despite its role in nutrient sensing.
Purpose of the Study:
- To determine the three-dimensional structure of the human GATOR2 complex.
- To elucidate the subunit stoichiometry and architecture of GATOR2.
- To provide a structural basis for understanding GATOR2's function in the mTORC1 pathway.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structure of the human GATOR2 complex.
- Biochemical and structural analyses were performed on the GATOR2 complex and its components.
- Integration of SEH1L and SEC13 subunits was analyzed within the GATOR2 scaffold.
Main Results:
- The human GATOR2 complex forms a large (1.1 MDa), cage-like structure with two-fold symmetry.
- The complex features an octagonal scaffold composed of WDR24, MIOS, and WDR59 subunits, decorated with WD40 β-propellers.
- SEH1L and SEC13 subunits stabilize the scaffold and suggest evolutionary links to nuclear pore and membrane-coating complexes.
- The WD40 β-propellers mediate interactions with nutrient sensors SESN2, CASTOR1, and GATOR1.
Conclusions:
- The study reveals the complete structure of the GATOR2 complex, a key component of nutrient sensing.
- The determined structure provides insights into GATOR2's subunit organization and its interactions with upstream regulators.
- This structural information serves as a foundation for further investigation into GATOR2's role in mTORC1 signaling and cellular growth control.
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