The function of our cells' signaling pathways is to coordinate growth with environmental signals. Cell growth is an important part of normal cell function and can go awry in diseases such as cancer. In order to control cell growth in response to environmental conditions, rapamycin complex 1 (mTORC1) and GATOR2 play important roles. GATOR2 and mTORC1 sense the levels of nutrition in the cell and either promote growth or stunt it. The structure of GATOR2 was revealed in a paper published in July in Nature. The research was done in the lab of a former member of the institute.
Function and form follow each other. Understanding what looks like can tell us a lot about how it works. We are trying to learn as much as we can. How is mTORC1 being activated?
The GATOR2 is made of five different parts. No one knew if there were multiple or single copies or how they fit together. There was a lot of confusing data. There are several copies of the RING finger domain in the GATOR2 units. The RING domain is a common structure that plays a role in ubiquitin-related function. Ubiquitin is a regulatoryProtein found throughout most tissues in organisms It can change their activity if it is attached to other genes. Valenstein expected GATOR2 to act as a ubiquitin ligase, but experiment after experiment failed to show that.
The 3D structure of GATOR2 was determined using Cryo-EM. Everything else was dead. We have to take it apart and look under the microscope to see how it works.
The project needed to extract GATOR2 from cells in the right quantity and quality. The process took two years. Lalgudi was a part of the project. The data started to make sense when the researchers visualized GATOR2 in 3D form. A "spartan handshake" is formed by crossing the RING domain of individual proteins. The RING domain is critical for holding GATOR2 together, a role that was previously unrecognized.
They showed that GATOR2 is a cage-like structure. Several copies of two additional subunits, SEH1L and SEC 13, are supported by the frame. The frame is reinforced by these extra subunits.
The octagonal scaffold is held together by eight pairs of RING domains and associated with function by eight pairs of wd40 propellers. The propellers are shaped like a plane with blade-shaped pieces pointing inward. The researchers were able to understand how the alpha-propionates interacted with GATOR2. In GATOR2, there are three different classes of alpha-pilots. The two interact with the proteins.
GATOR1 and KICSTOR are two of theProtein complexes involved in the pathway. GATOR1 and GATOR2 are like hand brake operators, they stop activity in the mTOR pathway and either intervene or pull the brake.
Their work is the first episode of a series. They hope to pin down the details of how GATOR2 communicate with each other. The researchers want to understand how cancer can affect normal functions of GATOR2 and the mTOR growth pathway as a whole.
Researchers may discover new targets for drugs that regulate mTOR by studying the structure and function of GATOR2.
There are drugs that bind in the crevices of the human body. Any type of structural work is a good example of how to find drugs.
More information: Max L. Valenstein et al, Structure of the nutrient-sensing hub GATOR2, Nature (2022). DOI: 10.1038/s41586-022-04939-z Journal information: Nature
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