GATOR2 mysterious no more [Nature]
Our lab has just made a huge dent in one of the most elusive problems of the nutrient sensing field — and that is the mechanism of how GATOR2 works on the molecular level. This was a collaborative project with Max Valenstein.
GATOR2 is a protein complex composed of five individual subunits which have been shown to work together to (1) receive signals from individual nutrient sensors that detect cellular levels of amino-acids leucine, arginine, and (2) to relay that information to mTORC1 machinery, to make informed metabolic decisions for the cell.
Full disclosure — we have not figured out how GATOR2 works just yet. But we made the first step towards that goal. Below is a short summary of what we found, and what’s now been published in Nature [paywall-free link].
Many congratulations to the whole team!
- We have determined a 3.7 Å cryo-EM structure of GATOR2, and built its atomic model.
- GATOR2 looks like a drone, with the central octagonal scaffold surrounded by multiple WD40 β-propellers. In fact, a single GATOR2 particle has sixteen β-propellers!
- The octagonal scaffold is assembled thanks to a set of two distinct protein-protein interactions:
- α-solenoid — α-soleonoid junctions.
- CTD—CTD junctions, which involve zinc-coordinating RING and zinc-finger domains.
- The CTD junctions constitute a structurally novel protein dimer, which has not been observed before. In fact, the presence of RING domains in GATOR2 initially fooled us into thinking that this complex must have an enzymatic function — similarly to RING domains involved in ubiquitin transfer. However, as we found out in this study, GATOR2 does not seem to transfer ubiquitin at any conditions tested, and neither is ubiquitylation required for passing the signal from GATOR2 to mTORC1. Instead, we discovered that the role of RING domains in GATOR2 is to assemble the GATOR2 octagon, which acts as a scaffold for signal transduction activities.
- The octagonal scaffold is supported by a number of extra β-propellers which rigidify the α-solenoid and CTD junctions.
- And most excitingly, there are three distinct sets of β-propellers that emanate from the scaffold and point outwards — which we found are critical for:
- Receiving signal from the leucine sensor Sestrin2
- Receiving signal from the arginine sensor CASTOR1
- Relaying these signals to mTORC1 (via GATOR1)
Our work continues.
Stay tuned for new discoveries coming from our lab. And please consider joining us (as a Post-doc or a PhD student) — to help us figure out how GATOR2 works!
Kacper presents at the Small GTPase conference
Kacper was invited to present our team’s efforts on deciphering how Rag GTPases work — at the FASEB conference Regulation and Function of Small GTPases in Vermont Academy [Saxtons River, Vermont]. It was the first time that Rags were featured at this famous conference, which is celebrating 30 years in the running.
Kacper was also involved in a career workshop with current trainees — by sharing the experience of applying to faculty positions and setting up a lab.
Thank you, Anne Ridley and Mark Philips for organizing a fantastic meeting. It was a humbling experience to meet so many giants in the field and to learn about the terrific research coming out from many labs around the globe. Lots of new ideas and potential collaborations!
Cannot wait for the next meeting in 2024!
INFORS shakers are here!
Kacper is unable to contain himself — our workhorse shakers have just arrived. Thank you to Eddie Nazzal and the INFORS team for making this happen in a timely manner.
These shakers are absolute beasts — we use them to grow tens of liters of bacteria, yeast, and insect cells. It’s time to put the shaker platforms and the racks together! We are going to need loads of flasks.
Rogala Lab opens at Stanford!
Exciting times — our lab opens today at Stanford! We are located in the Stanford Cancer Institute‘s open-floor space on the 4th floor of the brand new Biomedical Innovations Building. We cannot wait to make this space our home. There is a lot of work ahead of us — to install all instruments needed for cell and protein chemistry work, and to get stocked with lab supplies. It will be a busy summer!
We could not have asked for better neighbors with whom we’ll be sharing this space: Nathanael Gray and Steven Corsello. Massive thank you to Steven Artandi, Raj Rohatgi and the phenomenal folks at the SCI for bringing this dream team together.
We are excited and humbled to be an integral part of two world-class basic-science departments in the Stanford University School of Medicine: Structural Biology and Chemical & Systems Biology. We only hope that one day we will become as good scientifically as our more senior colleagues!
Stay tuned for more updates!