From protein mechanisms to targeted therapeutics

The key piece of our lab is in!

These high-speed and ultracentrifuges from Himac / Eppendorf are still considered rather niche in the US, but it’s a choice we’d make again because of the super high quality of build and features. Major thanks to Maria Ahmadi from the Eppendorf team for making this happen, and to Robert Jones for the installation! We actually needed a mini pallet jack to move things around in this small room — big thanks to Monica Mendoza for coordinating it.

Cannot wait to start spinning all sorts of biological materials in these rotors, from proteins, liposomes, to cells!

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 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!