Arguably our most important discovery to come from TENDO was the determination of a high-resolution structure of a native membrane microdomain, the eisosome, that functions upstream of TORC2 (10.1038/s41586-024-07720-6). In this work, we could observe how a peripheral protein coat stabilizes specific lipids species in the underlying membrane and how an increase in membrane tension triggers the release of these lipids and likely other signaling molecules. This work provides a major advance in our understanding of how mechanical stress impacting a membrane bilayer can be sensed and transmitted to effect intracellular signaling pathways that enable the cell to respond to these stresses. Furthermore, using a small molecule that we had previously discovered in a high-throughput drug screen for TORC2 inhibitors, we discovered that insults that lead to a reduction in plasma membrane tension trigger an unexpected mobilization of previously cloistered sterol molecules as well as the formation of giant membrane invaginations which appear to be mechanistically coupled to TORC2 inactivation. This work is currently under revision for publication (10.1101/2024.10.18.618785).
A second, far-reaching advance has been our determination of a high-resolution structure of the SEA Complex, a GTPase activating complex that plays a central role in TORC1 regulation in both yeast and humans (10.1038/s41586-022-05370-0). Moreover, we recently determined a structure of the SEA Complex together with its substrate, the EGO Complex (10.1101/2024.10.05.616782). These were important "missing links" in the TOR field important as they help us understand the molecular mechanisms coupling environmental stresses to TORC1 activity regulation. In related work, we discovered that the EGO Complex activates TORC1 by physically removing it from an inhibitory polymer (10.1038/s41594-022-00912-6) bringing critical insight into potentially conserved mechanisms by which TORC1 is regulated in all eukaryotes.
