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UNIGE scientists uncover a mechanism that regulates a central system for cellular balance, paving the way for new therapeutic strategies.
How do cells know when to activate or slow down their activity? A team from the University of Geneva (UNIGE) provides new insights by studying TORC2, an essential but still poorly understood protein complex. Using ultra-high-resolution imaging, scientists were able to observe its structure in detail for the first time. The team notably reveals the existence of a molecular "cork" that controls its activation at the cell surface. Published in the journal Molecular Cell, these findings pave the way for new strategies to target this mechanism, which is involved in diseases such as cancer and diabetes.
To function properly, cells must constantly decide when to grow, divide, or slow down their activity. A key player in these decisions is a protein called TOR (Target of Rapamycin), found in complex living organisms. TOR acts like a conductor: it integrates numerous signals – such as nutrient availability, energy levels and mechanical stress – and adjusts cellular behavior accordingly.
These features, previously unseen, represent especially promising targets for future drugs.
When conditions are optimal, TOR stimulates growth and the production of new proteins. Conversely, in situations of limited resources or stress, it slows these processes to maintain cellular balance. Understanding TOR is particularly important because its dysregulation is involved in many diseases. Excessive activity can promote uncontrolled cell growth, as seen in cancer. Disruptions in these signaling pathways are also associated to metabolic diseases, such as diabetes.
This protein operates within two distinct complexes, TORC1 and TORC2, which carry out complementary roles. The functioning of TORC1 is relatively well understood, whereas that of TORC2 remains unclear, even though it is essential for cell survival and their ability to adapt to their environment.
A long-hidden molecular "cork" in TORC2
Thanks to the recently created cutting-edge cryogenic electron microscopy facilities at the Dubochet Center in Geneva and Lausanne, which allow biological samples to be observed with exceptional precision on the order of an ångström (one ten-billionth of a meter), the team led by Robbie Loewith, professor in the Department of Molecular and Cellular Biology at the Faculty of Science of UNIGE, succeeded in visualizing the structure of TORC2 at unprecedented resolution.
This approach made it possible to reconstruct the full organization of the complex and to reveal structural elements that had previously escaped observation. In particular, the scientists identified an unexpected regulatory mechanism: part of the protein acts as a true molecular ''cork" by blocking the active site of TORC2, thereby preventing its activation.
At the same time, the team identified several protein domains specific to TORC2, absent from the related complex TORC1, which play an essential role in its anchoring to the membrane and in its function. "These features, previously unseen, represent particularly promising targets for future drugs. Specifically inhibiting TORC2 could make it possible to treat patients suffering from cancer or diabetes," concludes Lucas Tafur, former researcher in Robbie Loewith's group and now group leader at the Spanish National Cancer Research Center (CNIO).
