Researchers at Cornell University have uncovered a new way that cells regulate the movement of proteins using artificial intelligence (AI). This process, which is vital for cell growth, communication, and movement, is often disrupted in diseases like cancer. In a study published September 9 in the Journal of Cell Biology, scientists identified a protein called Avl9 that acts as an "off switch" for another protein, Arf1, which is responsible for directing the movement of materials inside cells. This discovery suggests the existence of a previously unknown system that cells use to control this essential function. The research, led by Chris Fromme, a professor of molecular biology and genetics at Cornell, utilized AlphaFold, an AI program that predicts the structures and interactions of proteins. This approach allowed the team to identify potential partners of Arf1 much faster than traditional lab methods. Arf1 functions as a molecular switch, guiding the transport of proteins and other substances within the cell. It plays a key role in processes like secretion and cell movement, which are important in both normal and diseased states. Avl9, which had been previously associated with secretion and cancer cell movement, was found to have the opposite function of what was expected based on its structure. Laboratory experiments confirmed that Avl9 deactivates Arf1 after it has completed its task. A single change in one of Avl9's amino acids — the building blocks of proteins — removed its ability to regulate Arf1. In human lung cancer cells, this change reduced their mobility, linking Avl9's function to a behavior important in cancer progression. The study also revealed that Avl9 belongs to a group of proteins known as DENN domain proteins, which were previously thought to act as "on switches." The new findings suggest that some of these proteins may instead function as "off switches," like Avl9, playing a role in regulating the transport of materials inside cells. This discovery prompted the team to search for other proteins with similar functions, and they confirmed that at least one related human protein behaves in the same way, indicating a broader system for controlling intracellular transport. Understanding how this system works could help researchers better grasp how disruptions in it contribute to disease. In cancer, changes in cell movement and transport can influence tumor growth and spread. Fromme emphasized that the discovery of this new class of proteins can guide future research and help scientists design experiments to explore related proteins in both healthy and diseased cells. The study also highlights the power of AI in accelerating biological discoveries by allowing researchers to ask more exploratory questions efficiently and identify promising areas for further investigation.