Cornell researchers used artificial intelligence and laboratory testing to identify a previously unknown way cells regulate the movement of proteins, a discovery that could help scientists better understand processes disrupted in cancer.
The study, published Sept. 9 in the Journal of Cell Biology, found that a little-understood protein called Avl9 acts as an off switch for Arf1, a protein that directs material inside cells.
Arf1 helps move proteins and other cargo from the Golgi apparatus to other destinations. Researchers said shutting it off at the right time is essential because prolonged activity can disorganize cellular transport.
The team was led by Chris Fromme, a Cornell professor of molecular biology and genetics and faculty member in the Weill Institute for Cell and Molecular Biology. Researchers used AlphaFold, software that predicts protein structures and interactions, to search for possible regulators of Arf1.
The software produced a short list of likely interactions for experimental testing, replacing a traditional screening process that can take months.
Laboratory work confirmed that Avl9 shuts down Arf1 after the transport protein completes its role. Researchers also tested normal and mutated forms of Avl9 and found that changing a single amino acid eliminated its ability to regulate Arf1.
In human lung cancer cells, that mutation reduced the cells' ability to move, linking Avl9's molecular role to a behavior involved in cancer growth and spread. The work did not establish a treatment, but it gave researchers a new mechanism to investigate.
The team also examined related DENN domain proteins, which had generally been understood as molecular on switches. At least one related human protein behaved as an off switch, suggesting that the newly identified function may be part of a broader system controlling transport inside cells.
Fromme said the results show how AI can accelerate exploratory science by identifying promising biological questions before researchers commit to deeper experiments.
The National Institutes of Health funded the study, with support from Cornell's Institute for Biotechnology imaging facility. Ryan Vignogna, a postdoctoral associate at the Weill Institute, was the first author.
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