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A team of international researchers led by scientists at City of Hope has made a significant breakthrough in understanding how tiny parts of cells stay organized, offering new insights for developing targeted cancer treatments. The findings, published in Science Advances, focus on the protein paxillin—a key player in cellular structure and signaling that helps cancer cells adapt, grow, and resist therapy.
Key Discovery
The study reveals the complex interaction between paxillin and another protein called focal adhesion kinase (FAK), particularly at a specific docking site. Paxillin, a highly disordered protein, is known for its flexibility and dynamic nature, making it a challenging target for drug development. However, the team discovered that when paxillin and the C-terminal targeting domain of FAK (FAT) interact, they undergo a structural change, shrinking to fit a restricted space while maintaining flexibility within the broader cellular network.
“Disrupting the interaction of paxillin with focal adhesions bears direct relevance in cancer treatment,” said Dr. Ravi Salgia, the Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope. “This can lead to precision therapeutics targeting a specific paxillin function that is dominant in cancer cells, but less prevalent in healthy cells”.
Advanced Techniques Yield New Insights
To overcome the challenge of studying these highly dynamic proteins, the team employed advanced spectroscopic techniques, dynamic simulations, and computer modeling. This multi-method approach allowed them to accurately characterize the structural features of the paxillin-FAK interaction for the first time.
“The combination of all these methods enabled us to accurately characterize the structural features of the paxillin-FAK interaction more than any single method on its own,” explained Dr. Supriyo Bhattacharya, assistant research professor and lead in protein structure and data analysis.
Broader Implications
The research highlights a novel mechanism of protein interaction that could be applicable to other disordered proteins, expanding the potential for developing new therapies. Understanding these interactions provides a roadmap for targeting proteins that have traditionally been considered too fluid and disordered for drug intervention.
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