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Researchers from St. Jude Children’s Research Hospital and the Medical College of Wisconsin have developed an innovative data science framework aimed at unraveling the complexities of cell movement throughout the body. By examining chemokines and their associated G protein-coupled receptors (GPCRs)—proteins essential for regulating cell migration—the team determined that specific locations within both structured and disordered regions of these proteins are crucial for their mutual binding. Utilizing these insights, the scientists were able to artificially modify the binding preferences between chemokines and GPCRs, leading to changes in cell migration patterns. Such advancements could enhance therapeutic strategies, such as improving the targeting of cellular treatments to tumor locations, and provide greater understanding of healthy biological processes like the formation of the heart and blood vessels. Their research findings were published in Cell today.
The dynamics of cell migration play a significant role in various physiological processes, including the movement of immune cells towards infection sites, brain development, and wound healing. Furthermore, this fundamental process can be co-opted by certain diseases, notably in metastatic cancer. While it is established that cell movement is largely directed by the interaction of GPCRs and chemokines, the high degree of similarity among the members of these protein families has made it challenging to pinpoint how specific pairs of proteins interact to control cell behavior. In response, the researchers employed data science methods to isolate the critical components within each protein that dictate their molecular interactions.
“We found that cells utilize a sophisticated mechanism that combines structured and disordered regions to regulate migration,” explained senior author M. Madan Babu, PhD, FRS, who also serves as St. Jude’s Senior Vice President of Data Science and director of the Center of Excellence for Data-Driven Discovery in the Department of Structural Biology. “With this knowledge, we can implement targeted modifications in a chemokine’s structure to influence cell migration in desired manners.”
Disordered Regions Enhance Chemokines-GPCR Interactions
The research team identified how chemokines and their receptors selectively bind to certain GPCR family members through an extensive analysis of protein sequences and structures. They studied all human chemokine-binding GPCRs and associated chemokines, even extending their comparisons to similar proteins present in other species. This comprehensive approach included examining individual proteins at a population level, allowing for the identification of consistent features across groups and noting key differences.
“Our analysis revealed that the determinants of how chemokines and GPCRs selectively interact are encapsulated in small, specific packages of disordered regions,” stated Andrew Kleist, MD, PhD, a postdoctoral researcher and co-author of the study. “The combination of these packages from both protein categories results in unique interactions, akin to the keys used in website data encryption, which ultimately govern cell migration.” Kleist began his research while working in the lab of Brian Volkman, PhD, Professor of Biochemistry at the Medical College of Wisconsin.
Digital transactions rely on public and private keys to ensure secure exchanges. In this analogy, the researchers found that the disordered regions within the proteins act like private keys, while the more structured regions represent public keys. The interaction between a chemokine’s disordered region and a GPCR’s structured region creates a unique chemical identifier for that specific chemokine-GPCR pairing, similar to the confirmation that public and private keys provide in secure communications. This identifier directs cells to respond appropriately to the binding interactions by migrating towards higher concentrations of the chemokine.
“Once we grasped the nature of these protein interactions, we could rationally induce mutations to modify their properties,” Babu noted. The scientists were able to change the regions responsible for a chemokine’s selectivity to modify its receptor-binding characteristics. Co-author Lindsay Talbot, MD, from the Department of Surgery at St. Jude, demonstrated that they could influence the movement of T cells, a kind of white blood cell, by reducing a signal that typically inhibits their motility.
Advancing Applications of Chemokines and GPCRs
“With our proof of concept established, we’re eager to explore new medicinal possibilities and enhance existing cellular therapies,” Kleist expressed. “For instance, we could potentially develop molecules that more effectively direct immune cells to tumors or increase the recruitment of blood stem cells for bone marrow transplants. Essentially, any therapeutic strategy that depends on cell movement could be augmented by applying these insights.”
To facilitate further research in this area, the team has made their data science framework publicly available online. This resource marks a significant step towards translating the manipulation of cell movement from a theoretical concept into practical applications for patient treatment.
“It’s a common misconception to view the body as a static entity, where cells remain stationary. In reality, cells constantly move depending on the tissue environment, and our newfound understanding of these systems opens up exciting opportunities for therapeutic innovations,” Babu added.
The framework designed for the systematic development of chemokines and receptors is accessible at: https://github.com/andrewbkleist/chemokine_gpcr_encoding.
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