Senior co-corresponding author M. Madan Babu, PhD, FRS, St. Jude Senior Vice President of Data Science and Center of Excellence for Data-Driven Discovery director, Department of Structural Biology and first and co-corresponding author Andrew Kleist, MD, PhD, St. Jude Center of Excellence for Data-Driven Discovery, Department of Structural Biology.
(MEMPHIS, Tenn. – April 23, 2025). Scientists from St. Jude Children’s Research Hospital and the Medical College of Wisconsin have created a data science framework to better understand how cells travel through the body. The researchers analyzed chemokines and their associated G protein-coupled receptors (GPCRs), proteins that govern cell movement. They found that specific positions within structured and disordered regions of both proteins determine how chemokines and GPCRs bind each other. The scientists used that information to change chemokine-GPCR binding preferences artificially and alter the resulting cell migration. This type of understanding may improve disease treatment, such as enhancing how cellular therapies travel to tumor sites, and increase clarity about healthy processes, such as the development of heart and blood vessels. The findings were published today in Cell.
Cell migration influences many processes in the body, including how immune cells travel to an infection site, how the brain develops and how wounds are repaired. It is also exploited by disease cells, such as in metastatic cancer. While cell movement is known to be directed by the interaction between two protein families, GPCRs and chemokines, the vast similarities between members of each family have presented a challenge in understanding how the correct pairs form and control the movement of relevant cells. The researchers developed data science approaches to identify the exact parts of each protein governing their molecular interactions.
“We found that cells have an elegant system that uses structure and disorder together to control cell migration,” said senior co-corresponding author , FRS, St. Jude Senior Vice President of Data Science and director, . “With that understanding, we can now rationally introduce small changes in a chemokine’s structure to ultimately alter cell migration in desired ways.”
Small, disordered regions provide order to chemokines-GPCR pairs
The scientists uncovered how chemokines and their receptors bind select members of the GPCR family by data mining protein sequences and structural information. They compared all human chemokine-binding GPCRs and all chemokines, then compared similar chemokines and GPCRs from other species. They also looked at each protein individually at a population level, finding places that stayed the same across groups and those that differed.
“Through our data analysis, we discovered that the information for how chemokines and GPCRs select for each other is stored in small, discrete packages of highly unstructured, disordered regions,” said first and co-corresponding author Andrew Kleist, MD, PhD, St. Jude Center of Excellence for Data-Driven Discovery, Department of Structural Biology. “The mix of those small packages from both the chemokine and receptor results in the unique interaction, similar to website data encryption keys, which governs cell migration.” Kleist started the work as a graduate student in the laboratory of co-corresponding author Brian Volkman, PhD, Professor of Biochemistry at the Medical College of Wisconsin.
Websites keep sales secure with public and private digital keys. The seller and buyer each possess a public key and a private key, both of which are prime numbers. When the private and public keys are multiplied together, the resulting unique number ensures that only the two parties taking part in the transaction can exchange information while protecting that information from bad actors. The scientists found the disordered regions in these proteins acted like private keys, while the structured regions acted like public keys. The interactions of a chemokine’s disordered region with a GPCR’s structured region, within the greater context of the highly structured portions of each protein, provide cells with a unique chemical identifier for that chemokine-GPCR pair, just like verifying a pair of public and private keys. That unique identifier contains the information for cells to respond appropriately to a particular chemokine-GPCR binding, migrating towards more of that chemokine.
“Once we understood how these proteins interacted, we demonstrated we could rationally mutate them to have different properties,” Babu said. The researchers changed the regions determining the selectivity of a chosen chemokine to alter its receptor binding preferences. Co-author , MD, St. Jude , showed that the scientists could change how T cells, a type of white blood cell, move, turning down a signal that normally stops their movement.
Making forward movements with chemokines and GPCRs
“Now that we’ve shown a proof of concept, our approach will guide exploration into new medicines and improvements for existing cellular therapies,” Kleist said. “For example, it may be possible to create molecules that better lead immune cells to cancers or help recruit more blood stem cells for bone marrow transplants. In theory, any therapy using cell movement could benefit from applying these principles.”
To enable scientists and clinicians to test this, the collaborators published their data science framework online. The resource is the first step in pushing cell movement manipulation from concept into reality for patients.
“When people think about the body, we think every cell stays in place, but that’s a simplistic view,” Babu said. “Depending on the tissue, cells are moving all the time, and our new understanding of those systems opens novel avenues for therapeutic development.”
The framework to assist the rational design of chemokines and receptors is freely available at: .
Authors and funding
The study’s other authors are Monica Thomas, Kyler Crawford, Acacia Dishman, Michael Wedemeyer and Francis Peterson, Medical College of Wisconsin; Martyna Szpakowska and Andy Chevigné, Luxembourg Institute of Health; Greg Slodkowicz, MRC Laboratory of Molecular Biology; Daniel McGrail, University of Texas MD Anderson Cancer Center; Stephen Yi, University of Texas at Austin; Nidhi Sahni, Baylor College of Medicine and Duccio Malinverni and Madison Sluter, St. Jude.
The study was supported by grants from the Medical Research Council (MC_U105185859), the National Institutes of Health (F30CA196040, R37AI058072, F30HL134253, F30CA236182, T32GM080202, R35GM137836 and K99CA240689), the Luxembourg Institute of Health NanoLux Platform, the Luxembourg National Research Fund (INTER/FNRS INTER 20/15084569, CORE C23/BM/18068832), F.R.S.-FNRS-Télévie (7.8504.20, 7.4502.21 and 7.8508.22), the St. Jude GPCR Research Collaborative, AstraZeneca Blue Sky Fund (BSF17), the Swiss National Science Foundation (P2ELP3_18910), the Cancer Prevention and Research Institute of Texas (RR160021), the Alfred P. Sloan Scholar Research Fellowship (FG-2018-10723), the Andrew Sabin Family Foundation Fellowship, the Ovarian Cancer Research Alliance (Early Career Award 649968) and ALSAC, the fundraising and awareness organization of St. Jude.
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