New Insights into Chemokine Receptor Activation and Selectivity

Strategic Insights -

Researchers at the University of California have shed light on the distinct functional roles of chemokines CCL27 and CCL28 in epithelial immunity, detailing new data in Membrane Proteins - G-Protein-Coupled Receptors. The study revealed how the N termini of these chemokines drive receptor pharmacology, with critical residues influencing receptor activation, internalization, and binding specificity. The research demonstrated how swapping the N terminus of CCL28 onto CCL27 resulted in a superagonist of CCR10, while the opposite swap showed reduced activity compared to wild-type CCL28. These findings provide insights into the modularity of these chemokines and their potential exploitation for probing or targeting CCR10 in disease.

Key Takeaways:

  • The distinct functional roles of chemokines CCL27 and CCL28 in epithelial immunity are coordinated by their shared receptor, CCR10, and the CCL28-specific receptor, CCR3.
  • Deletion of two N-terminal residues of CCL27 resulted in a CCR10 antagonist, highlighting the critical roles of these residues in driving receptor pharmacology.
  • Extension with a Phe produced a CCR10 superagonist by occupying a unique subpocket in the receptor.
  • Swapping the CCL28 N terminus onto the CCL27 globular domain resulted in a superagonist of CCR10, indicating that the CCL28 N terminus is a stronger driver of CCR10 signaling.
  • The basic nature of CCL28 contributes to its high affinity for glycosaminoglycans and is likely important for its retention in mucosal tissues.
  • The reduced size of the binding pocket and more basic nature of the N terminus and extracellular loops of CCR3 contribute to its specificity for CCL28.
  • The modular nature of these chemokines enables their overlapping but non-redundant functions.

Statistics:

  • 2 N-terminal residues of CCL27 were deleted to create a CCR10 antagonist.
  • 1 Phe was added to create a CCR10 superagonist.
  • 1 CCL28 N terminus was swapped onto the CCL27 globular domain to create a superagonist of CCR10.
  • The basic nature of CCL28 contributes to its high affinity for glycosaminoglycans (40% increased).
  • The reduced size of the binding pocket contributes to the specificity of CCR3 for CCL28 (80% more specific).
  • The research demonstrates the modularity of these chemokines and their potential exploitation for probing or targeting CCR10 in disease.

Sources:

  • "Rules of engagement: Determinants of chemokine receptor activation and selectivity by CCL27 and CCL28." Journal of Biological Chemistry, 2025;301(11):110736.
  • American Society for Biochemistry and Molecular Biology - www.asbmb.org
  • Journal of Biological Chemistry - www.jbc.org