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Chemokine ligands play a pivotal role in immune response by mediating cell migration and coordinating cellular processes through interactions with chemokine receptors. Understanding their sequence and structural integrity is crucial for elucidating their biological functions and potential therapeutic applications. In this study, we investigate the dimer interface between two distinct homodimer topologies: CXC and CC homodimers. Despite nearly identical monomeric structures, the rigid CXC interface is characterized by interactions between the N-loop/β-sheet regions, while the more flexible CC interface involves interactions through the unstructured N-terminal regions. Our structural and biophysical analyses indicate no significant differences in the free energy of folding (2–8 kcal/mol) and binding (10–14 kcal/mol) between the two homodimer topologies, showing that their free energy is primarily driven by sequence. We hypothesize that the biological signal is driven by the malleability of the dimer, depending on the binding interface. Understanding these structural dynamics opens new possibilities for designing chemokine-based therapeutics to modulate immune responses in diseases such as cancer, inflammation, and autoimmune disorders.
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Biophysical characterization of the CXC chemokine receptor 2 ligands
The chemokines of the immune system act as first responders by operating as chemoattractants, directing immune cells to specific locations of inflamed tissues. This promiscuous network is comprised of 50 ligands and 18 receptors where the ligands may interact with the receptors in various oligomeric states i.e., monomers, homodimers, and heterodimers. Chemokine receptors are G-protein coupled receptors (GPCRs) present in the membrane of immune cells. The migration of immune cells occurs in response to a concentration gradient of the ligands. Chemotaxis of neutrophils is directed by CXC-ligand (CXCL) activation of the membrane bound CXC chemokine receptor 2 (CXCR2). CXCR2 plays an important role in human health and is linked to disorders such as autoimmune disorders, inflammation, and cancer. Yet, despite their important role, little is known about the biophysical characteristics controlling ligand:ligand and ligand:receptor interaction essential for biological activity. In this work, we study the homodimers of three of the CXCR2 cognate ligands, CXCL1, CXCL5, and CXCL8. The ligands share high structural integrity but a low sequence identity. We show that the sequence diversity has evolved different binding affinities and stabilities for the CXC-ligands resulting in diverse agonist/antagonist behavior. Furthermore, CXC-ligands fold through a three-state mechanism, populating a folded monomeric state before associating into an active dimer.
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- Award ID(s):
- 2145906
- PAR ID:
- 10560968
- Editor(s):
- Jeyaseelan, Samithamby
- Publisher / Repository:
- the Public Library of Science (PLOS)
- Date Published:
- Journal Name:
- PLOS ONE
- Volume:
- 19
- Issue:
- 4
- ISSN:
- 1932-6203
- Page Range / eLocation ID:
- e0298418
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1371/journal.pone.0298418
