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Published on: March 14, 2016
Probing receptor binding activity of interleukin-8 dimer using a disulfide trap
Krishna Rajarathnam1, Gregory N Prado, Harshica Fernando
1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA. krrajara@utmb.edu
Biochemistry
|June 21, 2006
Summary
Interleukin-8 (IL-8) monomers are high-affinity ligands for CXCR1 and CXCR2 receptors. This study reveals that IL-8 dimers exhibit significantly lower binding affinities, providing structural insights into chemokine receptor interactions.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Interleukin-8 (IL-8), a chemokine, functions by binding to neutrophil CXCR1 and CXCR2 receptors.
- While IL-8 monomers are known high-affinity ligands, the binding affinity of IL-8 dimers remains debated.
Purpose of the Study:
- To investigate the binding affinity of IL-8 dimers to CXCR1 and CXCR2 receptors.
- To elucidate the structural basis for potential differences in binding affinity between IL-8 monomers and dimers.
Main Methods:
- Creation of a nondissociating disulfide-bonded IL-8 dimer ('trapped' dimer).
- Nuclear Magnetic Resonance (NMR) studies to confirm dimer structure.
- Comparative receptor binding assays using trapped monomer and dimer.
Main Results:
- The trapped IL-8 dimer structure is identical to the native dimer.
- The trapped dimer showed 70-fold lower affinity for CXCR1 and 20-fold lower affinity for CXCR2 compared to the trapped monomer.
- The dimer significantly perturbed N-loop residue binding, unlike the monomer.
Conclusions:
- Only the IL-8 monomer acts as a high-affinity ligand for CXCR1 and CXCR2.
- Dimerization of IL-8 predominantly affects N-loop interactions, leading to reduced receptor binding affinity.
