Editors' ChoiceStructural Biology

Dimeric Chemokine May Be an Inhibitor

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Science's STKE  31 Aug 2004:
Vol. 2004, Issue 248, pp. tw307
DOI: 10.1126/stke.2482004tw307

Chemokines are peptide ligands that activate G protein-coupled receptors and that bind glycosaminoglycans (GAGs) on the cell surface. Through these two interactions, chemokines participate in leukocyte migration and inflammatory signaling. Although studies of crystals and solution structures indicate that chemokines are dimers, various experiments with monomeric interleukin 8 (IL-8) suggest that the monomer may activate its GPCR, CXCR1. Fernando et al. provide in vitro evidence from isothermal titration calorimetry (ITC) and sedimentation equilibrium studies that IL-8 interacts with the N-terminal domain of CXCR1 (site 1) as a monomer. Sedimentation equilibration experiments showed a 1:1 stoichiometry and suggested that the dimeric IL-8 in solution must dissociate to bind the receptor peptide. ITC experiments supported the conclusion that the ligand dimer dissociated and then IL-8 bound to the receptor as a monomer. The authors propose that the dimeric IL-8 serves as a negative regulator for GPCR activation, whereas the dimeric form is known to be the form that binds GAGs. Thus, the oligomeric state of IL-8 serves to control its relative activity toward the GPCR and GAGs, allowing different cellular effects at different ligand concentrations.

H. Fernando, C. Chin, J. Rosgen, K. Rajarathnam, Dimer dissociation is essential for interleukin-8 (IL-8) binding to CXCR1 receptor. J. Biol. Chem. 279, 36175-36178 (2004). [Abstract] [Full Text]

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