Solution NMR characterization of chemokine CXCL8/IL-8 monomer and dimer binding to glycosaminoglycans: Structural plasticity mediates differential binding interactions

Prem Raj B Joseph, Philip D. Mosier, Umesh R. Desai, Krishna Rajarathnam

    Research output: Contribution to journalArticle

    50 Scopus citations

    Abstract

    Chemokine CXCL8/interleukin-8 (IL-8) plays a crucial role in directing neutrophils and oligodendrocytes to combat infection/injury and tumour cells in metastasis development. CXCL8 exists as monomers and dimers and interaction of both forms with glycosaminoglycans (GAGs) mediate these diverse cellular processes. However, very little is known regarding the structural basis underlying CXCL8-GAG interactions. There are conflicting reports on the affinities, geometry and whether the monomer or dimer is the high-affinity GAG ligand. To resolve these issues, we characterized the binding of a series of heparin-derived oligosaccharides [heparin disaccharide (dp2), heparin tetrasaccharide (dp4), heparin octasaccharide (dp8) and heparin 14-mer (dp14)] to the wild-type (WT) dimer and a designed monomer using solution NMR spectroscopy. The pattern and extent of binding-induced chemical shift perturbation (CSP) varied between dimer and monomer and between longer and shorter oligosaccharides. NMR-based structural models show that different interaction modes coexist and that the nature of interactions varied between monomer and dimer and oligosaccharide length. MD simulations indicate that the binding interface is structurally plastic and provided residue-specific details of the dynamic nature of the binding interface. Binding studies carried out under conditions at which WT CXCL8 exists as monomers and dimers provide unambiguous evidence that the dimer is the high-affinity GAG ligand. Together, our data indicate that a set of core residues function as the major recognition/binding site, a set of peripheral residues define the various binding geometries and that the structural plasticity of the binding interface allows multiplicity of binding interactions. We conclude that structural plasticity most probably regulates in vivo CXCL8 monomer/dimer-GAG interactions and function.

    Original languageEnglish (US)
    Pages (from-to)121-133
    Number of pages13
    JournalBiochemical Journal
    Volume472
    Issue number1
    DOIs
    StatePublished - Nov 15 2015

    Keywords

    • Chemokine
    • Glycosaminoglycan (GAG)
    • Heparin
    • Nuclear magnetic resonance (NMR)
    • Structural plasticity
    • Structure-function study

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology
    • Molecular Biology

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