Solution NMR characterization of chemokine CXCL8/IL-8 monomer and dimer binding to glycosaminoglycans: structural plasticity mediates differential binding interactions
| Autor: | Philip D. Mosier, Prem Raj B. Joseph, Krishna Rajarathnam, Umesh R. Desai |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Magnetic Resonance Spectroscopy
nuclear magnetic resonance (NMR) Stereochemistry Dimer Molecular Sequence Data Oligosaccharides Iduronic acid Molecular Dynamics Simulation Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine glycosaminoglycan (GAG) medicine Humans Amino Acid Sequence Binding site Molecular Biology Research Articles Glycosaminoglycans 030304 developmental biology 0303 health sciences Binding Sites Sequence Homology Amino Acid Heparin Chemistry chemokine Interleukin-8 Cell Biology Heparan sulfate Nuclear magnetic resonance spectroscopy structural plasticity Protein Structure Tertiary 3. Good health Molecular Docking Simulation Solutions Kinetics Monomer Docking (molecular) 030220 oncology & carcinogenesis Protein Multimerization structure–function study Research Article Protein Binding medicine.drug |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | Structural plasticity plays a major role in determining differential binding of CXCL8 monomer and dimer to glycosaminoglycans (GAGs) and that dimer is the high-affinity GAG ligand. We propose that these properties play important roles in orchestrating in vivo chemokine-mediated neutrophil function. 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. |
| Databáze: | OpenAIRE |
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