title: Differential structural remodelling of heparan sulfate by chemokines: the role of chemokine oligomerization.
abstract: Chemokines control the migration of cells in normal physiological processes and in the context of disease such as inflammation, autoimmunity and cancer. Two major interactions are involved: (i) binding of chemokines to chemokine receptors, which activates the cellular machinery required for movement; and (ii) binding of chemokines to glycosaminoglycans (GAGs), which facilitates the organization of chemokines into haptotactic gradients that direct cell movement. Chemokines can bind and activate their receptors as monomers; however, the ability to oligomerize is critical for the function of many chemokines in vivo Chemokine oligomerization is thought to enhance their affinity for GAGs, and here we show that it significantly affects the ability of chemokines to accumulate on and be retained by heparan sulfate (HS). We also demonstrate that several chemokines differentially rigidify and cross-link HS, thereby affecting HS rigidity and mobility, and that HS cross-linking is significantly enhanced by chemokine oligomerization. These findings suggest that chemokine-GAG interactions may play more diverse biological roles than the traditional paradigms of physical immobilization and establishment of chemokine gradients; we hypothesize that they may promote receptor-independent events such as physical re-organization of the endothelial glycocalyx and extracellular matrix, as well as signalling through proteoglycans to facilitate leukocyte adhesion and transmigration.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0684, USA.|Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Douglas P
authors.identifier: 0000-0001-5567-6241
authors.initials: DP
authors.lastname: Dyer
authors.affiliation: CIC biomaGUNE, 20009 Donostia-San Sebastian, Spain.|Département de Chimie Moléculaire, Université Grenoble Alpes-CNRS, 38041 Grenoble Cedex 9, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Migliorini
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0684, USA.
authors.forename: Catherina L
authors.initials: CL
authors.lastname: Salanga
authors.affiliation: Département de Chimie Moléculaire, Université Grenoble Alpes-CNRS, 38041 Grenoble Cedex 9, France.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Thakar
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0684, USA thandel@ucsd.edu.
authors.forename: Tracy M
authors.identifier: 0000-0002-2558-6138
authors.initials: TM
authors.lastname: Handel
authors.affiliation: CIC biomaGUNE, 20009 Donostia-San Sebastian, Spain r.richter@leeds.ac.uk.|Département de Chimie Moléculaire, Université Grenoble Alpes-CNRS, 38041 Grenoble Cedex 9, France.|School of Biomedical Sciences and School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Ralf P
authors.identifier: 0000-0003-3071-2837
authors.initials: RP
authors.lastname: Richter
mesh_terms: D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D018925:Chemokines / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018925:Chemokines; D006497:Heparan Sulfate; D019707:Receptors, Chemokine
keywords: chemokine; extracellular matrix; glycocalyx; glycosaminoglycan; heparan sulfate; quartz crystal microbalance with dissipation monitoring