Cytokines and growth factors cross-link heparan sulfate

Author:

Migliorini Elisa123,Thakar Dhruv12,Kühnle Jens4,Sadir Rabia567,Dyer Douglas P.8,Li Yong9,Sun Changye9,Volkman Brian F.10,Handel Tracy M.8,Coche-Guerente Liliane12,Fernig David G.9,Lortat-Jacob Hugues567,Richter Ralf P.12311ORCID

Affiliation:

1. Université Grenoble Alpes, Departement de Chimie Moléculaire (DCM), Grenoble, France

2. CNRS, DCM, Grenoble, France

3. CIC biomaGUNE, San Sebastian, Spain

4. Department of Biophysical Chemistry, University of Heidelberg, Heidelberg, Germany

5. Université Grenoble Alpes, Institut de Biologie Structurale (IBS), Grenoble, France

6. CNRS, IBS, Grenoble, France

7. CEA, IBS, Grenoble, France

8. University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA

9. Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK

10. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA

11. Max Planck Institute for Intelligent Systems, Stuttgart, Germany

Abstract

The glycosaminoglycan heparan sulfate (HS), present at the surface of most cells and ubiquitous in extracellular matrix, binds many soluble extracellular signalling molecules such as chemokines and growth factors, and regulates their transport and effector functions. It is, however, unknown whether upon binding HS these proteins can affect the long-range structure of HS. To test this idea, we interrogated a supramolecular model system, in which HS chains grafted to streptavidin-functionalized oligoethylene glycol monolayers or supported lipid bilayers mimic the HS-rich pericellular or extracellular matrix, with the biophysical techniques quartz crystal microbalance (QCM-D) and fluorescence recovery after photobleaching (FRAP). We were able to control and characterize the supramolecular presentation of HS chains—their local density, orientation, conformation and lateral mobility—and their interaction with proteins. The chemokine CXCL12 α (or SDF-1 α ) rigidified the HS film, and this effect was due to protein-mediated cross-linking of HS chains. Complementary measurements with CXCL12 α mutants and the CXCL12 γ isoform provided insight into the molecular mechanism underlying cross-linking. Fibroblast growth factor 2 (FGF-2), which has three HS binding sites, was also found to cross-link HS, but FGF-9, which has just one binding site, did not. Based on these data, we propose that the ability to cross-link HS is a generic feature of many cytokines and growth factors, which depends on the architecture of their HS binding sites. The ability to change matrix organization and physico-chemical properties (e.g. permeability and rigidification) implies that the functions of cytokines and growth factors may not simply be confined to the activation of cognate cellular receptors.

Publisher

The Royal Society

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology,General Neuroscience

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