Cytokines and growth factors cross-link heparan sulfate. Open Biol 2015 Aug;5(8)
Date
08/14/2015Pubmed ID
26269427Pubmed Central ID
PMC4554917DOI
10.1098/rsob.150046Scopus ID
2-s2.0-84942437037 (requires institutional sign-in at Scopus site) 55 CitationsAbstract
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 CXCL12α (or SDF-1α) rigidified the HS film, and this effect was due to protein-mediated cross-linking of HS chains. Complementary measurements with CXCL12α mutants and the CXCL12γ 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.
Author List
Migliorini E, Thakar D, Kühnle J, Sadir R, Dyer DP, Li Y, Sun C, Volkman BF, Handel TM, Coche-Guerente L, Fernig DG, Lortat-Jacob H, Richter RPAuthor
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Chemokine CXCL12Cytokines
Extracellular Matrix
Glycosaminoglycans
Heparitin Sulfate
Humans
Intercellular Signaling Peptides and Proteins
Models, Molecular
Molecular Conformation
Protein Binding
