The sweet spot: how GAGs help chemokines guide migrating cells

Abstract

Glycosaminoglycans are polysaccharides that occur both at the cell surface and within extracellular matrices. Through their ability to bind to a large array of proteins, almost 500 of which have been identified to date, including most chemokines, these molecules regulate key biologic processes at the cell-tissue interface. To do so, glycosaminoglycans can provide scaffolds to ensure that proteins mediating specific functions will be presented at the correct site and time and can also directly contribute to biologic activities or signaling processes. The binding of chemokines to glycosaminoglycans, which, at the biochemical level, has been mostly studied using heparin, has traditionally been thought of as a mechanism for maintaining haptotactic gradients within tissues along which cells can migrate directionally. Many aspects of chemokine-glycosaminoglycan interactions, however, also suggest that the formation of these complexes could serve additional purposes that go well beyond a simple immobilization process. In addition, progress in glycobiology has revealed that glycosaminoglycan structures, in term of length, sulfation, and epimerization pattern, are specific for cell, tissue, and developmental stage. Glycosaminoglycan regulation and glycosaminoglycan diversity, which cannot be replicated using heparin, thus suggests that these molecules may fine-tune the immune response by selectively recruiting specific chemokines to cell surfaces. In this context, the aim of the present text is to review the chemokine-glycosaminoglycan complexes described to date and provide a critical analysis of the tools, molecules, and strategies that can be used to structurally and functionally investigate the formation of these complexes.

Transferring the C-terminus of the chemokine CCL21 to CCL19 confers enhanced heparin binding

“…[30]. Heparin is often used when studying chemokine GAG interactions [15], but longer chain heparin and chemokine complexes are not conducive to structural studies using protein NMR [25]. Hence, heparin disaccharide I-S, representing the smallest repeating subunit of heparin, was chosen to investigate the interaction of CCL21 with heparin.…”

“…Subsequent investigations into CCL21’s limited specificity for heparin, or potentially other GAGs, must involve investigating CCL21 mutants in the context of GAGs with various sulfation and epimerization patterns [15]. This may be a difficult task as reduced sulfation inherently means a reduction in negative charge making parsing out changes in binding affinity that equate to loss of specific interactions versus generic electrostatic interactions challenging.…”

“…Chemokines orchestrate cell trafficking through activating cellular chemokine receptors and through GAG binding [1, 15], an interaction that is required for in vivo recruitment of cells by chemokines [16]. GAG binding, as was shown for CCL21, allows for the formation of a stationary chemokine concentration gradient that migrating cells follow through haptotaxis [17].…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…They are usually associated with cellular mechanisms involving cell–cell and cell–matrix interactions, immune response, and signal transduction [2, 3]. It is estimated that more than 50% of human proteins have a carbohydrate portion, and that this process represents one of the most important protein post-translational modifications [4, 5].…”

Binding of the chemokine CXCL12α to its natural extracellular matrix ligand heparan sulfate enables myoblast adhesion and facilitates cell motility

“…GAGs bind to a plethora of proteins, including chemokines, and via these interactions, regulate matrix assembly and remodelling, as well as cell-matrix and cell-cell interactions [17]. The interaction between GAGs and chemokines is reversible and chemokines retain a certain degree of mobility in the ECM: by binding chemokines, GAGs help organizing and maintaining extracellular gradients of chemokines, thus providing directional cues for migrating cells [18][19][20][21][22]. Even though the functional importance of HS as an ECM ligand for chemokines is well established, the effects that the presentation of CXCL12 chemokines through HS has on the recognition of chemokines by the cells and the ensuing cellular responses such as spreading and migration has not been studied in detail.…”