Cytokines and growth factors cross-link heparan sulfate

Migliorini, Elisa; Thakar, Dhruv; Kühnle, Jens; Sadir, Rabia; Dyer, Douglas P.; Li, Yong; Sun, Changye; Volkman, Brian F.; Handel, Tracy M.; Coche-Guérente, Liliane; Fernig, David G.; Lortat‐Jacob, Hugues; Richter, Ralf P.

doi:10.1098/rsob.150046

Cited by 61 publications

(82 citation statements)

References 63 publications

(140 reference statements)

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“…51 Comparative assays with b-SLBs (“fluid surface”) and b-SAMs (“immobile surface”), therefore, enable us to evaluate the effect of biotin lateral mobility. SLBs and SAMs were designed to display biotin at tunable surface densities (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, assuming l b < 100 nm and a lipid diffusion constant D lipid > 1 μm 2 /s, 51 the time needed for lipids to diffuse over an area of l b 2 is roughly l b 2 / D lipid < 10 –2 s. This implies that two biotins will get close to each other within a few milliseconds, which is much shorter than the time scale of the SAv binding process (seconds to minutes, Figure 6A).…”

Section: Discussionmentioning

confidence: 96%

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Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin

et al. 2017

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Although multivalent binding to surfaces is an important tool in nanotechnology, quantitative information about the residual valency and orientation of surface-bound molecules is missing. To address these questions, we study streptavidin (SAv) binding to commonly used biotinylated surfaces such as supported lipid bilayers (SLBs) and self-assembled monolayers (SAMs). Stability and kinetics of SAv binding are characterized by quartz crystal microbalance with dissipation monitoring, while the residual valency of immobilized SAv is quantified using spectroscopic ellipsometry by monitoring binding of biotinylated probes. Purpose-designed SAv constructs having controlled valencies (mono-, di-, trivalent in terms of biotin-binding sites) are studied to rationalize the results obtained on regular (tetravalent) SAv. We find that divalent interaction of SAv with biotinylated surfaces is a strict requirement for stable immobilization, while monovalent attachment is reversible and, in the case of SLBs, leads to the extraction of biotinylated lipids from the bilayer. The surface density and lateral mobility of biotin, and the SAv surface coverage are all found to influence the average orientation and residual valency of SAv on a biotinylated surface. We demonstrate how the residual valency can be adjusted to one or two biotin binding sites per immobilized SAv by choosing appropriate surface chemistry. The obtained results provide means for the rational design of surface-confined supramolecular architectures involving specific biointeractions at tunable valency. This knowledge can be used for the development of well-defined bioactive coatings, biosensors and biomimetic model systems.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin

et al. 2017

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“…Proteoglycans can have multiple GAG chains, and it may be that initial binding to one GAG chain promotes binding to the second GAG chain because of spatial proximity on the cell surface (Fig. 10C) (34).…”

Section: Discussionmentioning

confidence: 99%

CXCL1/MGSA Is a Novel Glycosaminoglycan (GAG)-binding Chemokine

Sepuru

Rajarathnam

2016

Journal of Biological Chemistry

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In humans, the chemokine CXCL1/MGSA (hCXCL1) plays fundamental and diverse roles in pathophysiology, from microbial killing to cancer progression, by orchestrating the directed migration of immune and non-immune cells. Cellular trafficking is highly regulated and requires concentration gradients that are achieved by interactions with sulfated glycosaminoglycans (GAGs). However, very little is known regarding the structural basis underlying hCXCL1-GAG interactions. We addressed this by characterizing the binding of GAG heparin oligosaccharides to hCXCL1 using NMR spectroscopy. Binding experiments under conditions at which hCXCL1 exists as monomers and dimers indicate that the dimer is the high-affinity GAG ligand. NMR experiments and modeling studies indicate that lysine and arginine residues mediate binding and that they are located in two non-overlapping domains. One domain, consisting of N-loop and C-helical residues (defined as ␣-domain) has also been identified previously as the GAG-binding domain for the related chemokine CXCL8/IL-8. The second domain, consisting of residues from the N terminus, 40s turn, and third ␤-strand (defined as ␤-domain) is novel. Eliminating ␤-domain binding by mutagenesis does not perturb ␣-domain binding, indicating two independent GAG-binding sites. It is known that N-loop and N-terminal residues mediate receptor activation, and we show that these residues are also involved in extensive GAG interactions. We also show that the GAG-bound hCXCL1 completely occlude receptor binding. We conclude that hCXCL1-GAG interactions provide stringent control over regulating chemokine levels and receptor accessibility and activation, and that chemotactic gradients mediate cellular trafficking to the target site.Chemokines, a large family of small soluble proteins, are highly versatile and play fundamental roles in diverse functions, from combating infection and initiating tissue repair to regulating metabolism and organ development (1, 2). Common to these various functions is the directed movement of various cell types to distal and remote locations. Cellular trafficking must be highly coordinated to elicit the required biological function, and its dysregulation could be detrimental, resulting in disease. There is now increasing evidence that the ability of a chemokine to reversibly exist as monomers and dimers and binding glycosaminoglycans is coupled and plays important roles in mediating these functions (3, 4).Glycosaminoglycans (GAGs) 2 such as heparan sulfate (HS) are highly sulfated polysaccharides. They are expressed ubiquitously by many cell types, are anchored to the cell surface by covalent attachment to membrane proteins, and form non-covalent complexes with proteins in the extracellular matrix (5-7). Animal models and cellular studies have established that GAG interactions dictate chemokine concentration gradients and that these gradients orchestrate cellular trafficking (8 -10). GAGs are acidic, and chemokines are basic or contain clusters of basic residues, indicating that electr...

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“…As cells migrate toward areas of higher extracellular matrix rigidity, GAGs likely contribute by promoting oriented cell migration through regulating substrate rigidity. Interestingly, using biophysical techniques, such as quartz crystal microbalance and fluorescence recovery after photobleaching, various HS-binding cytokines, including chemokines, rigidify HS and that this effect, which depends on the architecture of the chemokines' HS-binding sites, was due to protein cross-linking of the GAG chains [160]. The ability of chemokines to physically change matrix organization and mechanical properties suggests that the functions of chemokines may not be restricted simply to cellular receptor activation.…”

Section: Mechanical Forces and Durotaxismentioning

confidence: 99%

The sweet spot: how GAGs help chemokines guide migrating cells

Monneau

Arenzana-Seisdedos

Lortat‐Jacob

2015

Journal of Leukocyte Biology

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115

113

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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.

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Cytokines and growth factors cross-link heparan sulfate

Cited by 61 publications

References 63 publications

Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin

Controlling Multivalent Binding through Surface Chemistry: Model Study on Streptavidin

CXCL1/MGSA Is a Novel Glycosaminoglycan (GAG)-binding Chemokine

The sweet spot: how GAGs help chemokines guide migrating cells

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