Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands

Deshauer, Courtney; Morgan, Ashli; Ryan, Eathen; Handel, Tracy M.; Prestegard, James H.; Wang, Xu

doi:10.1016/j.str.2015.03.024

Cited by 37 publications

(49 citation statements)

References 42 publications

(72 reference statements)

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“…For example, rigidification of matrix could alter cell phenotype through changes in mechanical sensing 80–82 . The structural reorganization of CS could also modulate the binding of matrix-associated signaling molecules, such as the chemokine CCL5 83 ; interestingly, TSG-6 binds to CCL5 84 as well as CS, and therefore may be able to interfere with its presentation (e.g. on endothelial cells).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Magnetic Resonance Insight into the Multiple Glycosaminoglycan Binding Modes of the Link Module from Human TSG-6

et al. 2016

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Tumor necrosis factor-stimulated gene-6 (TSG-6) is a hyaluronan (HA) binding protein that is essential for stabilizing and remodelling the extracellular matrix (ECM) during ovulation and inflammatory disease processes such as arthritis. The Link module, one of the domains of TSG-6, is responsible for binding hyaluronan and other glycosaminoglycans (GAGs) found in the ECM. In this study, we used a well-defined chondroitin sulfate (CS) hexasaccharide (ΔC444S) to determine the structure of the Link module, in solution, in its chondroitin sulfate bound state. A variety of NMR techniques were employed, including chemical shift perturbation, residual dipolar couplings (RDCs), NOEs, spin relaxation measurements, and paramagnetic relaxation enhancements (PREs) from a spin-labeled analog of ΔC444S. The binding site for ΔC444S on the Link module overlapped with that of HA. Surprisingly, ΔC444S binding induced dimerization of the Link module (as confirmed by analytical ultracentrifugation), and a second weak binding site that partially overlapped with a previously identified heparin site was detected. A dimer model was generated using chemical shift perturbations and RDCs as restraints in the docking program HADDOCK. We postulate that the molecular cross-linking enhanced by the multiple binding modes of the Link module may be critical for remodeling the ECM during inflammation/ovulation and may contribute to other functions of TSG-6.

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Section: Discussionmentioning

confidence: 99%

Nuclear Magnetic Resonance Insight into the Multiple Glycosaminoglycan Binding Modes of the Link Module from Human TSG-6

et al. 2016

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“…This means that no single GAG-binding conformation can simultaneously account for all perturbations. The sulfation pattern heterogeneity in the CSE dp6 sample, which is known to result in heterogeneous binding orientations in protein-GAG interactions [40], is a possible explanation for this observation. In the NTD, although only side chains of NTD residues (residues Q51, W18 and W20) showed significant PRE, backbone HN atoms of NTD residues, with the exception of K54, are only lightly perturbed, which is consistent with the lower GAG affinity of NTD.…”

Section: Determining Cs-binding Site Of Ptn Using Paramagnetic Cse Anmentioning

confidence: 95%

Structural studies reveal an important role for the pleiotrophin C‐terminus in mediating interactions with chondroitin sulfate

2016

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Pleiotrophin (PTN) is a potent glycosaminoglycan-binding cytokine important in neural development, angiogenesis and tissue regeneration. Much of its activity is attributed to its interactions with the chondroitin sulfate (CS) proteoglycan, receptor type protein tyrosine phosphatase ζ (PTPRZ). However, there is little high resolution structural information on interactions between PTN and CS, nor is it clear why the C-terminal tail of PTN is necessary for signaling through PTPRZ even though it does not contribute to binding heparin. We determined the first structure of PTN and analyzed its interactions with CS. Our structure shows PTN possesses large basic surfaces on both of its structured domains and residues in the hinge segment connecting the domains have significant contacts with the C-terminal domain. Our analysis of PTN-CS interactions showed the C-terminal tail of PTN is essential for maintaining stable interactions with CSA, the type of CS commonly found on PTPRZ. These results offer the first possible explanation of why truncated PTN missing the C-terminal tail is unable to signal through PTPRZ. NMR analysis of PTN’s interactions with CS revealed that the C-terminal domain and hinge of PTN make up the major CS binding site in PTN, and that removal of the C-terminal tail weakened the site’s affinity for CSA, but not for other high sulfation density CS.

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“…The bound GAG bulk exchanges with the free GAG, and thereby, signal attenuation is transferred. The differences between 1-dimensional [ 1 H] spectra, with or without irradiation, allow for the determination of which protons of the GAG molecule are tightly involved in binding [131,132]. CSP analysis of GAGs, upon binding to chemokines, can also be used as long as [ 13 C]-labeled GAG is available.…”

Section: The Structures Recognized By Chemokinesmentioning

confidence: 99%

“…Recently, however, the NMR structures of a dimeric CCL5 mutant E66S, in complex with CS-derived hexasaccharides were reported [131]. Thanks to the relatively simple sulfation pattern of CS (compared to that of HS), 2 well-defined hexasaccharides were prepared from natural sources by partial depolymerization.…”

Section: The 3d Structures Of Chemokine-gag Complexesmentioning

confidence: 99%

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The sweet spot: how GAGs help chemokines guide migrating cells

Monneau

Arenzana-Seisdedos

Lortat‐Jacob

2015

Journal of Leukocyte Biology

112

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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Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands

Cited by 37 publications

References 42 publications

Nuclear Magnetic Resonance Insight into the Multiple Glycosaminoglycan Binding Modes of the Link Module from Human TSG-6

Nuclear Magnetic Resonance Insight into the Multiple Glycosaminoglycan Binding Modes of the Link Module from Human TSG-6

Structural studies reveal an important role for the pleiotrophin C‐terminus in mediating interactions with chondroitin sulfate

The sweet spot: how GAGs help chemokines guide migrating cells

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