The monomer-dimer equilibrium and glycosaminoglycan interactions of chemokine CXCL8 regulate tissue-specific neutrophil recruitment

Gangavarapu, Pavani; Rajagopalan, Lavanya; Kolli, Deepthi; Guerrero-Plata, Antonieta; Garofalo, Roberto P.; Rajarathnam, Krishna

doi:10.1189/jlb.0511239

Cited by 74 publications

(116 citation statements)

References 27 publications

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“…Our NMR-derived structural model of the murine CXCL1 dimer-octasaccharide complex shows that GAG binds perpendicularly to the C-terminal helices, is consistent with model II, and completely rules out model III. In model III, GAG is nestled between the helices and does not interact with the 3 10 helix, which contradicts our data and also the binding and functional data for human CXCL8 and murine CXCL2 (28,29,49). Our data are also inconsistent with model I but cannot completely rule it out and require structural studies using heparan sulfate GAGs containing both sulfated (NS) and non-sulfated (NA) domains.…”

Section: Discussioncontrasting

confidence: 56%

“…NACs reversibly exist as monomers, dimers, and/or tetramers, and recent in vivo studies using disulfide-trapped dimers have shown that dimers are highly efficient in recruiting neutrophils. As dimers have a similar or lower receptor activity, the higher recruitment may be due to GAG interactions (5,28). However, the molecular mechanisms by which GAG interactions mediate recruitment are not known because there is a lack of experimental data on the structural architecture of NAC dimer-GAG complexes.…”

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confidence: 99%

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Molecular Basis of Glycosaminoglycan Heparin Binding to the Chemokine CXCL1 Dimer

Poluri

Joseph

Sawant³

et al. 2013

Journal of Biological Chemistry

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Background: Glycosaminoglycan (GAG)-chemokine dimer interactions regulate neutrophil trafficking, but the molecular basis underlying their interactions is not well understood. Results: NMR studies of murine CXCL1 indicate that heparin spans the dimer interface and enhances its structural integrity and stability. Conclusion: Heparin binding modulates multiple structural properties of the chemokine dimer. Significance: This study provides novel structural insights into how chemokine dimers orchestrate neutrophil recruitment.

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Section: Discussioncontrasting

confidence: 56%

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confidence: 99%

Molecular Basis of Glycosaminoglycan Heparin Binding to the Chemokine CXCL1 Dimer

Poluri

Joseph

Sawant³

et al. 2013

Journal of Biological Chemistry

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“…Animal model studies have shown that the ability to reversibly exist as monomers and dimers regulates recruitment (3,4,13). Under conditions of active neutrophil trafficking, the local chemokine concentration could vary by orders of magnitude, and, therefore, in principle, hCXCL1 could exist as monomers, dimers, or both at different times and locations.…”

Section: Discussionmentioning

confidence: 99%

“…A series of HSQC spectra was collected on titrating dp8 and dp14 until essentially no changes in chemical shifts were observed. We used heparin oligosaccharides because they are nearly fully sulfated, are available commercially, and have been shown to capture endogenous interactions (4). Considering that hCXCL1 exists as monomers and dimers (monomer-dimer equilibrium constant, ϳ4 M), we initially characterized binding at low concentrations.…”

Section: Characterization Of Gag-hcxcl1mentioning

confidence: 99%

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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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Syndecans in chronic inflammatory and autoimmune diseases: Pathological insights and therapeutic opportunities

Agere¹,

Kim²,

Akhtar³

et al. 2018

Journal Cellular Physiology

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Syndecans (SDCs) are a family of heparan sulfate proteoglycans (HSPGs) glycoproteins ubiquitously expressed on the cell surfaces and extracellular matrix of all mammalian tissues. There are four mammalian syndecans, SDC-1 thorough 4, which play a critical role in cell adhesion, migration, proliferation, differentiation, and angiogenesis through independent and growth factor mediated signaling. An altered expression of SDCs is often observed in autoimmune disorders, cancer, HIV infection, and many other pathological conditions. SDCs modulate disease progression by interacting with a diverse array of ligands, receptors, and other proteins, including extracellular matrix, glycoproteins, integrins, morphogens, and various growth factors and chemokines, along with their receptors and kinases. Specifically, SDCs present on cell surface can bind directly to chemokines to enhance their binding to receptors, downstream signaling, and migration. Alternatively, SDCs can be cleaved and shed to mediate negative regulation of chemokine and growth factor signaling pathways and ligand sequestration. Importantly, SDC shedding may be a biomarker of inflammation, especially in chronic inflammatory diseases. While the current therapies for cancer and several autoimmune disorders have revolutionized treatment outcomes, understanding the pathophysiological role of SDCs and the use of HSPG mimetic or antagonists on cytokine signaling networks may uncover potentially novel targeted therapeutic approaches. This review mainly summarizes the current findings on the role of individual SDCs in disease processes, mechanisms through which SDCs mediate their biological functions, and the possibility of targeting SDCs as future potential therapeutic approaches.

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The monomer-dimer equilibrium and glycosaminoglycan interactions of chemokine CXCL8 regulate tissue-specific neutrophil recruitment

Cited by 74 publications

References 27 publications

Molecular Basis of Glycosaminoglycan Heparin Binding to the Chemokine CXCL1 Dimer

Molecular Basis of Glycosaminoglycan Heparin Binding to the Chemokine CXCL1 Dimer

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

Syndecans in chronic inflammatory and autoimmune diseases: Pathological insights and therapeutic opportunities

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