Chemokine CXCL7 Heterodimers: Structural Insights, CXCR2 Receptor Function, and Glycosaminoglycan Interactions

Brown, Aaron J.; Joseph, Prem Raj B.; Sawant, Kirti V.; Rajarathnam, Krishna

doi:10.3390/ijms18040748

Cited by 30 publications

(54 citation statements)

References 64 publications

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“…In addition, it is known that CXCL7 forms heterodimers with other chemokines, e.g., CXCL1. This CXCL1/CXCL7 heterodimer interacts differently with GAGs compared to the CXCL7 monomer and the GAG-bound heterodimer cannot interact with the receptor (178). These data suggest that GAG interactions play a prominent role in determining heterodimer function in vivo.…”

Section: Consequences Of Cxcl5 and Cxcl7 Binding To Glycosaminoglycansmentioning

confidence: 87%

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

2020

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Leukocyte migration into tissues depends on the activity of chemokines that form concentration gradients to guide leukocytes to a specific site. Interaction of chemokines with their specific G protein-coupled receptors (GPCRs) on leukocytes induces leukocyte adhesion to the endothelial cells, followed by extravasation of the leukocytes and subsequent directed migration along the chemotactic gradient. Interaction of chemokines with glycosaminoglycans (GAGs) is crucial for extravasation in vivo. Chemokines need to interact with GAGs on endothelial cells and in the extracellular matrix in tissues in order to be presented on the endothelium of blood vessels and to create a concentration gradient. Local chemokine retention establishes a chemokine gradient and prevents diffusion and degradation. During the last two decades, research aiming at reducing chemokine activity mainly focused on the identification of inhibitors of the interaction between chemokines and their cognate GPCRs. This approach only resulted in limited success. However, an alternative strategy, targeting chemokine-GAG interactions, may be a promising approach to inhibit chemokine activity and inflammation. On this line, proteins derived from viruses and parasites that bind chemokines or GAGs may have the potential to interfere with chemokine-GAG interactions. Alternatively, chemokine mimetics, including truncated chemokines and mutant chemokines, can compete with chemokines for binding to GAGs. Such truncated or mutated chemokines are characterized by a strong binding affinity for GAGs and abrogated binding to their chemokine receptors. Finally, Spiegelmers that mask the GAG-binding site on chemokines, thereby preventing chemokine-GAG interactions, were developed. In this review, the importance of GAGs for chemokine activity in vivo and strategies that could be employed to target chemokine-GAG interactions will be discussed in the context of inflammation.

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Section: Consequences Of Cxcl5 and Cxcl7 Binding To Glycosaminoglycansmentioning

confidence: 87%

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

2020

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“…Our future studies will address the relationship between dimer-tetramer equilibrium and GAG interactions. Recent studies have shown CXCL7 forms heterodimers with other platelet-derived chemokines ( 6 – 8 , 49 , 50 ), and that the heterodimer binds GAG with high affinity suggesting GAG interactions of both homodimers and heterodimers could regulate function.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk

et al. 2017

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Platelet-derived chemokine CXCL7 (also known as NAP-2) plays a crucial role in orchestrating neutrophil recruitment in response to vascular injury. CXCL7 exerts its function by activating the CXC chemokine receptor 2 (CXCR2) receptor and binding sulfated glycosaminoglycans (GAGs) that regulate receptor activity. CXCL7 exists as monomers, dimers, and tetramers, and previous studies have shown that the monomer dominates at lower and the tetramer at higher concentrations. These observations then raise the question: what, if any, is the role of the dimer? In this study, we make a compelling observation that the dimer is actually the favored form in the GAG-bound state. Further, we successfully characterized the structural basis of dimer binding to GAG heparin using solution nuclear magnetic resonance (NMR) spectroscopy. The chemical shift assignments were obtained by exploiting heparin binding-induced NMR spectral changes in the WT monomer and dimer and also using a disulfide-linked obligate dimer. We observe that the receptor interactions of the dimer are similar to the monomer and that heparin-bound dimer is occluded from receptor interactions. Cellular assays also show that the heparin-bound CXCL7 is impaired for CXCR2 activity. We conclude that the dimer–GAG interactions play an important role in neutrophil–platelet crosstalk, and that these interactions regulate gradient formation and the availability of the free monomer for CXCR2 activation and intrathrombus neutrophil migration to the injury site.

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“…There is evidence that GAG binding is also driven by H-bonding interactions mediated by polar residues such as asparagine (Asn) and glutamine (Gln) (98,99). NMR and MD studies of several ELR chemokines suggest Asn and Gln are involved in GAG interactions (54,100). Considering these residues form weak H-bonds compared to lysines and arginines, the impact of mutating these residues on affinity, geometry, and neutrophil trafficking should give definitive insights into whether they play a role in defining specificity or affinity or both.…”

Section: Future Directions and Challengesmentioning

confidence: 99%

Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges

Rajarathnam

Desai

2020

Front. Immunol.

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Proteoglycans (PGs), present in diverse environments, such as the cell membrane surface, extracellular milieu, and intracellular granules, are fundamental to life. Sulfated glycosaminoglycans (GAGs) are covalently attached to the core protein of proteoglycans. PGs are complex structures, and are diverse in terms of amino acid sequence, size, shape, and in the nature and number of attached GAG chains, and this diversity is further compounded by the phenomenal diversity in GAG structures. Chemokines play vital roles in human pathophysiology, from combating infection and cancer to leukocyte trafficking, immune surveillance, and neurobiology. Chemokines mediate their function by activating receptors that belong to the GPCR class, and receptor interactions are regulated by how, when, and where chemokines bind GAGs. GAGs fine-tune chemokine function by regulating monomer/dimer levels and chemotactic/haptotactic gradients, which are also coupled to how they are presented to their receptors. Despite their small size and similar structures, chemokines show a range of GAG-binding geometries, affinities, and specificities, indicating that chemokines have evolved to exploit the repertoire of chemical and structural features of GAGs. In this review, we summarize the current status of research on how GAG interactions regulate ELR-chemokine activation of CXCR1 and CXCR2 receptors, and discuss knowledge gaps that must be overcome to establish causal relationships governing the impact of GAG interactions on chemokine function in human health and disease.

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Chemokine CXCL7 Heterodimers: Structural Insights, CXCR2 Receptor Function, and Glycosaminoglycan Interactions

Cited by 30 publications

References 64 publications

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk

Structural Insights Into How Proteoglycans Determine Chemokine-CXCR1/CXCR2 Interactions: Progress and Challenges

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