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

Barmore, Austin J.; Castex, Sally M.; Gouletas, Brittany A.; Griffith, Alex J.; Metz, Slater W.; Muelder, Nicolas G.; Populin, Michael J.; Sackett, David M.; Schuster, Abigail M.; Veldkamp, Christopher T.

doi:10.1016/j.bbrc.2016.06.098

Cited by 19 publications

(34 citation statements)

References 36 publications

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“…30 Here we show that transfer of the CCL21-tail to CCL19 (CCL19 CCL21-tail ) does not negatively affect CCL19's ability to induce chemotaxis in human DCs, despite the increased surface binding of this chimera to DC surfaces, ruling out that binding to the cell surface per se interferes with chemotaxis. Our finding is consistent with a study by Barmore et al 31 that reveals increased heparin binding by the same chimera, CCL19 CCL21-tail compared to CCL19, which demonstrates that the basic C-terminal tail of CCL21 is enough to confer high GAG affinity. Interestingly, we show here, that CCR7 internalization driven by CCL19 CCL21-tail decreased compared to CCL19 but is not as low as for CCL21, indicating that high GAG affinity somehow has an effect on the ability of CCR7 to internalize.…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, CCL19 and CCL21 only display 32% sequence identity and differ in length with CCL21 encoding a 37 amino acid long C‐terminal tail extension that is lacking in CCL19, giving rise to significant differences in GAG affinity . We have previously shown that CCL21 is captured on the surface of human monocyte derived DCs (moDCs) to a much higher extent than CCL19, a characteristic that is dependent on the basic C‐terminal tail of CCL21.…”

Section: Introductionmentioning

confidence: 99%

“…28 Furthermore, CCL19 and CCL21 only display 32% sequence identity and differ in length with CCL21 encoding a 37 amino acid long C-terminal tail extension that is lacking in CCL19, giving rise to significant differences in GAG affinity. [29][30][31] We have previously shown that CCL21 is captured on the surface of human monocyte derived DCs (moDCs) to a much higher extent than CCL19, a characteristic that is dependent on the basic C-terminal tail of CCL21. This extensive GAG binding is hypothesized to disturb both gradient sensing in three-dimensional (3D) chemotaxis and the immediate availability of the ligand for receptor interaction and signaling.…”

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confidence: 99%

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CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells

Jørgensen

Adogamhe

Laufer

et al. 2018

Journal of Leukocyte Biology

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CCL19 is more potent than CCL21 in inducing chemotaxis of human dendritic cells (DC). This difference is attributed to 1) a stronger interaction of the basic C-terminal tail of CCL21 with acidic glycosaminoglycans (GAGs) in the environment and 2) an autoinhibitory function of this C-terminal tail. Moreover, different receptor docking modes and tissue expression patterns of CCL19 and CCL21 contribute to fine-tuned control of CCR7 signaling. Here, we investigate the effect of the tail of CCL21 on chemokine binding to GAGs and on CCR7 activation. We show that transfer of CCL21-tail to CCL19 (CCL19 ) markedly increases binding of CCL19 to human dendritic cell surfaces, without impairing CCL19-induced intracellular calcium release or DC chemotaxis, although it causes reduced CCR7 internalization. The more potent chemotaxis induced by CCL19 and CCL19 compared to CCL21 is not transferred to CCL21 by replacing its N-terminus with that of CCL19 (CCL21 ). Measurements of cAMP production in CHO cells uncover that CCL21-tail transfer (CCL19 ) negatively affects CCL19 potency, whereas removal of CCL21-tail (CCL21 ) increases signaling compared to full-length CCL21, indicating that the tail negatively affects signaling via cAMP. Similar to chemokine-driven calcium mobilization and chemotaxis, the potency of CCL21 in cAMP is not improved by transfer of the CCL19 N-terminus to CCL21 (CCL21 ). Together these results indicate that ligands containing CCL21 core and C-terminal tail (CCL21 and CCL21 ) are most restricted in their cAMP signaling; a phenotype attributed to a stronger GAG binding of CCL21 and defined structural differences between CCL19 and CCL21.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells

Jørgensen

Adogamhe

Laufer

et al. 2018

Journal of Leukocyte Biology

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“…In addition, full-length CCL21 induced integrin-dependent dendritic cell spreading, polarization and haptotactic movement, whereas CCL21 missing the positively charged COOH-terminus induced non-adhesive and integrin-independent directional migration (218). Interestingly, linking the COOH-terminal tail of CCL21 to the related CCR7 ligand CCL19 enhanced its affinity for heparin (219).…”

Section: Consequences Of Ccl19 and Ccl21 Binding To Glycosaminoglycansmentioning

confidence: 99%

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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“…For example, only CCL19 activation of CCR7 results in receptor internalization and desensitization [ 21 , 42 ]. A truncated version of CCL21, in which CCL21’s unique, glycosaminoglycan-binding C-terminal tail has been proteolytically removed by plasmin, also results in signaling that is unique compared to CCL19 and full length CCL21 [ 43 , 44 , 45 , 46 ]. This ligand bias likely results from different CCR7 conformations in the presence of CCL19 and either full length or truncated CCL21 [ 43 ], but tyrosine sulfation in CCR7 could also be a contributing factor.…”

Section: Discussionmentioning

confidence: 99%

CCR7 Sulfotyrosine Enhances CCL21 Binding

Phillips

Taleski

Koplinski

et al. 2017

IJMS

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Chemokines are secreted proteins that direct the migration of immune cells and are involved in numerous disease states. For example, CCL21 (CC chemokine ligand 21) and CCL19 (CC chemokine ligand 19) recruit antigen-presenting dendritic cells and naïve T-cells to the lymph nodes and are thought to play a role in lymph node metastasis of CCR7 (CC chemokine receptor 7)-expressing cancer cells. For many chemokine receptors, N-terminal posttranslational modifications, particularly the sulfation of tyrosine residues, increases the affinity for chemokine ligands and may contribute to receptor ligand bias. Chemokine sulfotyrosine (sY) binding sites are also potential targets for drug development. In light of the structural similarity between sulfotyrosine and phosphotyrosine (pY), the interactions of CCL21 with peptide fragments of CCR7 containing tyrosine, pY, or sY were compared using protein NMR (nuclear magnetic resonance) spectroscopy in this study. Various N-terminal CCR7 peptides maintain binding site specificity with Y8-, pY8-, or sY8-containing peptides binding near the α-helix, while Y17-, pY17-, and sY17-containing peptides bind near the N-loop and β3-stand of CCL21. All modified CCR7 peptides showed enhanced binding affinity to CCL21, with sY having the largest effect.

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

Cited by 19 publications

References 36 publications

CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells

CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

CCR7 Sulfotyrosine Enhances CCL21 Binding

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