CCR7 Sulfotyrosine Enhances CCL21 Binding

Phillips, Andrew J.; Taleski, Deni; Koplinski, Chad A.; Getschman, Anthony E.; Moussouras, Natasha A.; Richard, Amanda M; Peterson, Francis C.; Dwinell, Michael B.; Volkman, Brian F.; Payne, Richard J.; Veldkamp, Christopher T.

doi:10.3390/ijms18091857

Cited by 22 publications

(38 citation statements)

References 52 publications

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“…It was also reported that de-glycosylation with enzymes produced by DCs changed the folding of CCR7 protein to increase the activity of this receptor (9). Conversely, the induction of sulfation in tyrosine residue of the CCR7 protein N-terminus can increase the affinity between CCR7 and its ligands (72).…”

Section: Epigenetic and Post-translational Modification (Ptm) Of Ccr7mentioning

confidence: 99%

The Roles of CCR7 for the Homing of Memory CD8+ T Cells into Their Survival Niches

2020

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Memory CD8+ T cells in the immune system are responsible for the removal of external Ags for a long period of time to protect against re-infection. Naïve to memory CD8+ T cell differentiation and memory CD8+ T cell maintenance require many different factors including local environmental factors. Thus, it has been suggested that the migration of memory CD8+ T cells into specific microenvironments alters their longevity and functions. In this review, we have summarized the subsets of memory CD8+ T cells based on their migratory capacities and described the niche hypothesis for their survival. In addition, the basic roles of CCR7 in conjunction with the migration of memory CD8+ T cells and recent understandings of their survival niches have been introduced. Finally, the applications of altering CCR7 signaling have been discussed.

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Section: Epigenetic and Post-translational Modification (Ptm) Of Ccr7mentioning

confidence: 99%

The Roles of CCR7 for the Homing of Memory CD8+ T Cells into Their Survival Niches

2020

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“…The binding influences intra-cellular signaling pathways including Janus kinase (JNK), mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). It plays an important role, in addition to chemotaxis, in cell survival, cellular proliferation, and metastatic spread of cancer cells that express CXCL12, leading to the formation of secondary colonies [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], and a particular role in HIV infection has also been discovered. Cancer cell metastasis contributes to most of the mortality rates.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

2020

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CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and in-house databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.

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“…For instance, ubiquitylation of CCR7 has been found to control receptor trafficking and hence cell migration . Tyrosine sulfation in the N‐terminus of CCR7 was recently identified to significantly enhance CCL21 binding . In addition, polysialylation of CCR7 was found to be essential for CCL21 recognition and hence dendritic cell homing to lymph nodes .…”

Section: Introductionmentioning

confidence: 99%

“…12 Tyrosine sulfation in the N-terminus of CCR7 was recently identified to significantly enhance CCL21 binding. 13 In addition, polysialylation of CCR7 was found to be essential for CCL21 recognition and hence dendritic cell homing to lymph nodes. 14 Moreover, we identified that distinct glycosylation patterns on CCR7's N-terminus and third extracellular loop shape receptor signaling and endocytosis to control leukocyte migration by CCL19 and CCL21.…”

mentioning

confidence: 99%

A unique signal sequence of the chemokine receptor CCR7 promotes package into COPII vesicles for efficient receptor trafficking

Allmen

Rippl

Farhan

et al. 2018

Journal of Leukocyte Biology

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Chemokine receptors are considered to belong to the group of G protein-coupled receptors that use the first transmembrane domain as signal anchor sequence for membrane insertion instead of a cleavable N-terminal signal sequence. Chemokine recognition is determined by the N-termini of chemokine receptors. Here, we show that the chemokine receptor CCR7, which is essential for directed migration of adaptive immune cells, possesses a 24 amino acids long N-terminal signal sequence that is unique among chemokine receptors. This sequence is cleaved off the mature human and mouse protein. Introducing single point mutations in the hydrophobic core h-region or in the polar C-terminal segment (c-region) of the signal sequence to interfere with its cleavage retained CCR7 in the ER and prevented its surface expression. Furthermore, we demonstrate the correct topology of the 35 amino acids short extracellular N-tail of CCR7 in a deletion mutant lacking the natural signal sequence. This signal sequence deletion mutant of CCR7 is fully functional as it efficiently binds its ligand, elicits chemokine-induced calcium mobilization, and directs cell migration. However, we show that the signal sequence promotes efficient recruitment of the GPCR to ER exit sites, thereby controlling efficient ER to Golgi trafficking of CCR7 on its way to reach the plasma membrane.

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CCR7 Sulfotyrosine Enhances CCL21 Binding

Cited by 22 publications

References 52 publications

The Roles of CCR7 for the Homing of Memory CD8+ T Cells into Their Survival Niches

The Roles of CCR7 for the Homing of Memory CD8+ T Cells into Their Survival Niches

Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

A unique signal sequence of the chemokine receptor CCR7 promotes package into COPII vesicles for efficient receptor trafficking

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