The C-terminal peptide of CCL21 drastically augments CCL21 activity through the dendritic cell lymph node homing receptor CCR7 by interaction with the receptor N-terminus

The endogenous chemokines CCL19 and CCL21 signal via their common receptor CCR7. CCL21 is the main lymph node homing chemokine, but a weak chemo-attractant compared to CCL19. Here we show that the 41-amino acid positively charged peptide, released through C-terminal cleavage of CCL21, C21TP, boosts...

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Published in:	Cellular and molecular life sciences : CMLS Vol. 78; no. 21-22; pp. 6963 - 6978
Main Authors:	Jørgensen, Astrid Sissel, Brandum, Emma Probst, Mikkelsen, Jeppe Malthe, Orfin, Klaudia A., Boilesen, Ditte Rahbæk, Egerod, Kristoffer Lihme, Moussouras, Natasha A., Vilhardt, Frederik, Kalinski, Pawel, Basse, Per, Chen, Yen-Hsi, Yang, Zhang, Dwinell, Michael B., Volkman, Brian F., Veldkamp, Christopher T., Holst, Peter Johannes, Lahl, Katharina, Goth, Christoffer Knak, Rosenkilde, Mette Marie, Hjortø, Gertrud Malene
Format:	Journal Article
Language:	English
Published:	Cham Springer International Publishing 01-11-2021 Springer Nature B.V
Subjects:	Amino acids Animals Basic Medicine Binding Biochemistry Biochemistry and Molecular Biology Biokemi och molekylärbiologi Biologi Biological Sciences Biomedical and Life Sciences Biomedicine CC chemokine receptors CCL19 protein CCL21 protein CCR7 CCR7 protein Cell Biology Cell surface Cells, Cultured Channel gating Chemokine Chemokine CCL21 - metabolism Chemokines CHO Cells Cricetulus Dendritic cell Dendritic cells Dendritic Cells - metabolism Electrostatic properties Glycosaminoglycans Glycosylation Homing Humans Immune system Immunologi inom det medicinska området Immunology in the medical area Life Sciences Ligands Lymph nodes Lymph Nodes - metabolism Lymphatic system Medical and Health Sciences Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper N-Terminus Natural Sciences Naturvetenskap Original Original Article Peptide Peptides Peptides - metabolism Polysaccharides Protein Binding - physiology Receptors Receptors, CCR7 - metabolism Receptors, Lymphocyte Homing - metabolism Signal Transduction - physiology Signaling Static Electricity Chemokine Dendritic cell CCR7 Glycosylation Peptide
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Summary:	The endogenous chemokines CCL19 and CCL21 signal via their common receptor CCR7. CCL21 is the main lymph node homing chemokine, but a weak chemo-attractant compared to CCL19. Here we show that the 41-amino acid positively charged peptide, released through C-terminal cleavage of CCL21, C21TP, boosts the immune cell recruiting activity of CCL21 by up to 25-fold and the signaling activity via CCR7 by ~ 100-fold. Such boosting is unprecedented. Despite the presence of multiple basic glycosaminoglycan (GAG) binding motifs, C21TP boosting of CCL21 signaling does not involve interference with GAG mediated cell-surface retention. Instead, boosting is directly dependent on O -glycosylations in the CCR7 N-terminus. As dictated by the two-step binding model, the initial chemokine binding involves interaction of the chemokine fold with the receptor N-terminus, followed by insertion of the chemokine N-terminus deep into the receptor binding pocket. Our data suggest that apart from a role in initial chemokine binding, the receptor N-terminus also partakes in a gating mechanism, which could give rise to a reduced ligand activity, presumably through affecting the ligand positioning. Based on experiments that support a direct interaction of C21TP with the glycosylated CCR7 N-terminus, we propose that electrostatic interactions between the positively charged peptide and sialylated O -glycans in CCR7 N-terminus may create a more accessible version of the receptor and thus guide chemokine docking to generate a more favorable chemokine-receptor interaction, giving rise to the peptide boosting effect.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-682X 1420-9071
DOI:	10.1007/s00018-021-03930-7