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
(2021) In Cellular and Molecular Life Sciences 78(21-22). p.6963-6978- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- CCR7, Chemokine, Dendritic cell, Glycosylation, Peptide
- in
- Cellular and Molecular Life Sciences
- volume
- 78
- issue
- 21-22
- pages
- 6963 - 6978
- publisher
- Birkhäuser Verlag
- external identifiers
-
- scopus:85116031161
- pmid:34586443
- ISSN
- 1420-682X
- DOI
- 10.1007/s00018-021-03930-7
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021, The Author(s).
- id
- e74744c8-e3f7-43a3-ba8d-7d9c555d6ba1
- date added to LUP
- 2021-10-22 15:51:57
- date last changed
- 2024-06-15 18:49:17
@article{e74744c8-e3f7-43a3-ba8d-7d9c555d6ba1,
abstract = {{<p>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.</p>}},
author = {{Jørgensen, Astrid Sissel and Brandum, Emma Probst and Mikkelsen, Jeppe Malthe and Orfin, Klaudia A. and Boilesen, Ditte Rahbæk and Egerod, Kristoffer Lihme and Moussouras, Natasha A. and Vilhardt, Frederik and Kalinski, Pawel and Basse, Per and Chen, Yen Hsi and Yang, Zhang and Dwinell, Michael B. and Volkman, Brian F. and Veldkamp, Christopher T. and Holst, Peter Johannes and Lahl, Katharina and Goth, Christoffer Knak and Rosenkilde, Mette Marie and Hjortø, Gertrud Malene}},
issn = {{1420-682X}},
keywords = {{CCR7; Chemokine; Dendritic cell; Glycosylation; Peptide}},
language = {{eng}},
number = {{21-22}},
pages = {{6963--6978}},
publisher = {{Birkhäuser Verlag}},
series = {{Cellular and Molecular Life Sciences}},
title = {{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}},
url = {{http://dx.doi.org/10.1007/s00018-021-03930-7}},
doi = {{10.1007/s00018-021-03930-7}},
volume = {{78}},
year = {{2021}},
}