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The C-terminal pept...
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
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- Jørgensen, Astrid Sissel (author)
- University of Copenhagen
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- Brandum, Emma Probst (author)
- University of Copenhagen
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- Mikkelsen, Jeppe Malthe (author)
- University of Copenhagen
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- Orfin, Klaudia A. (author)
- University of Copenhagen
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- Boilesen, Ditte Rahbæk (author)
- University of Copenhagen
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- Egerod, Kristoffer Lihme (author)
- University of Copenhagen
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- Moussouras, Natasha A. (author)
- Medical College of Wisconsin
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- Vilhardt, Frederik (author)
- University of Copenhagen
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- Kalinski, Pawel (author)
- Roswell Park Cancer Institute
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- Basse, Per (author)
- Roswell Park Cancer Institute
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- Chen, Yen Hsi (author)
- University of Copenhagen
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- Yang, Zhang (author)
- University of Copenhagen
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- Dwinell, Michael B. (author)
- Medical College of Wisconsin
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- Volkman, Brian F. (author)
- Medical College of Wisconsin
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- Veldkamp, Christopher T. (author)
- University of Wisconsin-Whitewater
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- Holst, Peter Johannes (author)
- University of Copenhagen
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- Lahl, Katharina (author)
- Lund University,Lunds universitet,Virusrekognition,Forskargrupper vid Lunds universitet,Virus Recognition,Lund University Research Groups,Technical University of Denmark
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- Goth, Christoffer Knak (author)
- University of Copenhagen
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- Rosenkilde, Mette Marie (author)
- University of Copenhagen
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- Hjortø, Gertrud Malene (author)
- University of Copenhagen
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(creator_code:org_t)
- 2021-09-29
- 2021
- English.
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In: Cellular and Molecular Life Sciences. - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 78:21-22, s. 6963-6978
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Keyword
- CCR7
- Chemokine
- Dendritic cell
- Glycosylation
- Peptide
Publication and Content Type
- art (subject category)
- ref (subject category)
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Jørgensen, Astri ...
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Brandum, Emma Pr ...
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Mikkelsen, Jeppe ...
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Orfin, Klaudia A ...
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Boilesen, Ditte ...
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Egerod, Kristoff ...
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Moussouras, Nata ...
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Vilhardt, Freder ...
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Kalinski, Pawel
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Basse, Per
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Chen, Yen Hsi
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Yang, Zhang
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Dwinell, Michael ...
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Volkman, Brian F ...
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Veldkamp, Christ ...
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Holst, Peter Joh ...
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Lahl, Katharina
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Goth, Christoffe ...
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Rosenkilde, Mett ...
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Hjortø, Gertrud ...
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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Cellular and Mol ...
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Lund University