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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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. / Jorgensen, Astrid Sissel; Brandum, Emma Probst; Mikkelsen, Jeppe Malthe; Orfin, Klaudia A.; Boilesen, Ditte Rahbaek; 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; Hjorto, Gertrud Malene.

In: Cellular and Molecular Life Sciences, Vol. 78, 2021, p. 6963-6978.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Jorgensen, AS, Brandum, EP, Mikkelsen, JM, Orfin, KA, Boilesen, DR, Egerod, KL, Moussouras, NA, Vilhardt, F, Kalinski, P, Basse, P, Chen, Y-H, Yang, Z, Dwinell, MB, Volkman, BF, Veldkamp, CT, Holst, PJ, Lahl, K, Goth, CK, Rosenkilde, MM & Hjorto, GM 2021, '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', Cellular and Molecular Life Sciences, vol. 78, pp. 6963-6978. https://doi.org/10.1007/s00018-021-03930-7

APA

Jorgensen, A. S., Brandum, E. P., Mikkelsen, J. M., Orfin, K. A., Boilesen, D. R., Egerod, K. L., Moussouras, N. A., Vilhardt, F., Kalinski, P., Basse, P., Chen, Y-H., Yang, Z., Dwinell, M. B., Volkman, B. F., Veldkamp, C. T., Holst, P. J., Lahl, K., Goth, C. K., Rosenkilde, M. M., & Hjorto, G. M. (2021). 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. Cellular and Molecular Life Sciences, 78, 6963-6978. https://doi.org/10.1007/s00018-021-03930-7

Vancouver

Jorgensen AS, Brandum EP, Mikkelsen JM, Orfin KA, Boilesen DR, Egerod KL et al. 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. Cellular and Molecular Life Sciences. 2021;78:6963-6978. https://doi.org/10.1007/s00018-021-03930-7

Author

Jorgensen, Astrid Sissel ; Brandum, Emma Probst ; Mikkelsen, Jeppe Malthe ; Orfin, Klaudia A. ; Boilesen, Ditte Rahbaek ; 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 ; Hjorto, Gertrud Malene. / 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. In: Cellular and Molecular Life Sciences. 2021 ; Vol. 78. pp. 6963-6978.

Bibtex

@article{75fed3307fae4e10a0b17fbac9b559e0,
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",
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 similar to 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.",
keywords = "Chemokine, CCR7, Glycosylation, Peptide, Dendritic cell, HIGH-AFFINITY BINDING, MOLECULAR-MECHANISM, CHEMOKINE, LIGAND, ACTIVATION, GRADIENTS, MIGRATION, PATTERNS, RECOGNITION, RECRUITMENT",
author = "Jorgensen, {Astrid Sissel} and Brandum, {Emma Probst} and Mikkelsen, {Jeppe Malthe} and Orfin, {Klaudia A.} and Boilesen, {Ditte Rahbaek} and Egerod, {Kristoffer Lihme} and Moussouras, {Natasha A.} and Frederik Vilhardt and Pawel Kalinski and Per Basse and Yen-Hsi Chen and Zhang Yang and Dwinell, {Michael B.} and Volkman, {Brian F.} and Veldkamp, {Christopher T.} and Holst, {Peter Johannes} and Katharina Lahl and Goth, {Christoffer Knak} and Rosenkilde, {Mette Marie} and Hjorto, {Gertrud Malene}",
year = "2021",
doi = "10.1007/s00018-021-03930-7",
language = "English",
volume = "78",
pages = "6963--6978",
journal = "EXS",
issn = "1023-294X",
publisher = "Springer Basel AG",

}

RIS

TY - JOUR

T1 - 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

AU - Jorgensen, Astrid Sissel

AU - Brandum, Emma Probst

AU - Mikkelsen, Jeppe Malthe

AU - Orfin, Klaudia A.

AU - Boilesen, Ditte Rahbaek

AU - Egerod, Kristoffer Lihme

AU - Moussouras, Natasha A.

AU - Vilhardt, Frederik

AU - Kalinski, Pawel

AU - Basse, Per

AU - Chen, Yen-Hsi

AU - Yang, Zhang

AU - Dwinell, Michael B.

AU - Volkman, Brian F.

AU - Veldkamp, Christopher T.

AU - Holst, Peter Johannes

AU - Lahl, Katharina

AU - Goth, Christoffer Knak

AU - Rosenkilde, Mette Marie

AU - Hjorto, Gertrud Malene

PY - 2021

Y1 - 2021

N2 - 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 similar to 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.

AB - 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 similar to 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.

KW - Chemokine

KW - CCR7

KW - Glycosylation

KW - Peptide

KW - Dendritic cell

KW - HIGH-AFFINITY BINDING

KW - MOLECULAR-MECHANISM

KW - CHEMOKINE

KW - LIGAND

KW - ACTIVATION

KW - GRADIENTS

KW - MIGRATION

KW - PATTERNS

KW - RECOGNITION

KW - RECRUITMENT

U2 - 10.1007/s00018-021-03930-7

DO - 10.1007/s00018-021-03930-7

M3 - Journal article

C2 - 34586443

VL - 78

SP - 6963

EP - 6978

JO - EXS

JF - EXS

SN - 1023-294X

ER -

ID: 281220752