Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21

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Standard

Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21. / Moussouras, Natasha A.; Hjortø, Gertrud M.; Peterson, Francis C.; Szpakowska, Martyna; Chevigné, Andy; Rosenkilde, Mette M.; Volkman, Brian F.; Dwinell, Michael B.

I: Biochemistry, Bind 59, Nr. 13, 07.04.2020, s. 1338-1350.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Moussouras, NA, Hjortø, GM, Peterson, FC, Szpakowska, M, Chevigné, A, Rosenkilde, MM, Volkman, BF & Dwinell, MB 2020, 'Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21', Biochemistry, bind 59, nr. 13, s. 1338-1350. https://doi.org/10.1021/acs.biochem.0c00047

APA

Moussouras, N. A., Hjortø, G. M., Peterson, F. C., Szpakowska, M., Chevigné, A., Rosenkilde, M. M., Volkman, B. F., & Dwinell, M. B. (2020). Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21. Biochemistry, 59(13), 1338-1350. https://doi.org/10.1021/acs.biochem.0c00047

Vancouver

Moussouras NA, Hjortø GM, Peterson FC, Szpakowska M, Chevigné A, Rosenkilde MM o.a. Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21. Biochemistry. 2020 apr. 7;59(13):1338-1350. https://doi.org/10.1021/acs.biochem.0c00047

Author

Moussouras, Natasha A. ; Hjortø, Gertrud M. ; Peterson, Francis C. ; Szpakowska, Martyna ; Chevigné, Andy ; Rosenkilde, Mette M. ; Volkman, Brian F. ; Dwinell, Michael B. / Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21. I: Biochemistry. 2020 ; Bind 59, Nr. 13. s. 1338-1350.

Bibtex

@article{543d6ca6e643460793270c838ef9aca8,
title = "Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21",
abstract = "The chemokines CCL21 and CCL19, through binding of their cognate receptor CCR7, orchestrate lymph node homing of dendritic cells and na{\"i}ve T cells. CCL21 differs from CCL19 via an unstructured 32 residue C-terminal domain. Previously described roles for the CCL21 C-terminus include GAG-binding, spatial localization to lymphatic vessels, and autoinhibitory modulation of CCR7-mediated chemotaxis. While truncation of the C-terminal tail induced chemical shift changes in the folded chemokine domain, the structural basis for its influence on CCL21 function remains largely unexplored. CCL21 concentration-dependent NMR chemical shifts revealed weak, nonphysiological self-association that mimics the truncation of the C-terminal tail. We generated a series of C-terminal truncation variants to dissect the C-terminus influence on CCL21 structure and receptor activation. Using NMR spectroscopy, we found that CCL21 residues 80-90 mediate contacts with the chemokine domain. In cell-based assays for CCR7 and ACKR4 activation, we also found that residues 92-100 reduced CCL21 potency in calcium flux, cAMP inhibition, and β-arrestin recruitment. Taken together, these structure-function studies support a model wherein intramolecular interactions with specific residues of the flexible C-terminus stabilize a less active monomer conformation of the CCL21. We speculate that the autoinhibitory intramolecular contacts between the C-terminal tail and chemokine body are disrupted by GAG binding and/or interactions with the CCR7 receptor to ensure optimal functionality.",
author = "Moussouras, {Natasha A.} and Hjort{\o}, {Gertrud M.} and Peterson, {Francis C.} and Martyna Szpakowska and Andy Chevign{\'e} and Rosenkilde, {Mette M.} and Volkman, {Brian F.} and Dwinell, {Michael B.}",
year = "2020",
month = apr,
day = "7",
doi = "10.1021/acs.biochem.0c00047",
language = "English",
volume = "59",
pages = "1338--1350",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "13",

}

RIS

TY - JOUR

T1 - Structural Features of an Extended C-Terminal Tail Modulate the Function of the Chemokine CCL21

AU - Moussouras, Natasha A.

AU - Hjortø, Gertrud M.

AU - Peterson, Francis C.

AU - Szpakowska, Martyna

AU - Chevigné, Andy

AU - Rosenkilde, Mette M.

AU - Volkman, Brian F.

AU - Dwinell, Michael B.

PY - 2020/4/7

Y1 - 2020/4/7

N2 - The chemokines CCL21 and CCL19, through binding of their cognate receptor CCR7, orchestrate lymph node homing of dendritic cells and naïve T cells. CCL21 differs from CCL19 via an unstructured 32 residue C-terminal domain. Previously described roles for the CCL21 C-terminus include GAG-binding, spatial localization to lymphatic vessels, and autoinhibitory modulation of CCR7-mediated chemotaxis. While truncation of the C-terminal tail induced chemical shift changes in the folded chemokine domain, the structural basis for its influence on CCL21 function remains largely unexplored. CCL21 concentration-dependent NMR chemical shifts revealed weak, nonphysiological self-association that mimics the truncation of the C-terminal tail. We generated a series of C-terminal truncation variants to dissect the C-terminus influence on CCL21 structure and receptor activation. Using NMR spectroscopy, we found that CCL21 residues 80-90 mediate contacts with the chemokine domain. In cell-based assays for CCR7 and ACKR4 activation, we also found that residues 92-100 reduced CCL21 potency in calcium flux, cAMP inhibition, and β-arrestin recruitment. Taken together, these structure-function studies support a model wherein intramolecular interactions with specific residues of the flexible C-terminus stabilize a less active monomer conformation of the CCL21. We speculate that the autoinhibitory intramolecular contacts between the C-terminal tail and chemokine body are disrupted by GAG binding and/or interactions with the CCR7 receptor to ensure optimal functionality.

AB - The chemokines CCL21 and CCL19, through binding of their cognate receptor CCR7, orchestrate lymph node homing of dendritic cells and naïve T cells. CCL21 differs from CCL19 via an unstructured 32 residue C-terminal domain. Previously described roles for the CCL21 C-terminus include GAG-binding, spatial localization to lymphatic vessels, and autoinhibitory modulation of CCR7-mediated chemotaxis. While truncation of the C-terminal tail induced chemical shift changes in the folded chemokine domain, the structural basis for its influence on CCL21 function remains largely unexplored. CCL21 concentration-dependent NMR chemical shifts revealed weak, nonphysiological self-association that mimics the truncation of the C-terminal tail. We generated a series of C-terminal truncation variants to dissect the C-terminus influence on CCL21 structure and receptor activation. Using NMR spectroscopy, we found that CCL21 residues 80-90 mediate contacts with the chemokine domain. In cell-based assays for CCR7 and ACKR4 activation, we also found that residues 92-100 reduced CCL21 potency in calcium flux, cAMP inhibition, and β-arrestin recruitment. Taken together, these structure-function studies support a model wherein intramolecular interactions with specific residues of the flexible C-terminus stabilize a less active monomer conformation of the CCL21. We speculate that the autoinhibitory intramolecular contacts between the C-terminal tail and chemokine body are disrupted by GAG binding and/or interactions with the CCR7 receptor to ensure optimal functionality.

U2 - 10.1021/acs.biochem.0c00047

DO - 10.1021/acs.biochem.0c00047

M3 - Journal article

C2 - 32182428

AN - SCOPUS:85083041593

VL - 59

SP - 1338

EP - 1350

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 13

ER -

ID: 247034935