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Identification of a conserved chemokine receptor motif that enables ligand discrimination
ID
Larsen, Olav
(
Author
),
ID
Velden, Wijnand J. C. van der
(
Author
),
ID
Mavri, Maša
(
Author
),
ID
Schuermans, Sara
(
Author
),
ID
Rummel, Pia C.
(
Author
),
ID
Karlshøj, Stefanie
(
Author
),
ID
Gustavsson, Martin
(
Author
),
ID
Proost, Paul
(
Author
),
ID
Våbenø, Jon
(
Author
),
ID
Rosenkilde, Mette Marie
(
Author
)
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MD5: 7188BA2256289B91CF6BF0E22359B1AB
URL - Source URL, Visit
https://www.science.org/doi/10.1126/scisignal.abg7042
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Abstract
Extensive ligand-receptor promiscuity in the chemokine signaling system balances beneficial redundancy and specificity. However, this feature poses a major challenge to selectively modulate the system pharmacologically. Here, we identified a conserved cluster of three aromatic receptor residues that anchors the second extracellular loop (ECL2) to the top of receptor transmembrane helices (TM) 4 and 5 and enables recognition of both shared and specific characteristics of interacting chemokines. This cluster was essential for the activation of several chemokine receptors. Furthermore, characteristic motifs of the ß$_1$ strand and 30s loop make the two main CC-chemokine subgroups—the macrophage inflammatory proteins (MIPs) and monocyte chemoattractant proteins (MCPs)—differentially dependent on this cluster in the promiscuous receptors CCR1, CCR2, and CCR5. The cluster additionally enabled CCR1 and CCR5 to discriminate between closely related MIPs based on the N terminus of the chemokine. G protein signaling and β-arrestin2 recruitment assays confirmed the importance of the conserved cluster in receptor discrimination of chemokine ligands. This extracellular site may facilitate the development of chemokine-related therapeutics.
Language:
English
Keywords:
GTP-binding proteins
,
monocyte chemoattractant proteins
,
macrophage inflammatory proteins
,
receptors
,
chemokine
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
VF - Veterinary Faculty
Publication status:
Published
Publication version:
Author Accepted Manuscript
Year:
2022
Number of pages:
13 str.
Numbering:
Vol. 15, iss. 724, art. eabg7042
PID:
20.500.12556/RUL-137252
UDC:
577
ISSN on article:
1937-9145
DOI:
10.1126/scisignal.abg7042
COBISS.SI-ID:
110570499
Publication date in RUL:
08.06.2022
Views:
647
Downloads:
257
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Record is a part of a journal
Title:
Science signaling
Shortened title:
Sci. signal.
Publisher:
American Association for the Advancement of Science
ISSN:
1937-9145
COBISS.SI-ID:
3564168
Licences
License:
CC BY 4.0, Creative Commons Attribution 4.0 International
Link:
http://creativecommons.org/licenses/by/4.0/
Description:
This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:
08.03.2022
Projects
Funder:
Other - Other funder or multiple funders
Funding programme:
Novo Nordisk Foundation
Project number:
NNF14OC0013491
Funder:
Other - Other funder or multiple funders
Funding programme:
Novo Nordisk Foundation
Project number:
NNF12OC0001900
Funder:
Other - Other funder or multiple funders
Funding programme:
Carlsberg Foundation
Project number:
CF18-1013
Funder:
Other - Other funder or multiple funders
Funding programme:
Carlsberg Foundation
Project number:
CF14-0707
Funder:
ARRS - Slovenian Research Agency
Project number:
P4-0053
Name:
Endokrini, imunski in encimski odzivi pri zdravih in bolnih živalih
Funder:
Other - Other funder or multiple funders
Funding programme:
Vlaanderen, FWO
Project number:
GOF7519N
Funder:
Other - Other funder or multiple funders
Funding programme:
V. A. T. Eichmuller
Project number:
2020-117043
Funder:
Other - Other funder or multiple funders
Funding programme:
Kirsten and Freddy Johansens Foundation
Project number:
2017-112697
Funder:
Other - Other funder or multiple funders
Funding programme:
Lundbeck Foundation
Project number:
R268-2017-409
Funder:
Other - Other funder or multiple funders
Funding programme:
Novo Nordisk Foundation
Project number:
NNF17OC0029222
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