Identification of a Salt Bridge That Is Functionally Important for Chemokine Receptor CXCR1 but not CXCR2

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CXC chemokine receptors 1 (CXCR1) and 2 (CXCR2) have high sequence similarity and overlapping chemokine ligand profiles. Residue positions 3.32 and 7.39 are critical for signal transduction in the related CXCR4, and in these positions CXCR1 and CXCR2 contain oppositely charged residues (Lys3.32 and Glu7.39). Experimental and computed receptor structures reveal the possible formation of a salt bridge between transmembrane (TM) helices 3 and 7 via these two residues. To investigate the functional importance of Lys1173.32 and Glu2917.39 in CXCR1, along with the flanking Glu1183.33, we performed a signaling study on 16 CXCR1 mutants using two different CXCL8 isoforms. While single Ala-mutation (K1173.32A, E2917.39A) and charge reversal (K1173.32E, E2917.39K) resulted in nonfunctional receptors, double (K1173.32E-E2917.39K) and triple (K1173.32E-E1183.33A-E2917.39K) mutants rescued CXCR1 function. In contrast, the corresponding mutations did not affect the CXCR2 function to the same extent. Our findings show that the Lys3.32-Glu7.39 salt bridge between TM3 and −7 is functionally important for CXCR1 but not for CXCR2, meaning that signal transduction for these highly homologous receptors is not conserved.

Original languageEnglish
JournalACS Pharmacology and Translational Science
Issue number8
Pages (from-to)1120-1128
Number of pages9
Publication statusPublished - 2023

Bibliographical note

Funding Information:
Maibritt Sigvardt Baggesen and Søren Petersen are thanked for their excellent technical assistance. Financial support was obtained from The NovoNordisk Foundation (NF20OC0062899), The Carlsberg Foundation (CF14-0707), Kirsten and Freddy Johansens (KFJ) Foundation (2017-112697), and as a donation from the deceased Valter Alex Torbjørn (VAT) Eichmuller (2020-117043).

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

    Research areas

  • chemokine receptor, chemokine recognition site, CKR signaling, CXCR1, CXCR2, GPCR, inositol triphosphate, salt bridge

ID: 373669519