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Session: Session 4

Chemokine receptors binding to their ligands: insights from structural mass spectrometry

Christelle ALJAMOUS1, Omolade OTUN1, Tristan GIRBAU1,2, Elise DEL NERO1, Sébastien GRANIER1, Cherine BECHARA1,2

1Institut de Génomique Fonctionnelle (IGF), CNRS UMR5203, INSERM U1191, Univ. Montpellier., Montpellier, France
2Pôle Protéome Montpellier (PPM), Montpellier, France

Chemokines bind to chemokine receptors (CKRs), a subgroup of G protein-coupled receptors (GPCRs), to regulate immune cell migration, impacting immune modulation, wound healing, inflammation, and host-pathogen interactions[1]. ACKR3 is an atypical CKR that can bind two endogenous chemokine ligands CXCL11 and CXCL12, impacting therefore other CKRs by scavenging these chemokines[2]. However, the stoichiometry of the formed chemokine/ACKR3 complexes as well as the different allosteric conformational changes of the receptor upon chemokine binding remain under investigation. Here, using a combination of native mass spectrometry (nMS) and Hydrogen/Deuterium exchange MS (HDX-MS), we explore the binding of both CXCL11 and CXC12 to ACKR3 and their effect on the intracellular signaling of ACKR3 . nMS shows a 1:1 and a 2:1 binding stoichiometry of CXCL12 to ACKR3, which could explain its scavenging role vis-à-vis other chemokine receptors. In addition, HDX-MS analysis shows G-protein binding to ACKR3 in the presence of its ligands, questioning therefore the signaling mechanisms previously established for ACKR3. Our results open the way to understand the physiological impact of ACKR3 on the regulation of chemokine concentration, and the formation of chemokine gradients for the signaling chemokine receptors [3].



[1]          J. W. Griffith, C. L. Sokol, et A. D. Luster, « Chemokines and chemokine receptors: positioning cells for host defense and immunity », Annu. Rev. Immunol., vol. 32, p. 659‑702, 2014, doi: 10.1146/annurev-immunol-032713-120145.

[2]          M. Gustavsson et al., « Structural basis of ligand interaction with atypical chemokine receptor 3 », Nat. Commun., vol. 8, no 1, Art. no 1, janv. 2017, doi: 10.1038/ncomms14135.

[3]          M. Szpakowska et al., « New pairings and deorphanization among the atypical chemokine receptor family — physiological and clinical relevance », Front. Immunol., vol. 14, avr. 2023, doi: 10.3389/fimmu.2023.1133394.