Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t

Ward, R. J., Pediani, J. D. , Marsango, S., Jolly, R., Stoneman, M. R., Biener, G., Handel, T. M., Raicu, V. and Milligan, G. (2021) Chemokine receptor CXCR4 oligomerization is disrupted selectively by the antagonist ligand IT1t. Journal of Biological Chemistry, 296, 100139. (doi: 10.1074/jbc.RA120.016612) (PMID:33268380)

[img] Text
226645.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

Abstract

CXCR4, a member of the family of chemokine-activated G protein-coupled receptors, is widely expressed in immune response cells. It is involved in both cancer development and progression as well as viral infection, notably by HIV-1. A variety of methods, including structural information, have suggested the receptor may exist as a dimer or oligomer. However, the mechanistic details surrounding receptor oligomerization and its potential dynamic regulation remain unclear. Using both biochemical and biophysical means we confirm that CXCR4 can exist as a mixture of monomers, dimers and higher-order oligomers in cell membranes and show that oligomeric structure becomes more complex as receptor expression levels increase. Mutations of CXCR4 residues located at a putative dimerization interface result in monomerization of the receptor. Additionally, binding of the CXCR4 antagonist IT1t— a small, drug-like isothiourea derivative — rapidly destabilizes the oligomeric structure, while AMD3100, another well-characterized CXCR4 antagonist, does not. Although a mutation that regulates constitutive activity of CXCR4 also results in monomerization of the receptor, binding of IT1t to this variant promotes receptor dimerization. These results provide novel insights into the basal organization of CXCR4 and how antagonist ligands of different chemotypes differentially regulate its oligomerization state.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pediani, Dr John and Ward, Dr Richard and Milligan, Professor Graeme and Raicu, Professor Valerica and Marsango, Dr Sara
Authors: Ward, R. J., Pediani, J. D., Marsango, S., Jolly, R., Stoneman, M. R., Biener, G., Handel, T. M., Raicu, V., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Biological Chemistry
Publisher:Elsevier
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:04 January 2021
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Journal of Biological Chemistry 296: 100139
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170430The organisational structure of class A GPCRs: Implications for pharmacology, function and therapeutic regulationGraeme MilliganMedical Research Council (MRC)MR/L023806/1MCSB - Molecular Pharmacology
171219ONCORNETGraeme MilliganEuropean Commission (EC)641833MCSB - Molecular Pharmacology