CXCR4 is the G-Protein Coupled Receptor (GPCR) which mediates signalling for chemotaxis. The only known ligand is CXCL12 or SDF-1, which initiates the signalling process. It is well-known that cholesterol plays a significant role in modulating GPCR signalling across the membrane. Further, studies have shown that reduced cholesterol concentration leads to a reduced level of calcium ion signalling. Nevertheless, it is unknown how the presence of oxysterols affects the signalling process of a GPCR. In this study, we use all-atom Molecular Dynamics (MD) simulations to understand the role of oxysterols on CXCR4-mediated signalling. The results illustrate that the bindings of oxysterols on CXCR4 are more robust and less dynamic than cholesterol. We observe that the membrane dynamics are altered by the presence of oxysterols indicated by the lesser root mean square fluctuations of the protein and lesser root mean square displacement of lipids in the system. The interaction of oxysterols with the vital signalling residues changes the residue's conformation, critical for the signalling process. Tail-oxidised sterol also emerged as the potential ligand to occupy the dimerisation site & hence a potential barrier in oligomerisation and signalling. We connect our simulation results with the experiments and give a molecular explanation of why tail-oxidised sterols have a more drastic effect on signalling compared to the ring-oxidised sterols. This is the first molecular dynamics study where interactions of oxysterols with a GPCR and their effect on signalling are analysed. It brings forth a detailed view of the compromised signalling of CXCR4 in the presence of oxysterols and provides molecular insights into it.

Understanding the loss of CXCR4-mediated signalling in the presence of oxysterols

ACS Spring 2022

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