Reduced level of docosahexaenoic acid shifts GPCR neuroreceptors to less ordered membrane regions

0507094 - ÚOCHB 2020 RIV US eng J - Journal Article
Javanainen, Matti - Enkavi, G. - Guixa-González, R. - Kulig, W. - Martinez-Seara, Hector - Levental, I. - Vattulainen, I.
Reduced level of docosahexaenoic acid shifts GPCR neuroreceptors to less ordered membrane regions.
PLoS Computational Biology. Roč. 15, č. 5 (2019), č. článku e1007033. ISSN 1553-734X. E-ISSN 1553-7358
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : lipid-protein interactions * A2A adenosine receptor * surface roughness
OECD category: Biochemistry and molecular biology
Impact factor: 4.700, year: 2019
Method of publishing: Open access
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1007033

G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs. Here, using free energy techniques and multiscale simulations of numerous membrane proteins, we show that the presence of the PUFA DHA helps helical multi-pass proteins such as GPCRs partition into ordered membrane domains. The mechanism is based on hybrid lipids, whose PUFA chains coat the rough protein surface, while the saturated chains face the raft environment, thus minimizing perturbations therein. Our findings suggest that the reduction of GPCR partitioning to their native ordered environments due to PUFA depletion might affect the function of these receptors in numerous neurodegenerative diseases, where the membrane PUFA levels in the brain are decreased. We hope that this work inspires experimental studies on the connection between membrane PUFA levels and GPCR signaling.
Permanent Link: http://hdl.handle.net/11104/0298164


Research data: Zenodo, Zenodo, Zenodo