Lipid nanoparticle technologies for the study of G protein-coupled receptors in lipid environments
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REVIEW
Lipid nanoparticle technologies for the study of G protein-coupled receptors in lipid environments Steven Lavington 1 & Anthony Watts 1 Received: 2 November 2020 / Accepted: 6 November 2020 # The Author(s) 2020
Abstract G protein-coupled receptors (GPCRs) are a large family of integral membrane proteins which conduct a wide range of biological roles and represent significant drug targets. Most biophysical and structural studies of GPCRs have been conducted on detergentsolubilised receptors, and it is clear that detergents can have detrimental effects on GPCR function. Simultaneously, there is increasing appreciation of roles for specific lipids in modulation of GPCR function. Lipid nanoparticles such as nanodiscs and styrene maleic acid lipid particles (SMALPs) offer opportunities to study integral membrane proteins in lipid environments, in a form that is soluble and amenable to structural and biophysical experiments. Here, we review the application of lipid nanoparticle technologies to the study of GPCRs, assessing the relative merits and limitations of each system. We highlight how these technologies can provide superior platforms to detergents for structural and biophysical studies of GPCRs and inform on roles for protein-lipid interactions in GPCR function. Keywords Nanodisc . rHDL . Lipodisq . SMALP . Lipid-protein interactions . G protein-coupled receptor
Introduction G protein-coupled receptors (GPCRs) constitute a family of over 800 integral membrane proteins, unified by a shared seven transmembrane helix architecture (Pierce et al. 2002; Fredriksson et al. 2003). Together, GPCRs respond to a diverse array of ligands, including ions, fatty acids, nucleotides and peptides, and their signalling is a component of a great many biological processes. Similarly, GPCR dysfunction is associated with a range of pathologies, including diabetes and obesity (Riddy et al. 2018), cancers (Dorsam and Gutkind 2007) and neurodegenerative diseases (Huang et al. 2017). GPCRs are also valuable drug targets, with a large portion of FDAapproved drugs targeting a relatively small number of receptors (Hauser et al. 2017). There is therefore considerable value in understanding the mechanism of action of these receptors. Canonically, GPCR signalling involves the binding of ligands to the extracellular portion of a receptor, which in turn promotes signalling through heterotrimeric G proteins, of
* Anthony Watts [email protected] 1
Biochemistry Department, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
which there are four subtypes (Strathmann and Gautam 1991; Downes and Gautam 1999). Interactions of GPCRs with arrestins can modulate these signals and produce G protein-independent signals (Reiter and Lefkowitz 2006). Given that a single receptor may signal to multiple G protein subtypes, a great diversity of signalling responses is possible for a single receptor. There has been tremendous effort in trying to understand the molecular basis of GPCR signalling (reviewed in (Manglik and Kruse 2017; Weis
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