GPCRs in the round: SMA-like copolymers and SMALPs as a platform for investigating GPCRs

Hoor Ayub, Rebecca J Murray, Gestél C Kuyler, Farhaan Napier-Khwaja, Joseph Gunner, Tim R Dafforn, Bert Klumperman, David R Poyner, Mark Wheatley

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Abstract

G-protein-coupled receptors (GPCRs) are the largest family of membrane proteins, regulate a plethora of physiological responses and are the therapeutic target for 30-40% of clinically-prescribed drugs. They are integral membrane proteins deeply embedded in the plasma membrane where they activate intracellular signalling via coupling to G-proteins and β-arrestin. GPCRs are in intimate association with the bilayer lipids and that lipid environment regulates the signalling functions of GPCRs. This complex lipid 'landscape' is both heterogeneous and dynamic. GPCR function is modulated by bulk membrane properties including membrane fluidity, microdomains, curvature, thickness and asymmetry but GPCRs are also regulated by specific lipid:GPCR binding, including cholesterol and anionic lipids. Understanding the molecular mechanisms whereby GPCR signalling is regulated by lipids is a very active area of research currently. A major advance in membrane protein research in recent years was the application of styrene maleic acid (SMA) copolymers. These spontaneously generate SMA lipid particles (SMALPs) encapsulating membrane protein in a nano-scale disc of cell membrane, thereby removing the historical need for detergent and preserving lipid:GPCR interaction. The focus of this review is how GPCR-SMALPs are increasing our understanding of GPCR structure and function at the molecular level. Furthermore, an increasing number of 'second generation' SMA-like copolymers have been reported recently. These are reviewed from the context of increasing our understanding of GPCR molecular mechanisms. Moreover, their potential as a novel platform for downstream biophysical and structural analyses is assessed and looking ahead, the translational application of SMA-like copolymers to GPCR drug discovery programmes in the future is considered.
Original languageEnglish
Article number109946
Number of pages7
JournalArchives of Biochemistry and Biophysics
Volume754
Early online date22 Feb 2024
DOIs
Publication statusPublished - Apr 2024

Bibliographical note

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Funder

The authors acknowledge funding support from the Biotechnology and Biological Sciences Research Council (BBSRC: BB/R016615/1 to MW and TRD; BB/R016755/1 to DRP). TRD, GCK and BK acknowledge funding from the Wellcome Trust via a Technology Development grant entitled ‘Unshackling Membrane Protein Research: New Amphiphilic Copolymers for Extraction of Stable, Active Membrane Proteins’ (grant nr 223728/Z/21/Z).

Keywords

  • G-protein-coupled receptor (GPCR)
  • SMA
  • SMALP
  • SMI
  • SMILP
  • DIBMA
  • DIBMALP
  • Membrane protein
  • Lipids

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