Spatiotemporally resolved GPCR interactome uncover mediators of receptor agonism

A collaboration between the Tate and Hanyaloglu groups has led to the discovery of unique mediators of luteinizing hormone receptor (LHR) agonism.

The LHR is a key G protein-coupled receptor (GPCR) involved in human reproduction. It is known that after LH stimulation, LHR undergoes rapid endocytosis and traffics to the very early endosome (VEE) where it participates in G protein signalling and post-endocytic sorting. However, resolving this trafficking at a minute-to-minute timescale remains challenging, particularly for poorly characterized GPCRs that lack pharmacological tools.

In this study, published in Cell Chemical Biology, ascorbate peroxidase (APEX2) proximity proteomics was applied to study the LH induced interactome of LHR, leading to identification of RAP2B and RAB38 as potential modulators of LHR signalling and trafficking. This publication provides a much needed resource for studying the interactome of LHR, as well as providing a novel proximity proteomics based pipeline that can be applied to the studying of receptors with minimal ligands, spatial markers, or known interactors.

The lead early career researcher on this work, Dr Masha Shchepinova, has now gone on to set up her own group at the University of Bath where she will be building on this work by developing proteomics and chemical approaches to study G protein-coupled receptors in metabolic diseases. This work was supported by funding from the Health@InnoHK Program and the BBSRC.