Escaping the flatlands: new approaches for studying the dynamic assembly and activation of GPCR signaling complexes

Despite significant recent advances in molecular and structural studies of G protein-coupled receptors (GPCRs), an understanding of transmembrane signal transduction with chemical precision requires new approaches. Simple binary receptor–ligand or receptor–G protein complex models cannot adequately describe the relevant macromolecular signaling machineries. GPCR signalosomes undergo complex dynamic assembly–disassembly reactions to create allosteric signaling conduits whose properties cannot necessarily be predicted from individual elements alone. The combinatorial possibilities inherent in a system with hundreds of potential components suggest that high-content miniaturized experimental platforms and computational approaches will be required. To study allosteric effects involved in signalosome reaction pathways, a bottom-up approach using multicolor single-molecule detection fluorescence experiments in biochemically defined systems and complemented by molecular dynamics models of macromolecular complexes is proposed. In bridging the gap between molecular and systems biology, this synthetic approach suggests a way forward from the flatlands to multi-dimensional data collection.