Adhesion GPCRs in the neural and vascular systems: from complex structures to cellular functions

Adhesion G-protein-coupled receptors (adhesion GPCRs) are characterised by a large extracellular ligand-binding domain and are broadly expressed in the neural and vascular systems. The mechanistic details of adhesion GPCR functions are still poorly understood, hampering progress in understanding their biological roles. Recently, my pioneering work has shown that the extracellular region of the adhesion GPCR 'Latrophilin3’ forms large assemblies (super-complexes) with two structurally unrelated receptors: 'Fibronectin-leucine-rich transmembrane protein' (Flrt) and 'Uncoordinated-5' (Unc5). Crystal structures revealed Latrophilin multimerisation within this super-complex. I now aim to answer a series of key questions in adhesion GPCR biology using Latrophilin as a starting point: What is the function of adhesion GPCR multimerisation? Which Latrophilin/Flrt/Unc5 complexes are formed in the developing cortex? How do other neuronal ligands impact on Latrophilin structure and function? What are the structures and functions of adhesion GPCRs in endothelial cells? To answer these questions I will use a combination of structural biology, biophysical analysis and cell biology, and address biological functions in vivo using mouse developmental models through collaborations. Robust preliminary results suggest that these high-affinity 'super-complexes' have distinct functions, providing exciting new clues into the regulation and biological roles of adhesion GPCRs in the vascular and neural systems.