Brain development relies on the coordinated migration of neuronal cells and their cellular extensions (axons, dendrites). Correct navigation during these cell migration events is essential and requires the combined actions of 'cell guidance receptors' and their ligands. These cell membrane receptors typically trigger repulsive or attractive/adhesive cell responses depending on the receptor type(s) and ligands involved. In addition to their role in neuronal cell guidance, membrane receptor-ligand interactions have important roles in adult brain such as synapse formation and ability of synapses to change their activity level. As a result, malfunction of these proteins has been associated with many neurological and neurodevelopmental disorders. Therefore, deciphering the complete function of these ligands and the molecular mechanism of their interactions with the receptors is a major task towards understanding the biology of brain, pathology of neuronal disorders as well as their clinical applications.
Research in the last four decades has led to the identification of major guidance protein families. However, our understating so far is limited to the effect of individual receptor-ligand interactions. How multiple ligands and receptors work together to generate the complexity found in brain tissues is poorly understood. Multifunctional ligands and receptors are thought to interact in context-dependent combinations to increase their functional versatility, but the mechanistic details underpinning these 'combinatorial' interactions remain largely elusive. Even less understood is the role of other extracellular molecules, for example, sugars of the heparan sulphate family. Recent studies have shown that many receptors bind these sugars, adding a further layer of functional complexity and versatility.
Recently, our group has made a pioneering progress and elucidated the structure of a “super-complex” fragment consisting of three types of cell receptors: FLRT proteins, adhesion GPCRs Latrophilin (Lphn) and guidance receptors Unc5. This has opened up a series of questions that need to be addressed to fully exploit the initial findings. In this project, our goal is to investigate how super-complex formation impacts on the downstream soluble and transmembrane signalling domains to direct cell behaviour. We specifically aim at elucidating the full length structure of the super-complex to reveal the molecular details of the interactions, understanding how complex formation impacts on the functions of these receptors, and exploring the influence of heparan sulphate sugars on the super-complex structure and function.
