Jonathan Elegheert

Synapses are the specialized cellular junctions that form the basic units of communication between neuronal cells, thereby connecting neurons into the millions of dedicated circuits that sustain virtually all aspects of brain function. It is of fundamental importance to understand how synapses are formed and how their properties are specified, not only given the variety of network-dependent functions that synapses need to support, but also because many neurodevelopmental disorders and neurodegenerative diseases are closely related to loss of synapses and dysfunction of synaptic transmission.

Within this context, my team uses techniques of structural biology to determine the structures and interaction determinants of synaptic proteins that are important for synapse development. We also use Nanobody discovery to target neuronal proteins and receptors, as well as protein engineering to manipulate neuronal protein sequence, structure and function.

Concretely, my team is developing the following 4 research axes:

1.   Structure and function of novel synaptic adhesion complexes

We study the structure and function of novel synaptic adhesion protein complexes, discovered using proteomics.

2.   Synthetic Nanobody discovery workflow

We use recently developed, in vitro synthetic nanobody (Nb) libraries as an alternative to animal immunizations. We are implementing this technology with the goal of generating Nbs against a range of neuronal proteins and receptors. Applications include their use as probes for advanced imaging, chaperones to aid protein crystallization, tools to aid particle alignment and classification in single-particle cryo-EM, as well as therapeutics.

3.   Affinity engineering of neuronal ligand-receptor complexes

We are implementing techniques of protein engineering for the directed evolution of low affinity or transient synaptic protein-protein interactions, with the goal of increasing their interaction strength and thus enabling structure determination by X-ray crystallography and/or cryo-EM.

4.   Synthetic synaptic organizer molecules

Expanding on our previous research, and integrating the aforementioned methods of protein chemistry, structural biology, Nb discovery and protein engineering, we are working on developing synthetic synaptic organizer proteins, which are custom molecules that can link specified pre- and postsynaptic receptors, with applications in remodeling or repair of neuronal circuits.