Figure 1: A small molecule modeled in the netrin/DCC interface that contributes to receptor binding.
Figure 2: Footprint of DCC and Draxin binding on the EGF-3 domain of netrin (Liu et al. 2018). Netrin residues that bind both draxin and DCC are colored a red hue. Residues only binding draxin are colored pink, and residues only binding DCC are colored yellow.
The Meijers group investigates signaling mechanisms across the cell membrane using integrated structural biology and biophysical techniques.
Previous and current research
Single-pass transmembrane receptors cluster with other receptors and ligands to pass environmental signals across the membrane. These signaling hubs are especially fine-tuned in the developing nervous system, where axons migrate over long distances to make connections. We have established human protein expression technology to produce large quantities of glycosylated receptor and ligand fragments. We also developed the RUBIC sample optimization screens to improve protein stability during purification, characterization, crystallization and storage (Boivin et al. 2013). Complexes between fragments of receptors and their ligands are characterized by crystallography, SAXS and electron microscopy, giving a holistic view of single-pass membrane receptor signaling. We are currently pursuing further understanding of the molecular mechanisms of two related systems:
Netrin and its receptors
The soluble guidance cue netrin clusters receptors such as deleted in colorectal cancer (DCC), UNC5 and Down syndrome cell adhesion molecule (DSCAM) together in various combinations. We are investigating how such a small guidance cue can bind different receptors and how receptor binding is regulated. We have determined the crystal structure of a complex between netrin and DCC, and showed with complementary biophysical and cell biology assays that DCC and UNC5 compete for binding at the same site on netrin (Finci et al., 2014). Interestingly, we found that small molecules may regulate which receptor will bind preferentially. We also investigated cross-talk between netrin and another guidance cue called draxin. Structural studies suggest that netrin and draxin enhance adhesion between cells decorated with DCC (Liu et al. 2018), and we are further pursuing the functional implications using cell biology studies.
Down syndrome cell adhesion molecule
Drosophila Dscam is a fascinating cell surface receptor that is alternatively spliced to generate ~18,000 variable receptor ectodomains. We have determined how Dscam forms a homodimer along the hyper-variable domains that are unique for each isoform (Meijers et al. 2007). We are now investigating the conserved features of DSCAM function in humans, where it is a dosage dependent adhesion molecule that plays a crucial role in congenital heart disease in Down syndrome patients.
Future Projects and Goals
- Investigate how small molecules regulate netrin/receptor signaling.
- Study the role of guidance cues in cell/cell adhesion, and how this relates to guidance cue signaling.
- Elucidate the molecular mechanisms underlying the cross-talk between different receptor/ligand systems.