Research

We identified how two different proteins, Unc5 and GPC3, work together to guide the movements of cells. The study was made possible by the detailed structural view of how Unc5 and GPC3 come together using the sugars that they carry on their surface. Another big surprise came as we realised that Unc5-GPC3 proteins direct migrating cells in two completely unrelated biological areas: during formation of the brain and in the spreading of cancer cells. 

Published in Akkermans et al. Cell 2022

Structures of Teneurin-Latrophilin complexes demonstrate how the lectin and olfactomedin domains of Latrophilin bind across the spiraling beta-barrel domain of Teneurin. Protein engineering, biophysical analysis, cell migration assays, and electroporation experiments show that the binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons in the developing brain. 

Published in del Toro et al. Cell 2020

Teneurins are ancient cell–cell adhesion receptors that are vital for brain development and synapse organisation. They originated in early metazoan evolution through a horizontal gene transfer event when a bacterial YD-repeat toxin fused to a eukaryotic receptor. We present structures of Teneurins, revealing a ~200 kDa super-fold in which eight sub-domains form an intricate structure centred on a spiralling YD-repeat shell. Unexpectedly, we discovered that these proteins are widespread also amongst modern bacteria.

Published in Jackson et al. Nature Communications 2018

Latrophilin adhesion-GPCRs and Unc5 cell guidance receptors interact with FLRT proteins, thereby promoting cell adhesion and repulsion, respectively. How the three proteins interact and function simultaneously is poorly understood. We show that the ectodomains of the three proteins bind cooperatively in a stoichiometry of 1:1:2. Our data exemplify how receptors increase their functional repertoire by forming different context-dependent higher-order complexes.

Published in Jackson et al. Nature Communications 2016

FLRTs are broadly expressed proteins acting as cell adhesion molecules and as repulsive ligands. The molecular mechanisms by which they execute these opposing functions are enigmatic. We reveal how FLRT binds repulsive Unc5 receptors through a binding surface that does not overlap with its cell-adhesive surface. FLRT-mediated cell adhesion and repulsion seem to be mechanistically conserved between cortical neurons migrating radially during development, and vascular endothelial cells.

Published in Seiradake et al. Neuron 2014