Abstract
SummaryTeneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the adhesion GPCR Latrophilin, forming a trans-cellular complex with synaptogenic functions. However, Teneurins, Latrophilins, and FLRT proteins are also expressed during murine cortical cell migration at earlier developmental stages. Here, we present crystal structures of Teneurin-Latrophilin complexes that reveal how the lectin and olfactomedin domains of Latrophilin bind across a spiraling beta-barrel domain of Teneurin, the YD shell. We couple structure-based protein engineering to biophysical analysis, cell migration assays, and in utero electroporation experiments to probe the importance of the interaction in cortical neuron migration. We show that binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons using a contact repulsion-dependent mechanism. The effect is observed with cell bodies and small neurites rather than their processes. The results exemplify how a structure-encoded synaptogenic protein complex is also used for repulsive cell guidance.
Highlights
Teneurins are eukaryotic cell adhesion receptors that are thought to have evolved through a horizontal gene transfer event, where fusion of a bacterial toxin gene to a eukaryotic receptor resulted in a large type II transmembrane protein (Tucker et al, 2012)
What is the structural mechanism of the Teneurin-Latrophilin interaction? Is it compatible with the known FN leucine-rich repeat proteins (FLRTs)-Latrophilin binding mechanism? What is the function of the synaptic proteins Teneurin, Latrophilin, and FLRT during early cortex development? With X-ray crystallography, we reveal the Latrophilin binding site on Teneurin at the lateral side of the YD shell domain
The Latrophilin Lec Domain Binds across the Spiraling Beta-Barrel of the Teneurin YD Shell Domain Previous studies have demonstrated that the Lec domain of Latrophilin is essential and sufficient for binding to Teneurin proteins (Boucard et al, 2014)
Summary
Teneurins are eukaryotic cell adhesion receptors that are thought to have evolved through a horizontal gene transfer event, where fusion of a bacterial toxin gene to a eukaryotic receptor resulted in a large type II transmembrane protein (Tucker et al, 2012). The structures revealed three signature motifs of the Teneurin fold: (1) the spiraling beta-barrel tyrosine-aspartate repeat ‘‘YD shell’’ domain, (2) a specialized ‘‘fibronectin plug’’ domain that seals off the YD shell at the N-terminal side, and (3) a beta-propeller referred to as the NCL-1, HT2A, and Lin-41 (NHL) domain. These three elements form a superfold that is widespread in bacterial genomes, suggesting that they represent an evolutionarily ancient uncharacterized family of secreted bacterial proteins (Jackson et al, 2018). C-terminal of the YD shell is an $200-amino-acid linker that resides in the YD repeat shell and leads through the shell wall to form the antibiotic-binding-like (ABD) and
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