Teneurins (TENs) are cell surface adhesion proteins known to play roles in embryonic development, neuronal pathfinding, and synapse formation. A new cryo-electron microscopy structure of the human TEN has revealed unusual features, including similarity to bacteria and an alternatively spliced region that defines the protein’s function. The work, published today in Cell, comes from a collaboration between teams in Stanford University and The University of Chicago.
"There are many proteins on the cell surface that are important for adhesion, and they all have characteristic structures. But until now, we had no idea what these teneurins looked like. No other eukaryotic protein was similar to this, so its resemblance to a bacterial toxin is unusual,” said senior study co-author Demet Araç.
TENs genetic sequences provided the first clues that hinted at the similarity to bacterial toxins. The team's 3.1-Å cryo-EM structure also followed suit. The protein’s extracellular region (ECR) featured an unusual cylindrical beta barrel architecture that most closely resembled bacterial Tc-toxins, as well as a propeller-like motif.
Going further into the protein’s function, the team showed that TEN had a functional alternatively spliced variant. The other differed by only seven amino acids (out of 2,500), yet this small change had clear effects. Structurally, the variant produced a change in the propeller region that acted like a switch, regulating the binding of TEN to a receptor protein in a different cell. One version lacking the seven residues could adhere to the receptor, while the other could not. The difference in the two variants determined the formation of synapses between neurons.
"Usually there are different proteins that do different things in the nervous system. One does axon pathfinding, another one does synapse formation, another does brain development, etc. This is one explanation for how teneurins do so many different things, by using different, alternatively-spliced isoforms."
Image: 3-D model of a teneurin protein. Image courtesy of Demet Araç and the University of Chicago.