Human Teneurin2 Structure Resembles Bacterial Toxin

Teneurin, a protein that plays a key role in embryonic development and nervous system wiring in humans appears to have been borrowed from bacteria, scientists from the University of Chicago and Stanford University report.

Proteins play a crucial role in helping cells communicate with each other. Teneurins sit on the surface of cells and bind to other proteins on the surface of other cells. They are involved in several processes, including embryonic development, guiding nerve cell axons to the right place to make connections with other nerve cells, and helping these connections, or synapses, form.

Instead of resembling other proteins that perform similar functions, however, the structure of teneurins most closely matches that of a bacterial toxin. This is the only known human protein with such a structure.

Unusual Resemblance

Senior author Demet Araç, PhD, assistant professor of biochemistry and molecular biology at U Chicago, said:

“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.”

Based on its genetic sequence, researchers had an inkling that teneurins resembled bacterial toxins, poison molecules bacteria use to attack and comprise host cells. Araç and Georgios Skiniotis from Stanford used high-resolution electron microscopy to define the structure of the human version of the teneurin protein.

When they compared it to reference databases of other protein structures, it most closely resembled a bacterial toxin with a barrel shape and propeller-like protrusion.

This toxin may have been incorporated into multicellular organisms very early in evolutionary history. Choanoflagellates, one of the earliest single-celled organisms believed to evolve into multicellular eukaryotes, have a teneurin-like protein.

It’s likely that bacteria transferred some of their genes to early choanoflagellates, which co-opted them for their own genomes. As these simple creatures evolved into more complex species, the original toxin-like protein has been conserved ever since.

Alternative Splicing

Once the structure was resolved, Araç and her colleagues also wanted to understand how teneurins perform so many different functions during development and in the nervous system. They suspect it may have something to do with its similarity to the toxin — perhaps it borrows some of the same tools bacteria use to infect cells and employs them to attach to and communicate with other cells instead.

A genetic process called alternative splicing may also help teneurins perform their various tasks. Alternative splicing, or differential splicing, is a process that results in a single gene coding for multiple proteins.

During this process, small segments of a gene called exons may be included or excluded in the final messenger RNA (mRNA) produced from that gene. These different mRNAs in turn translate into alternate versions of proteins that can perform various functions.

Araç and another collaborator from Stanford, Thomas Südhof, generated two different, alternatively spliced teneurins and tested their functionality. Just a tiny discrepancy — seven out of 2,500 amino acids — made a difference.

One version of the teneurin lacking seven specific amino acids could adhere to a cell receptor that is important for signaling between cells.

Another version of the teneurin that includes those seven amino acids couldn’t adhere to this receptor. Instead, it promoted formation of synapses between nerve cells.

“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.,” Araç said. “This is one explanation for how teneurins do so many different things, by using different, alternatively-spliced isoforms.”

Now that the structure of teneurins is clear, Araç says she and her postdoctoral scholar, Jingxian Li, PhD, one of the lead authors of the study, want to continue working to understand how these proteins carry out their many different roles.

Li, Jingxian et al.
Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse
Cell, Volume 173 , Issue 3 , 735 – 748.e15

Image: 3-D model of a teneurin protein. Credit: Araç, et al, UChicago