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Abstract
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 X-ray crystallography and cryo-EM structures of two Teneurins, revealing a ~200 kDa extracellular super-fold in which eight sub-domains form an intricate structure centred on a spiralling YD-repeat shell. An alternatively spliced loop, which is implicated in homophilic Teneurin interaction and specificity, is exposed and thus poised for interaction. The N-terminal side of the shell is ‘plugged’ via a fibronectin-plug domain combination, which defines a new class of YD proteins. Unexpectedly, we find that these proteins are widespread amongst modern bacteria, suggesting early metazoan receptor evolution from a distinct class of proteins, which today includes both bacterial proteins and eukaryotic Teneurins.
Highlights
Teneurins are ancient cell–cell adhesion receptors that are vital for brain development and synapse organisation
The structures were solved by X-ray crystallography (Ten2CT, Supplementary Fig. 1) and singleparticle cryo-electron microscopy (EM) (Ten3CT) to 2.4 and 3.8 Å resolution, respectively
Unlike previously described mammalian adhesion proteins, which contain small globular domain repeats in their extracellular regions, we show that Teneurins are derived from an evolutionarily ancient protein super-fold that is widespread across the bacterial kingdom
Summary
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. The Teneurin extracellular region defines its adhesive specificity and controls both homophilic and heterophilic trans interactions across the synapse. It contains eight membrane-proximal epidermal growth factor-like repeats (EGF1–8), which bear similarity to the vertebrate extracellular matrix protein tenascin[16,17,18] and harbour intermolecular disulphide bonds that covalently dimerise Teneurins[19,20]. Our data provide structural insights into early receptor evolution, YD-repeat protein architecture and Teneurin function
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