Structures of Teneurin adhesion receptors reveal an ancient fold for cell-cell interaction

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.

Structure of the teneurin-latrophilin complex: Alternative splicing controls synapse specificity by a novel mechanism

“…The Lec domain of Lphn3 interacts with the side of the barrel domain of Tenm2 ( Figure 1D-F). The Tenm2 ECR is assembled as a large cylindrical barrel sealed by the β -propeller and Ig-like domains at the bottom; and the toxin-like domain protrudes from and attaches to the side of the barrel as previously reported (Jackson et al, 2018;Li et al, 2018). The Lec domain of Lphn3 and the toxin-like domain of Tenm2 bind to opposite faces of the betabarrel in a seemingly parallel orientation to each other ( Figure 1D-F).…”

“…In this conformation, FLRT3 is also able to interact with Lphn3 and form a trimeric complex, consequently leading to excitatory synapse formation ( Figure 7A). However, the crystal structure of the Tenm2 +SS isoform showed that, in the presence of the splice insert, the two globular heads form a dimer that is facilitated by the interactions between the splice inserts ( Figure S7) (Jackson et al, 2018).…”

“…The DHR mutation breaks the interaction of Tenm2 -SS with Lphn3 and abolishes excitatory synapse formation. (B) The Tenm2 +SS isoform does not have rotational flexibility around the linker between the EGF repeats and the rest of the extracellular head as observed in the crystal structure of the Tenm2 +SS isoform, which shows that the splice insert mediates a dimeric interaction between the two Tenm2 +SS protomers (Jackson et al, 2018) (Figure S7, PDB ID: 6FB3). Instead, the Tenm2 +SS protomers are zipped-up due to the additional two salt bridges (black balls) between the propellers of the Tenm2 cisdimer.…”

“…Two salt bridges align almost parallel to each other and to the disulfide bonds between the EGF repeats and restricts the conformational flexibility of the Tenm2 head significantly (see Figure 7). The N-termini of both protomers face the same direction towards the EGF repeats, and thus, the dimer is positioned as a cis-dimer that will extend the zippering of the already existing EGF-mediated cis-dimer, although it was reported to form as a trans-homodimer, previously (Jackson et al, 2018). TEN protomers (PDB: 6FB3) are colored as cyan and palegreen, respectively, and splice sites are colored as tellow and magenta, respectively.…”

The Tenets of Teneurin: Conserved Mechanisms Regulate Diverse Developmental Processes in the Drosophila Nervous System

“…This may occur via modulation of the cytoskeleton (Zheng et al, 2011) at both the NMJ and in the CNS, revealing a fascinating instance of mechanistic conservation. Their widespread expression in both invertebrate and vertebrate systems (Antinucci et al, 2013;Dharmaratne et al, 2012;Feng et al, 2002;Kenzelmann et al, 2008;Li et al, 2006;Mörck et al, 2010;Mosca, 2015;Zhang et al, 2018) and conservation of protein structure and mechanistic function (Jackson et al, 2018) suggests they may represent a general and versatile matching mechanism across synapse types and evolutionary taxa.…”