Alternative splicing controls teneurin-3 compact dimer formation for neuronal recognition

Christos Gogou, J. Wouter Beugelink, Cátia P. Frias, Leanid Kresik, Natalia Jaroszynska, Uwe Drescher, Bert J. C. Janssen, Robert Hindges and Dimphna H. Meijer ()
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Christos Gogou: Delft University of Technology
J. Wouter Beugelink: Utrecht University
Cátia P. Frias: Delft University of Technology
Leanid Kresik: Delft University of Technology
Natalia Jaroszynska: Guy’s Campus
Uwe Drescher: Guy’s Campus
Bert J. C. Janssen: Utrecht University
Robert Hindges: Guy’s Campus
Dimphna H. Meijer: Delft University of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Neuronal network formation is facilitated by recognition between synaptic cell adhesion molecules at the cell surface. Alternative splicing of cell adhesion molecules provides additional specificity in forming neuronal connections. For the teneurin family of cell adhesion molecules, alternative splicing of the EGF-repeats and NHL domain controls synaptic protein-protein interactions. Here we present cryo-EM structures of the compact dimeric ectodomain of two teneurin-3 isoforms that harbour the splice insert in the EGF-repeats. This dimer is stabilised by an EGF8-ABD contact between subunits. Cryo-EM reconstructions of all four splice variants, together with SAXS and negative stain EM, reveal compacted dimers for each, with variant-specific dimeric arrangements. This results in specific trans-cellular interactions, as tested in cell clustering and stripe assays. The compact conformations provide a structural basis for teneurin homo- and heterophilic interactions. Altogether, our findings demonstrate how alternative splicing results in rearrangements of the dimeric subunits, influencing neuronal recognition and likely circuit wiring.

Date: 2024
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DOI: 10.1038/s41467-024-47763-x

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