Nature communications, 2020-05, Vol.11 (1), p.2140-17, Article 2140
2020
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- Autor(en) / Beteiligte
- Titel
- Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism
- Ist Teil von
- Nature communications, 2020-05, Vol.11 (1), p.2140-17, Article 2140
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs) with latrophilins (LPHNs/ADGRLs) promotes excitatory synapse formation when LPHNs simultaneously interact with FLRTs. Insertion of a short alternatively-spliced region within TENs abolishes the TEN-LPHN interaction and switches TEN function to specify inhibitory synapses. How alternative-splicing regulates TEN-LPHN interaction remains unclear. Here, we report the 2.9 Å resolution cryo-EM structure of the TEN2-LPHN3 complex, and describe the trimeric TEN2-LPHN3-FLRT3 complex. The structure reveals that the N-terminal lectin domain of LPHN3 binds to the TEN2 barrel at a site far away from the alternatively spliced region. Alternative-splicing regulates the TEN2-LPHN3 interaction by hindering access to the LPHN-binding surface rather than altering it. Strikingly, mutagenesis of the LPHN-binding surface of TEN2 abolishes the LPHN3 interaction and impairs excitatory but not inhibitory synapse formation. These results suggest that a multi-level coincident binding mechanism mediated by a cryptic adhesion complex between TENs and LPHNs regulates synapse specificity. The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs) with latrophilins (LPHNs) promotes excitatory synapse formation. Here authors report the high resolution cryo-EM structure of the TEN2-LPHN3 complex, describe the trimeric TEN2-LPHN3-FLRT3 complex and show how alternative-splicing regulates the TEN2-LPHN3 interaction.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-020-16029-7Titel-ID: cdi_doaj_primary_oai_doaj_org_article_40b62dc45fba43818c436bb498569426
- Format
- –
- Schlagworte
- 101/28, 13, 631/378/3920, 631/45/535, 82/16, 82/80, 96, 96/106, 96/31, 96/35, 96/95, Adhesion, Alternative splicing, Alternative Splicing - genetics, Alternative Splicing - physiology, Amino acids, Attention deficit hyperactivity disorder, Binding, Binding sites, Binding Sites - genetics, Cell adhesion, Cell adhesion molecules, HEK293 Cells, Humanities and Social Sciences, Humans, Ligands, Membrane Glycoproteins - chemistry, Membrane Glycoproteins - genetics, Membrane Glycoproteins - metabolism, Membrane Proteins - chemistry, Membrane Proteins - genetics, Membrane Proteins - metabolism, multidisciplinary, Mutagenesis, Mutation - genetics, Nerve Tissue Proteins - chemistry, Nerve Tissue Proteins - genetics, Nerve Tissue Proteins - metabolism, Protein Binding - genetics, Protein Structure, Secondary, Proteins, Receptors, G-Protein-Coupled - chemistry, Receptors, G-Protein-Coupled - genetics, Receptors, G-Protein-Coupled - metabolism, Receptors, Peptide - chemistry, Receptors, Peptide - genetics, Receptors, Peptide - metabolism, Roles, Science, Science (multidisciplinary), Splicing, Switches, Synapses, Synapses - metabolism, Synapses - physiology, Synaptogenesis, Transgenic animals