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Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism

Author

Listed:
  • Jingxian Li

    (The University of Chicago
    The University of Chicago)

  • Yuan Xie

    (The University of Chicago)

  • Shaleeka Cornelius

    (Stanford University
    Howard Hughes Medical Institute)

  • Xian Jiang

    (Stanford University
    Howard Hughes Medical Institute)

  • Richard Sando

    (Stanford University
    Howard Hughes Medical Institute)

  • Szymon P. Kordon

    (The University of Chicago
    The University of Chicago)

  • Man Pan

    (The University of Chicago)

  • Katherine Leon

    (The University of Chicago
    The University of Chicago)

  • Thomas C. Südhof

    (Stanford University
    Howard Hughes Medical Institute)

  • Minglei Zhao

    (The University of Chicago)

  • Demet Araç

    (The University of Chicago
    The University of Chicago)

Abstract

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.

Suggested Citation

  • Jingxian Li & Yuan Xie & Shaleeka Cornelius & Xian Jiang & Richard Sando & Szymon P. Kordon & Man Pan & Katherine Leon & Thomas C. Südhof & Minglei Zhao & Demet Araç, 2020. "Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16029-7
    DOI: 10.1038/s41467-020-16029-7
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    Cited by:

    1. Szymon P. Kordon & Przemysław Dutka & Justyna M. Adamska & Sumit J. Bandekar & Katherine Leon & Satchal K. Erramilli & Brock Adams & Jingxian Li & Anthony A. Kossiakoff & Demet Araç, 2023. "Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Matthew O. Ross & Yuan Xie & Ryan C. Owyang & Chang Ye & Olivia N. P. Zbihley & Ruitu Lyu & Tong Wu & Pingluan Wang & Olga Karginova & Olufunmilayo I. Olopade & Minglei Zhao & Chuan He, 2024. "PTPN2 copper-sensing relays copper level fluctuations into EGFR/CREB activation and associated CTR1 transcriptional repression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Christos Gogou & J. Wouter Beugelink & Cátia P. Frias & Leanid Kresik & Natalia Jaroszynska & Uwe Drescher & Bert J. C. Janssen & Robert Hindges & Dimphna H. Meijer, 2024. "Alternative splicing controls teneurin-3 compact dimer formation for neuronal recognition," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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