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Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes

Author

Listed:
  • Marieke Meijer

    (Amsterdam University Medical Center)

  • Miriam Öttl

    (Vrije Universiteit Amsterdam)

  • Jie Yang

    (Yale School of Medicine)

  • Aygul Subkhangulova

    (Vrije Universiteit Amsterdam)

  • Avinash Kumar

    (Yale School of Medicine)

  • Zicheng Feng

    (Yale School of Medicine)

  • Torben W. Voorst

    (Vrije Universiteit Amsterdam)

  • Alexander J. Groffen

    (Amsterdam University Medical Center)

  • Jan R. T. Weering

    (Amsterdam University Medical Center)

  • Yongli Zhang

    (Yale School of Medicine
    Yale University)

  • Matthijs Verhage

    (Amsterdam University Medical Center
    Vrije Universiteit Amsterdam)

Abstract

Tomosyns are widely thought to attenuate membrane fusion by competing with synaptobrevin-2/VAMP2 for SNARE-complex assembly. Here, we present evidence against this scenario. In a novel mouse model, tomosyn-1/2 deficiency lowered the fusion barrier and enhanced the probability that synaptic vesicles fuse, resulting in stronger synapses with faster depression and slower recovery. While wild-type tomosyn-1m rescued these phenotypes, substitution of its SNARE motif with that of synaptobrevin-2/VAMP2 did not. Single-molecule force measurements indeed revealed that tomosyn’s SNARE motif cannot substitute synaptobrevin-2/VAMP2 to form template complexes with Munc18-1 and syntaxin-1, an essential intermediate for SNARE assembly. Instead, tomosyns extensively bind synaptobrevin-2/VAMP2-containing template complexes and prevent SNAP-25 association. Structure-function analyses indicate that the C-terminal polybasic region contributes to tomosyn’s inhibitory function. These results reveal that tomosyns regulate synaptic transmission by cooperating with synaptobrevin-2/VAMP2 to prevent SNAP-25 binding during SNARE assembly, thereby limiting initial synaptic strength and equalizing it during repetitive stimulation.

Suggested Citation

  • Marieke Meijer & Miriam Öttl & Jie Yang & Aygul Subkhangulova & Avinash Kumar & Zicheng Feng & Torben W. Voorst & Alexander J. Groffen & Jan R. T. Weering & Yongli Zhang & Matthijs Verhage, 2024. "Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46828-1
    DOI: 10.1038/s41467-024-46828-1
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    References listed on IDEAS

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