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

Marieke Meijer (), Miriam Öttl, Jie Yang (), Aygul Subkhangulova, Avinash Kumar, Zicheng Feng, Torben W. Voorst, Alexander J. Groffen, Jan R. T. Weering, Yongli Zhang () and Matthijs Verhage ()
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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
Matthijs Verhage: Amsterdam University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46828-1

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