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

Marieke MeijerMiriam ÖttlJie YangAygul SubkhangulovaAvinash KumarZicheng FengTorben W van VoorstAlexander J GroffenJan R T van WeeringYongli ZhangMatthijs Verhage
Published in: Nature communications (2024)
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.
Keyphrases
  • single molecule
  • mouse model
  • prefrontal cortex
  • depressive symptoms
  • molecularly imprinted
  • atomic force microscopy
  • high frequency
  • living cells
  • genome wide
  • gene expression
  • dna methylation
  • high resolution