{Reference Type}: Journal Article
{Title}: Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes.
{Author}: Meijer M;Öttl M;Yang J;Subkhangulova A;Kumar A;Feng Z;van Voorst TW;Groffen AJ;van Weering JRT;Zhang Y;Verhage M;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Mar 26
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-46828-1
{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.