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bioRxiv · 10.1101/2021.07.28.454225

Synaptotagmin 1 oligomerization via the juxtamembrane linker regulates spontaneous and evoked neurotransmitter release

Courtney, K. C.·Li, Y.·Vevea, J. D.·Wu, Z.·Zhang, Z.·Chapman, E. R.
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Abstract

Synaptotagmin-1 (syt1) is a Ca2+ sensor that regulates synaptic vesicle exocytosis. Cell-based experiments suggest that syt1 functions as a multimer, however biochemical and electron microscopy studies have yielded contradictory findings regarding putative self-association. Here, we performed dynamic light scattering on syt1 in solution, followed by electron microscopy, and used atomic force microscopy to study syt1 self-association on supported lipid bilayers under aqueous conditions. Ring-like multimers were clearly observed. Multimerization was enhanced by Ca2+ and required anionic phospholipids. Large ring-like structures ([~]180 nm) were reduced to smaller rings ([~]30 nm) upon neutralization of a cluster of juxtamembrane lysine residues; further substitution of residues in the second C2-domain completely abolished self-association. When expressed in neurons, syt1 mutants with graded reductions in self-association activity exhibited concomitant reductions in: a) clamping spontaneous release, and b) triggering and synchronizing evoked release. Thus, the juxtamembrane linker of syt1 plays a crucial role in exocytosis by mediating multimerization.

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Courtney, K. C., Li, Y., Vevea, J. D., Wu, Z., Zhang, Z., Chapman, E. R.. 2021-07-29. Synaptotagmin 1 oligomerization via the juxtamembrane linker regulates spontaneous and evoked neurotransmitter release. https://doi.org/10.1101/2021.07.28.454225

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