Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 48, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2113859118
Keywords
exocytosis; synaptotagmin; oligomerization; neurotransmission
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Funding
- NIH [MH061876, NS097362]
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Studies on Synaptotagmin 1 (syt1) have shown that it plays a crucial role in synaptic vesicle exocytosis, with its self-assembling multimers being enhanced by Ca2+ and dependent on anionic phospholipids. Additionally, the juxtamembrane linker of syt1 plays a key role in exocytosis by mediating multimerization.
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 micros-copy studies have yielded contradictory findings regarding putative self-association. Here, we performed dynamic light scattering on syt1 in solution, followed by electron microscopy, and we 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 (similar to 180 nm) were reduced to smaller rings (similar to 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 1) clamping spontaneous release and 2) triggering and synchronizing evoked release. Thus, the juxtamembrane linker of syt1 plays a crucial role in exocytosis by mediating multimerization.
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