<br/>Synaptotagmin 1 (Syt 1) is a synaptic vesicle-localized integral membrane protein that senses the calcium ion influx to trigger synchronous release of neurotransmitter. The family of synaptotagmins have a commonality of being comprised of two tandem repeat domains (C2 domains) that are covalently linked to the transmembrane region by a variable peptide linker. We propose a model of how the two cytosolic C2 domains of Syt 1 communicate to propagate the calcium ion binding signal that is allosterically modulated by both its variable linker as well as by synaptic lipids. We provide experimental evidence that is consistent with the variable linker of Syt 1 being a functional domain that modulates sensing of calcium ion. The variable linker of Syt 1 has the hallmarks of an intrinsically disordered region. Intriguingly, this finding of the variable linker being an intrinsically disordered region extends to other members of the synaptotagmin family. This newly defined intrinsically disordered region of Syt 1 was found to interact with membranes whose lipid composition mimics that of the synaptic vesicle. We also define how the overall plasticity of Syt 1 impacts its function in its sensing of calcium ion. The role of lipids in modulating the structural disorder, coupling, sensing of calcium ion and disruption of the membrane by Syt 1 calls into question current models of Syt 1 action.

Domains of synaptotagmin 1 are structurally disordered, coupled and are allosterically modulated by synaptic vesicle lipids: Each modulates the calcium ion sensing capabilities of synaptotagmin 1

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.