The juxtamembrane linker of synaptotagmin 1 regulates Ca²⁺ binding via liquid-liquid phase separation.

ABSTRACT: Synaptotagmin (syt) 1, a Ca²⁺ sensor for synaptic vesicle exocytosis, is thought to act in vivo as a multimer. It senses Ca²⁺ via tandem C2-domains that are connected to a single transmembrane domain via a juxtamembrane linker. Here, we show that this linker segment harbors a lysine-rich, intrinsically disordered region that is necessary and sufficient to mediate liquid-liquid phase separation (LLPS). Unexpectedly, these interactions negatively regulate the Ca²⁺-sensitivity of the tandem C2-domains of syt1. Ca²⁺ and anionic phospholipids promote the observed phase separation. This potentially creates a feedback loop that might serve to fine-tune the ability of syt1 to trigger release, via alterations in Ca²⁺ binding activity and potentially through the impact of LLPS on membrane curvature during fusion reactions. In summary, the juxtamembrane linker of syt1 emerges as a regulator of syt1 function by driving self-association via LLPS.

SUBMITTER: Mehta N 

PROVIDER: S-EPMC10441399 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature