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

Nikunj Mehta, Sayantan Mondal, Emma T. Watson, Qiang Cui and Edwin R. Chapman ()
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Nikunj Mehta: University of Wisconsin−Madison
Sayantan Mondal: Boston University
Emma T. Watson: University of Wisconsin−Madison
Qiang Cui: Boston University
Edwin R. Chapman: University of Wisconsin−Madison

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Synaptotagmin (syt) 1, a Ca2+ sensor for synaptic vesicle exocytosis, functions in vivo as a multimer. Syt1 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). Interestingly, condensate formation negatively regulates the Ca2+-sensitivity of syt1. Moreover, Ca2+ and anionic phospholipids facilitate the observed phase separation, and increases in [Ca2+]i promote the fusion of syt1 droplets in living cells. Together, these observations suggest a condensate-mediated feedback loop that serves 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.

Date: 2024
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DOI: 10.1038/s41467-023-44414-5

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