RGD Reference Report - The juxtamembrane linker of synaptotagmin 1 regulates Ca2+ binding via liquid-liquid phase separation. - Rat Genome Database

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

Authors: Mehta, Nikunj  Mondal, Sayantan  Watson, Emma T  Cui, Qiang  Chapman, Edwin R 
Citation: Mehta N, etal., Nat Commun. 2024 Jan 4;15(1):262. doi: 10.1038/s41467-023-44414-5.
RGD ID: 407430008
Pubmed: PMID:38177243   (View Abstract at PubMed)
PMCID: PMC10766989   (View Article at PubMed Central)
DOI: DOI:10.1038/s41467-023-44414-5   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Syt1Ratmembraneless organelle assembly involved_inIDA PMID:38177243DisProt 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Syt1Ratidentical protein binding enablesEXP PMID:38177243DisProt 
Syt1Ratmolecular condensate scaffold activity enablesEXP PMID:38177243DisProt 
Syt1Ratmolecular condensate scaffold activity enablesIDA PMID:38177243DisProt 

Objects Annotated

Genes (Rattus norvegicus)
Syt1  (synaptotagmin 1)


Additional Information