Affinage

ESYT1

Extended synaptotagmin-1 · UniProt Q9BSJ8

Length
1104 aa
Mass
122.9 kDa
Annotated
2026-06-09
17 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ESYT1 is a Ca2+-regulated membrane contact-site tethering protein that couples cytosolic Ca2+ elevation to non-vesicular lipid transfer between the ER and apposed membranes (PMID:24183667, PMID:36821088). Upon Ca2+ rise, E-Syt1 translocates to ER-plasma membrane junctions, where it rearranges neighboring ER into stabilized ring-shaped contact sites and accelerates local ER Ca2+ replenishment during store-operated Ca2+ entry (PMID:24183667, PMID:30850711). At these junctions it nucleates phosphoinositide homeostasis machinery, recruiting the PI transfer protein Nir2 and ER-localized PI4KA to drive PM PIP2/PI4P replenishment in a feedback loop that sustains Ca2+ signaling (PMID:24183667, PMID:42258130). Through this junctional lipid- and scaffold-organizing role, E-Syt1 controls the trafficking and gating of ion channels, negatively regulating ANO1 surface delivery while assembling an ANO1-AC8-AKAP5-PKA signaling complex that phosphorylates ANO1 to tune its Ca2+ affinity (PMID:29154949, PMID:40204782), and supporting activity-dependent surface expression of AMPA receptors in hippocampal dendrites during LTP (PMID:37484831). E-Syt1 also tethers the ER to mitochondria: PERK and the outer mitochondrial membrane protein SYNJ2BP recruit E-Syt1 to ER-mitochondria contacts, where its SMP domain transfers phospholipids to maintain the mitochondrial lipidome (cardiolipins, phosphatidylethanolamines), ER-to-mitochondria Ca2+ flux, and respiration (PMID:36821088, PMID:37931956). Beyond membrane biology, Ca2+-driven E-Syt1 recruitment mediates HDL-derived cholesterol transfer for sterol synthesis (PMID:40437229), and the protein is a phosphorylation substrate of the oncogenic CD74-ROS kinase and of insulin-activated Cdk5, linking it to cell invasion and GLUT4-dependent glucose uptake respectively (PMID:22659450, PMID:19255425).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2009 Medium

    Established E-Syt1 as a regulated phosphoprotein in metabolic signaling by showing insulin-activated Cdk5 phosphorylates it to enable GLUT4 association and glucose uptake.

    Evidence Kinase assay, co-IP, Cdk5 silencing and roscovitine, glucose uptake in 3T3-L1 adipocytes

    PMID:19255425

    Open questions at the time
    • Phosphosite(s) and their structural consequence not mapped
    • Mechanism by which phospho-E-Syt1 engages GLUT4 trafficking unresolved
  2. 2012 Medium

    Connected E-Syt1 phosphorylation to malignancy by identifying it as a CD74-ROS substrate required for invasion and metastasis.

    Evidence Quantitative phosphoproteomics, siRNA knockdown, in vitro invasion and in vivo metastasis assays

    PMID:22659450

    Open questions at the time
    • Molecular pathway linking E-Syt1 to invasiveness not defined
    • Whether the lipid-transfer/tethering function underlies the invasion phenotype unknown
  3. 2013 High

    Defined the core ER-PM junction function: Ca2+ triggers E-Syt1 translocation that recruits Nir2 to replenish PM PIP2 and sustain Ca2+ signaling, framing E-Syt1 as a Ca2+ sensor in a phosphoinositide feedback loop.

    Evidence Genetically encoded ER-PM junction marker, live-cell imaging, siRNA knockdown with Ca2+/PIP2 readouts

    PMID:24183667

    Open questions at the time
    • Direct lipid-transfer activity not assayed in this study
    • Stoichiometry of E-Syt1-Nir2 recruitment unresolved
  4. 2017 Medium

    Revealed a channel-trafficking role by showing E-Syt1 negatively regulates ANO1 surface delivery and current density.

    Evidence siRNA screen with inducible ANO1 microscopy assay and whole-cell patch clamp

    PMID:29154949

    Open questions at the time
    • Mechanism of trafficking suppression not established
    • Direct vs indirect (lipid-mediated) effect on ANO1 not distinguished
  5. 2019 Medium

    Provided nanoscale structural insight, showing activated E-Syt1 moves toward the PM and remodels ER into ring-shaped contact sites distinct from STIM1's role in SOCE.

    Evidence Home-built live-cell super-resolution (TIRF/PALM) with quantitative nanoscale tracking

    PMID:30850711

    Open questions at the time
    • Single primary imaging method
    • Causal link between geometric remodeling and lipid transfer not tested
  6. 2023 High

    Extended E-Syt1 function to ER-mitochondria contacts, identifying PERK and SYNJ2BP as recruiting partners and demonstrating SMP-dependent phospholipid transfer required for mitochondrial respiration and lipidome integrity.

    Evidence BioID, reciprocal Co-IP, SMP-domain deletion, lipidomics, Ca2+ flux, respiration assays, genetic rescue (two studies)

    PMID:36821088 PMID:37931956

    Open questions at the time
    • Whether PERK and SYNJ2BP act in the same or parallel tethering complexes unclear
    • Direction and selectivity of SMP lipid transfer in cells not directly measured
  7. 2023 Medium

    Demonstrated a neuronal contact-site role, with E-Syt1-mediated dendritic ER-PM contacts required for activity-dependent AMPA receptor surface expression during LTP.

    Evidence Split-GFP ER-PM contact probe in hippocampal neurons, knockdown, surface AMPA receptor imaging

    PMID:37484831

    Open questions at the time
    • Molecular steps linking contact sites to receptor trafficking not defined
    • Lipid species involved not identified
  8. 2023 Medium

    Identified a Ca2+-gated signaling-suppressor interaction with the adhesion GPCR GPR133 via the C2C domain, relieved by Ca2+-driven dissociation to raise cAMP.

    Evidence Proximity biotinylation proteomics, domain mapping, cAMP measurements, thapsigargin (preprint)

    PMID:36798364

    Open questions at the time
    • Preprint, not peer-reviewed
    • Direct vs scaffold-mediated GPR133 contact unresolved
  9. 2024 Medium

    Showed E-Syt1 dosage controls mitochondrial quality, with overexpression causing Ca2+/ROS overload and blocking mitophagic flux while silencing rescues respiration and dynamics.

    Evidence Gain/loss-of-function in myoblasts, mitochondrial Ca2+/ROS/mitophagy/lysosomal pH assays, in vivo exercise capacity

    PMID:39675068

    Open questions at the time
    • Mechanism linking E-Syt1 to lysosomal acidification unknown
    • Whether effects are tether-dependent or signaling-dependent not separated
  10. 2024 Low

    Implicated E-Syt1 in regulated secretion, with PACS-1 promoting TRPC3-E-Syt1 interactions and PM localization to support SOCE and ACTH secretion.

    Evidence Co-IP, PM localization assays, SOCE measurement, ACTH secretion assay, siRNA knockdown

    PMID:39157130

    Open questions at the time
    • Mechanism downstream of E-Syt1 in ACTH secretion unresolved
    • Co-IP interactions lack reciprocal/structural validation
  11. 2025 Medium

    Resolved a junctional signaling complex in which E-Syt1 organizes an ANO1-VAPA-IRBIT-AC8-AKAP5-PKA assembly and modulates junctional lipids to tune ANO1 Ca2+ affinity via S673 phosphorylation.

    Evidence Co-IP, phosphosite mapping, Ca2+ affinity and lipid measurements, IRBIT knockout mouse

    PMID:40204782

    Open questions at the time
    • Assembly order/stoichiometry of the complex not defined
    • How E-Syt1 sets junctional lipid composition mechanistically unclear
  12. 2025 Medium

    Linked E-Syt1 to sterol metabolism, showing HDL-S1P/S1PR3/Gq/PLCβ3 Ca2+ signaling recruits E-Syt1 to drive non-vesicular HDL-cholesterol transfer for steroid/bile acid synthesis.

    Evidence Genetic/pharmacological S1P pathway disruption, live-cell imaging, cholesterol transport assays

    PMID:40437229

    Open questions at the time
    • Whether E-Syt1 directly transports cholesterol or organizes the transfer site not distinguished
    • Destination compartment specificity unresolved
  13. 2025 Medium

    Added an immunoregulatory dimension, with NLRP6 PYD binding the E-Syt1 SMP domain to suppress macrophage phagocytosis and promote HCC progression.

    Evidence Co-IP mass spectrometry, Co-IP, phagocytosis assays, adoptive macrophage transfer in vivo

    PMID:40473401

    Open questions at the time
    • How SMP-domain occupancy alters phagocytosis mechanistically unknown
    • Lipid-transfer dependence of the phagocytosis effect untested
  14. 2026 Medium

    Completed the phosphoinositide-replenishment circuit, showing Ca2+-activated E-Syt1 recruits ER PI4KA to ER-PM junctions to drive PM PI4P synthesis, including during neuronal LTP.

    Evidence Co-IP, live imaging of PI4KA localization, PI4P biosensors, knockdown/knockout, neuronal LTP model

    PMID:42258130

    Open questions at the time
    • Direct vs bridged E-Syt1-PI4KA contact not resolved
    • Relationship to Nir2 recruitment pathway not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether E-Syt1's distinct activities — ER-PM versus ER-mitochondria tethering, channel scaffolding, lipid transfer, and oncogenic phosphorylation — reflect one unified biochemical mechanism or separable functions in different contexts remains unresolved.
  • No structure of full-length E-Syt1 in a tethered/lipid-loaded state in the corpus
  • In-cell directionality and selectivity of SMP-mediated lipid transfer not directly measured
  • Quantitative partitioning between ER-PM and ER-mitochondria pools not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0140299 molecular sensor activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ANO1GLUT4GPR133NLRP6PACS-1PERKPI4KASYNJ2BP
Complex memberships
ANO1-VAPA-IRBIT-E-Syt1-AC8-AKAP5-PKA junctional complexESYT1-SYNJ2BP ER-mitochondria tether

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Elevation of cytosolic Ca2+ triggers translocation of E-Syt1 to ER-PM junctions, which subsequently facilitates recruitment of Nir2 (a phosphatidylinositol transfer protein) to ER-PM junctions, promoting replenishment of PM PIP2 after receptor-induced hydrolysis and sustaining Ca2+ signaling in a feedback loop. Genetically encoded ER-PM junction marker, live-cell imaging, siRNA knockdown with Ca2+ signaling and PIP2 readouts Cell reports High 24183667
2012 The oncogenic fusion kinase CD74-ROS phosphorylates E-Syt1, and this phosphorylation event is required for CD74-ROS-driven cell invasion in vitro and metastasis in vivo; E-Syt1 knockdown drastically reduces invasiveness without affecting CD74-ROS oncogenic signaling. Quantitative phosphoproteomics, siRNA knockdown, invasion assays in vitro, metastasis assay in vivo Cancer research Medium 22659450
2009 Insulin-activated Cdk5 phosphorylates E-Syt1 in a PI3K-dependent manner; phosphorylated E-Syt1 associates with GLUT4, and this interaction is required for insulin-dependent glucose uptake in 3T3-L1 adipocytes. Kinase assay, co-immunoprecipitation, Cdk5 silencing, glucose uptake assay, pharmacological inhibitor (roscovitine) Proceedings of the National Academy of Sciences of the United States of America Medium 19255425
2023 PERK acts as an adaptor recruiting E-Syt1 to ER-mitochondria contact sites (EMCS) via a direct heterotypic E-Syt1-PERK interaction; the SMP domain of E-Syt1 transfers phospholipids between ER and mitochondria at these contacts, and disruption of the interaction or deletion of the SMP domain impairs mitochondrial respiration. Co-immunoprecipitation, proximity labeling (BioID), confocal microscopy, subcellular fractionation, SMP-domain deletion mutants, mitochondrial respiration assays The Journal of cell biology High 36821088
2019 During store-operated Ca2+ entry, activated E-Syt1 moves ~12 nm toward the PM and re-arranges neighboring ER structures into ring-shaped ER-PM contact sites (230–280 nm diameter) enclosing E-Syt1 puncta, stabilizing these contact sites and accelerating local ER Ca2+ replenishment; E-Syt1 and STIM1 play distinct roles in MCS formation and SOCE. Home-built live-cell super-resolution microscopy (TIRF/PALM), quantitative nanoscale tracking of E-Syt1 and STIM1 Scientific reports Medium 30850711
2023 ESYT1 localizes to mitochondria-ER contact sites (MERCs) where it forms a complex with the outer mitochondrial membrane protein SYNJ2BP; deletion of ESYT1 or SYNJ2BP reduces MERC number and length, impairs ER-to-mitochondria Ca2+ flux, and alters the mitochondrial lipidome (reducing cardiolipins and phosphatidylethanolamines); these phenotypes are rescued by re-expression of WT ESYT1 or an artificial ER-mitochondria tether. BioID proximity labeling, co-immunoprecipitation, confocal microscopy, subcellular fractionation, CRISPR knockout, lipidomics, Ca2+ flux assays, rescue experiments Life science alliance High 37931956
2017 ESYT1 negatively regulates the trafficking of anoctamin 1 (ANO1) to the plasma membrane; siRNA knockdown of ESYT1 increases ANO1 PM localization, whereas ESYT1 overexpression decreases it; knockdown of ESYT1 (and ESYT2, ESYT3) also significantly decreases ANO1 current density. siRNA screen with inducible 3HA-ANO1-eGFP microscopy assay, electrophysiology (whole-cell patch clamp) Biochimica et biophysica acta. Molecular cell research Medium 29154949
2023 E-Syt1 mediates formation of ER-PM contact sites in hippocampal neuron dendrites during LTP and is required for neuronal activity-dependent surface expression of AMPA receptors. Split-GFP-based ER-PM contact probe in hippocampal neurons, E-Syt1 knockdown, surface AMPA receptor imaging Contact (Thousand Oaks (Ventura County, Calif.)) Medium 37484831
2025 NLRP6 interacts with E-Syt1 through its PYD domain binding to E-Syt1's SMP domain; this interaction negatively regulates E-Syt1-promoted macrophage phagocytosis, thereby facilitating hepatocellular carcinoma progression. Co-immunoprecipitation mass spectrometry, western blot, co-immunoprecipitation, phagocytosis assays, adoptive macrophage transfer in vivo Gut Medium 40473401
2025 E-Syt1 assembles an ANO1-VAPA-IRBIT-E-Syt1-AC8-AKAP5-PKA complex at STIM1 ER-PM junctions; PKA within this complex phosphorylates ANO1 at S673, increasing ANO1 Ca2+ affinity; E-Syt1 also modulates junctional PI(4)P, PI(4,5)P2 and PtdSer levels to regulate ANO1 function. Co-immunoprecipitation, phosphorylation site mapping, Ca2+ affinity measurements, lipid measurements at ER-PM junctions, IRBIT knockout mouse model Nature communications Medium 40204782
2025 HDL-resident sphingosine-1-phosphate (S1P) activates S1PR3/Gαq/PLCβ3 signaling, triggering cytosolic Ca2+ elevation that drives E-Syt1 recruitment to ER-PM contact sites; this recruitment is required for non-vesicular transfer of HDL-derived cholesterol to intracellular compartments for steroid and bile acid synthesis. Genetic and pharmacological disruption of S1P pathway, live-cell imaging of E-Syt1 recruitment, cholesterol transport assays Nature cell biology Medium 40437229
2024 E-Syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst in myoblasts, inhibits mitophagic flux by blocking fusion of mitophagosomes with lysosomes and impairing lysosomal acidification; E-Syt1 silencing rescues mitochondrial respiration, biogenesis, and dynamics. In vitro gain- and loss-of-function in myoblasts, mitochondrial Ca2+ measurements, ROS assays, mitophagy flux assays, lysosomal pH measurements, animal exercise capacity measurements Redox biology Medium 39675068
2024 PACS-1 interacts with ESyt1 and promotes interactions between TRPC3 and ESyt1, regulating their plasma membrane localization; PACS-1 is required for proper store-operated Ca2+ entry (SOCE), and ESyt1 regulates ACTH secretion in corticotropic cells through a mechanism dependent on PACS-1. Co-immunoprecipitation, plasma membrane localization assays, SOCE measurement, ACTH secretion assay, siRNA knockdown ACS omega Low 39157130
2023 ESYT1 interacts with the adhesion GPCR GPR133 via the Ca2+-sensing C2C domain of ESYT1; this interaction suppresses GPR133/Gαs signaling; elevated cytosolic Ca2+ (via thapsigargin) promotes ESYT1-GPR133 dissociation, relieving signaling suppression and raising cAMP levels. Proximity biotinylation proteomics, ESYT1 knockdown/knockout, overexpression, domain mapping (C2C mutant), cAMP measurements, thapsigargin Ca2+ manipulation bioRxivpreprint Medium 36798364
2026 In response to Ca2+, E-Syt1 recruits ER-localized PI4KA to ER-PM junctions, facilitating PI4KA PM localization and PI4P synthesis at the PM; in hippocampal neurons undergoing LTP, neuronal activity-induced PI4KA PM localization and PI4P synthesis also depend on E-Syt1. Co-immunoprecipitation, live-cell imaging of PI4KA localization, PI4P biosensors, E-Syt1 knockdown/knockout, Ca2+ manipulation, neuronal LTP model Science China. Life sciences Medium 42258130

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions. Cell reports 300 24183667
2012 The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation. Cancer research 88 22659450
2009 The atypical kinase Cdk5 is activated by insulin, regulates the association between GLUT4 and E-Syt1, and modulates glucose transport in 3T3-L1 adipocytes. Proceedings of the National Academy of Sciences of the United States of America 52 19255425
2023 PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration. The Journal of cell biology 49 36821088
2019 E-syt1 Re-arranges STIM1 Clusters to Stabilize Ring-shaped ER-PM Contact Sites and Accelerate Ca2+ Store Replenishment. Scientific reports 45 30850711
2019 The Foodborne Strain Lactobacillus fermentum MBC2 Triggers pept-1-Dependent Pro-Longevity Effects in Caenorhabditis elegans. Microorganisms 39 30736484
2017 A novel microscopy-based assay identifies extended synaptotagmin-1 (ESYT1) as a positive regulator of anoctamin 1 traffic. Biochimica et biophysica acta. Molecular cell research 23 29154949
2023 ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis. Life science alliance 20 37931956
2025 NLRP6 deficiency enhances macrophage-mediated phagocytosis via E-Syt1 to inhibit hepatocellular carcinoma progression. Gut 7 40473401
2025 Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2. Nature communications 5 40204782
2023 E-Syt1 Regulates Neuronal Activity-Dependent Endoplasmic Reticulum-Plasma Membrane Junctions and Surface Expression of AMPA Receptors. Contact (Thousand Oaks (Ventura County, Calif.)) 5 37484831
2023 Enriched Environment Enhances Sociability Through the Promotion of ESyt1-Related Synaptic Formation in the Medial Prefrontal Cortex. Molecular neurobiology 4 37964089
2025 Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport. Nature cell biology 2 40437229
2024 PACS-1 Interacts with TRPC3 and ESyt1 to Mediate Protein Trafficking while Promoting SOCE and Cooperatively Regulating Hormone Secretion. ACS omega 2 39157130
2024 Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function. Redox biology 2 39675068
2026 E-Syt1 recruits PI4KA to endoplasmic reticulum-plasma membrane junctions to enhance PI4P synthesis. Science China. Life sciences 0 42258130
2023 Modulation of GPR133 (ADGRD1) Signaling by its Intracellular Interaction Partner Extended Synaptotagmin 1 (ESYT1). bioRxiv : the preprint server for biology 0 36798364

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