ER membrane

Where it participates (unsigned role)

1. Calcium binding participates in ITPR3 gating after IP3/ATP priming, with both active and inactive calcium-bound conformations resolved.

   Calcium ion → Inositol 1,4,5-trisphosphate receptor type 3 / ITPR3 source_derived_draftungraded
   Experimental context and source evidence

   compartment_description

   Cytosolic regulatory regions of ER channel

   experimental_model

   Recombinant human ITPR3; cryo-EM in ligand-bound gating states

   limitations

   Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active.

   nutrient_topic

   Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

   organism

   Homo sapiens

   plain_language

   Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open.

   primary_references

   [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

   research_relationship_category

   regulation

   tissue_or_cell_type

   Recombinant ITPR3

   Calcium: mechanism-first literature curation (2026-09-17) · lines 492–503

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft

   ### ca-itpr3-calcium-coactivation Calcium binding participates in ITPR3 gating after IP3/ATP priming, with both active and inactive calcium-bound conformations resolved. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active. research_relationship_category: regulation compartment_description: Cytosolic regulatory regions of ER channel [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

   Complete structured claim and evidence

2. Human ITPR3 forms a calcium-release channel with an open pore in the IP3/ATP/Ca2+-bound structural state.

   Inositol 1,4,5-trisphosphate receptor type 3 / ITPR3 → Calcium ion source_derived_draftungraded
   Experimental context and source evidence

   compartment_description

   ER membrane

   experimental_model

   Recombinant human ITPR3; cryo-EM in ligand-bound gating states

   limitations

   Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype.

   nutrient_topic

   Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

   organism

   Homo sapiens

   plain_language

   ITPR3 provides a route for calcium to leave the ER.

   primary_references

   [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

   research_relationship_category

   transport

   tissue_or_cell_type

   Recombinant ITPR3

   transport_effect

   raises A calcium-release channel: the recorded direction is ER lumen to cytosol.

   transport_or_reaction_direction

   ER lumen to cytosol

   transport_pool

   cytosolic calcium A calcium-release channel: the recorded direction is ER lumen to cytosol.

   Calcium: mechanism-first literature curation (2026-09-17) · lines 478–490

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft

   ### ca-itpr3-er-calcium-channel Human ITPR3 forms a calcium-release channel with an open pore in the IP3/ATP/Ca2+-bound structural state. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ITPR3 provides a route for calcium to leave the ER. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype. research_relationship_category: transport transport_or_reaction_direction: ER lumen to cytosol compartment_description: ER membrane [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

   Complete structured claim and evidence

3. Human SERCA2b couples its ATPase cycle to sequestration of cytosolic calcium into the ER.

   SERCA2 → Calcium ion source_derived_draftungraded
   Experimental context and source evidence

   compartment_description

   ER membrane

   experimental_model

   Purified recombinant human SERCA2b; cryo-EM and ATPase characterization

   limitations

   Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform.

   nutrient_topic

   Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

   organism

   Homo sapiens

   plain_language

   SERCA2b uses ATP to refill ER calcium stores.

   primary_references

   [ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147

   research_relationship_category

   transport

   tissue_or_cell_type

   Recombinant SERCA2b

   transport_effect

   lowers Recorded as sequestration of cytosolic calcium into the ER.

   transport_or_reaction_direction

   Cytosol to ER lumen

   transport_pool

   cytosolic calcium Recorded as sequestration of cytosolic calcium into the ER.

   Calcium: mechanism-first literature curation (2026-09-17) · lines 571–583

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human SERCA2b; cryo-EM and ATPase characterization · source_derived_draft · unverified_draft

   ### ca-serca2b-er-uptake Human SERCA2b couples its ATPase cycle to sequestration of cytosolic calcium into the ER. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: SERCA2b uses ATP to refill ER calcium stores. organism: Homo sapiens tissue_or_cell_type: Recombinant SERCA2b experimental_model: Purified recombinant human SERCA2b; cryo-EM and ATPase characterization limitations: Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform. research_relationship_category: transport transport_or_reaction_direction: Cytosol to ER lumen compartment_description: ER membrane [ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147

   Complete structured claim and evidence

4. The cytosolic CRAC-activation domain of STIM1 binds ORAI1 directly and activates its calcium current.

   STIM1 → ORAI1 source_derived_draftungraded
   Experimental context and source evidence

   compartment_description

   ER-plasma-membrane junctions

   experimental_model

   Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays

   limitations

   Domain-expression experiments isolate coupling; physiological amplitude depends on cellular context.

   nutrient_topic

   Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

   organism

   Homo sapiens

   plain_language

   STIM1 directly opens the ORAI1 calcium-entry pathway.

   primary_references

   [ca-park2009] STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 (2009). https://pubmed.ncbi.nlm.nih.gov/19249086/ DOI: 10.1016/j.cell.2009.02.014

   research_relationship_category

   regulation

   tissue_or_cell_type

   HEK293 expression system and purified proteins

   Calcium: mechanism-first literature curation (2026-09-17) · lines 531–542

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays · source_derived_draft · unverified_draft

   ### ca-stim1-direct-orai1-gating The cytosolic CRAC-activation domain of STIM1 binds ORAI1 directly and activates its calcium current. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: STIM1 directly opens the ORAI1 calcium-entry pathway. organism: Homo sapiens tissue_or_cell_type: HEK293 expression system and purified proteins experimental_model: Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays limitations: Domain-expression experiments isolate coupling; physiological amplitude depends on cellular context. research_relationship_category: regulation compartment_description: ER-plasma-membrane junctions [ca-park2009] STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 (2009). https://pubmed.ncbi.nlm.nih.gov/19249086/ DOI: 10.1016/j.cell.2009.02.014

   Complete structured claim and evidence

5. STIM1 knockdown suppresses store-depletion-triggered calcium influx in HeLa cells.

   STIM1 → Store-operated calcium entry source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   machinery_impairment Imported condition classification; unverified.

   compartment_description

   ER-plasma-membrane signaling junction

   experimental_model

   Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis

   limitations

   RNA interference perturbs signaling machinery; it does not model low calcium intake.

   nutrient_topic

   Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

   organism

   Homo sapiens

   plain_language

   Reducing STIM1 weakens calcium entry after stores empty.

   primary_references

   [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

   research_relationship_category

   loss_of_function

   tissue_or_cell_type

   HeLa cells

   trigger_kind

   machinery_impairment Imported condition classification; unverified.

   Calcium: mechanism-first literature curation (2026-09-17) · lines 518–529

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis · source_derived_draft · unverified_draft

   ### ca-stim1-knockdown-influx STIM1 knockdown suppresses store-depletion-triggered calcium influx in HeLa cells. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing STIM1 weakens calcium entry after stores empty. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis limitations: RNA interference perturbs signaling machinery; it does not model low calcium intake. research_relationship_category: loss_of_function compartment_description: ER-plasma-membrane signaling junction [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

   Complete structured claim and evidence

6. ER-store depletion causes STIM1 to redistribute into peripheral puncta through a mechanism requiring its luminal calcium-sensing region.

   STIM1 → Calcium ion source_derived_draftungraded
   Experimental context and source evidence

   compartment_description

   ER lumen and ER-plasma-membrane junctions

   experimental_model

   Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis

   limitations

   Local store depletion is a cellular signal, not evidence of dietary calcium deficiency.

   nutrient_topic

   Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

   organism

   Homo sapiens

   plain_language

   STIM1 detects falling calcium inside the ER.

   primary_references

   [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

   research_relationship_category

   regulation

   tissue_or_cell_type

   HeLa cells

   Calcium: mechanism-first literature curation (2026-09-17) · lines 505–516

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis · source_derived_draft · unverified_draft

   ### ca-stim1-store-sensing ER-store depletion causes STIM1 to redistribute into peripheral puncta through a mechanism requiring its luminal calcium-sensing region. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: STIM1 detects falling calcium inside the ER. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis limitations: Local store depletion is a cellular signal, not evidence of dietary calcium deficiency. research_relationship_category: regulation compartment_description: ER lumen and ER-plasma-membrane junctions [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

   Complete structured claim and evidence

7. SELENOK supports ZDHHC6 by stabilizing the palmitoyl-ZDHHC6 acyl-enzyme intermediate.

   SELENOK → ZDHHC6 source_derived_draftsupplied_source_only
   Experimental context and source evidence

   cell_type

   · T cell

   evidence_scope

   Source-derived draft; primary-source verification required

   organism

   · Human

   Selenium in immune cells · lines 11–20

   Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

   # I. THE CLEANEST CHAIN — SELENOK → Ca²⁺ → NFAT → IL-2 This is the one to memorize. It's a direct, non-redox, molecule-by-molecule path from a selenium atom to a cytokine. ``` 1. Se → Sec-tRNA → SELENOK (ER membrane, single C-terminal Sec, tail in cytosol) 2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate

   Selenium: the molecular cascade · lines 135–143

   Selenium molecular cascade draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

   **SELENOO** — the strangest protein in the set. Its bacterial ortholog **SelO** looks exactly like a protein kinase but binds ATP **flipped backwards** in the pocket, so it transfers **AMP instead of phosphate**. It's an **AMPylase**, activated by oxidative stress, AMPylating GAPDH and other redox enzymes. A pseudokinase that runs in reverse. Human SELENOO is mitochondrial and largely uncharacterized. **MSRB1 (SELENOR)** — redox control of the cytoskeleton. **MICAL1/2** oxidizes actin **Met44 and Met47** to the R-sulfoxide → actin depolymerizes. MSRB1 reduces it back → repolymerization. In macrophages this gates phagocytic cup formation. **Selenium is a direct rheostat on actin dynamics.** Almost nobody knows this. **SELENOK** — not a peroxidase. It's the essential cofactor for **ZDHHC6**, the palmitoyl transferase. No SELENOK → failed palmitoylation of IP3R, calnexin, and others → broken Ca²⁺ flux in T cells. **Selenium regulating lipid post-translational modification.** **SELENOI (EPT1)** — the only selenoprotein with **zero redox function**. It's an ethanolamine phosphotransferase making phosphatidylethanolamine. Mutations → hereditary spastic paraplegia **SPG81**. (And PE is exactly the lipid GPX4 protects. There's a loop there worth pulling on.) **SELENON** — ER membrane, regulates **RyR1** redox state and SERCA2b. Mutations → SEPN1-related myopathy / rigid spine syndrome.

   Complete structured claim and evidence

8. ZDHHC6 palmitoylates IP3R, producing the palmitoylated receptor state.

   ZDHHC6 → Palmitoylated IP3R source_derived_draftsupplied_source_only
   Experimental context and source evidence

   cell_type

   · T cell

   evidence_scope

   Source-derived draft; primary-source verification required

   organism

   · Human

   Selenium in immune cells · lines 22–28

   Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

   3. ZDHHC6 palmitoylates: • IP3R (all three isoforms) • calnexin • itself (autopalmitoylation) 4. Palmitoylated IP3R = stable, correctly localized, functional channel Non-palmitoylated IP3R = degraded / non-functional

   Selenium: the molecular cascade · lines 135–143

   Selenium molecular cascade draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

   **SELENOO** — the strangest protein in the set. Its bacterial ortholog **SelO** looks exactly like a protein kinase but binds ATP **flipped backwards** in the pocket, so it transfers **AMP instead of phosphate**. It's an **AMPylase**, activated by oxidative stress, AMPylating GAPDH and other redox enzymes. A pseudokinase that runs in reverse. Human SELENOO is mitochondrial and largely uncharacterized. **MSRB1 (SELENOR)** — redox control of the cytoskeleton. **MICAL1/2** oxidizes actin **Met44 and Met47** to the R-sulfoxide → actin depolymerizes. MSRB1 reduces it back → repolymerization. In macrophages this gates phagocytic cup formation. **Selenium is a direct rheostat on actin dynamics.** Almost nobody knows this. **SELENOK** — not a peroxidase. It's the essential cofactor for **ZDHHC6**, the palmitoyl transferase. No SELENOK → failed palmitoylation of IP3R, calnexin, and others → broken Ca²⁺ flux in T cells. **Selenium regulating lipid post-translational modification.** **SELENOI (EPT1)** — the only selenoprotein with **zero redox function**. It's an ethanolamine phosphotransferase making phosphatidylethanolamine. Mutations → hereditary spastic paraplegia **SPG81**. (And PE is exactly the lipid GPX4 protects. There's a loop there worth pulling on.) **SELENON** — ER membrane, regulates **RyR1** redox state and SERCA2b. Mutations → SEPN1-related myopathy / rigid spine syndrome.

   Complete structured claim and evidence