Affinage

TMEM109

Voltage-gated monoatomic cation channel TMEM109 · UniProt Q9BVC6

Length
243 aa
Mass
26.2 kDa
Annotated
2026-06-10
18 papers in source corpus 10 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM109 is a multi-transmembrane endoplasmic/sarcoplasmic reticulum protein that operates as the membrane-insertase component of the SRP-independent (SND) protein-targeting pathway, originally defined in yeast where Snd3, together with Snd1 and Snd2, provides a backup route for delivering proteins to the ER in parallel with the SRP and GET pathways (PMID:27905431, PMID:36139500). Cryo-EM of a ribosome-associated SND3 translocon shows an insertase of atypical fold that drives co-translational integral membrane protein insertion through a membrane-embedded hydrophilic groove that locally disrupts the lipid bilayer; in this complex SND3 associates with the SEC61 translocon, CCDC47, and TRAPα, where the SEC61β N-terminus and CCDC47 occlude the SEC61 channel to redirect substrates toward SND3 (PMID:41162385). Independently of its insertase role, reconstituted TMEM109 (MG23) forms homo-oligomeric, bowl-shaped assemblies with a central pore that conduct a voltage-dependent, non-selective cation current permeable to both K+ and Ca2+ (PMID:21381722), and this channel is activated by cytosolic Zn2+ in cardiac SR membranes, contributing to SR Ca2+ leak (PMID:28630041). Consistent with a pathophysiological Ca2+-handling role, TMEM109 protein rises during cardiac stress and its loss in mice reduces SR Ca2+ leak and protects against angiotensin II-induced cardiac hypertrophy and dysfunction (PMID:41568959). TMEM109 additionally modulates DNA-damage- and UV-induced apoptosis, in part through binding the small heat-shock protein αB-crystallin (PMID:20060811, PMID:23542032), and its expression is transcriptionally repressed by ZBTB20 to influence ferroptosis in glioblastoma cells (PMID:40999982).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2016 High

    Established that the TMEM109 ortholog Snd3 defines a third ER-targeting route, answering how proteins reach the ER when SRP and GET pathways fail.

    Evidence Systematic visual screen and genetic epistasis in S. cerevisiae showing synthetic compensation with SRP and GET mutants

    PMID:27905431

    Open questions at the time
    • Did not define the human ortholog or molecular insertase mechanism
    • Client repertoire and biochemical activity unresolved
  2. 2022 Medium

    Extended the SND pathway to humans by identifying TMEM109 as hSnd3, addressing whether the yeast backup-targeting system is conserved.

    Evidence siRNA knockdown of hSnd2 in HeLa cells with quantitative proteomics of client abundance

    PMID:36139500

    Open questions at the time
    • Single lab
    • Direct insertase activity of human TMEM109 not demonstrated
    • Membrane topology within a translocon undefined
  3. 2025 High

    Resolved the molecular mechanism of SND-pathway insertion, showing TMEM109/SND3 is a membrane insertase that opens a hydrophilic groove within a SEC61/CCDC47/TRAPα translocon.

    Evidence Cryo-EM of a ribosome-associated SND3 translocon with molecular dynamics simulations

    PMID:41162385

    Open questions at the time
    • Substrate selection rules between SEC61 and SND3 not fully defined
    • Human complex structure inferred from fungal ortholog
  4. 2011 High

    Demonstrated that TMEM109/MG23 is itself an ion channel, answering whether the protein has an activity independent of protein targeting.

    Evidence Cryo-EM 3D reconstruction plus reconstitution into planar phospholipid bilayers and electrophysiology of purified MG23

    PMID:21381722

    Open questions at the time
    • Physiological gating stimulus not identified
    • Native membrane context and selectivity regulation unknown
  5. 2017 High

    Identified Zn2+ as a physiological activator of the channel and linked it to cardiac SR Ca2+ leak, connecting channel activity to disease.

    Evidence Bilayer electrophysiology of cardiac SR vesicles at defined Zn2+ concentrations plus H9C2 ischemia model

    PMID:28630041

    Open questions at the time
    • Distinction from RyR2 sub-conductance gating in situ not fully resolved
    • In vivo contribution to heart failure not tested here
  6. 2026 Medium

    Tested the in vivo cardiac role, showing TMEM109 loss reduces SR Ca2+ leak and protects against pressure-overload hypertrophy.

    Evidence Mg23 knockout mice with AngII infusion, pressure-volume measurements, Fluo-4 Ca2+ imaging, and H9C2 overexpression

    PMID:41568959

    Open questions at the time
    • Single lab
    • Mechanistic link between channel activity and hypertrophy signaling not fully dissected
    • No change in canonical Ca2+-handling proteins leaves leak mechanism partly open
  7. 2010 Medium

    Linked TMEM109 to DNA-damage-induced apoptosis, raising the question of how an ER channel modulates cell death.

    Evidence MG23 overexpression in HEK293T cells and knockout mice with irradiation, apoptosis assays, and p53 Western blot

    PMID:20060811

    Open questions at the time
    • Molecular pathway connecting MG23 to p53 induction unresolved
    • Single lab
  8. 2013 Medium

    Provided a candidate effector for the apoptosis role by identifying αB-crystallin as a TMEM109 binding partner.

    Evidence siRNA knockdown, co-immunoprecipitation, and ER-anchored αBC overexpression with UVC death assays

    PMID:23542032

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Direct binding interface and stoichiometry undefined
  9. 2021 Medium

    Showed that the yeast ortholog Snd3 regulates nucleus-vacuole junction contact sites in response to glucose signaling, adding a membrane-contact-site function.

    Evidence Live-cell fluorescence microscopy, co-immunoprecipitation, and genetic deletion in S. cerevisiae under glucose manipulation

    PMID:33472077

    Open questions at the time
    • Conservation of NVJ role to human TMEM109 not shown
    • Relationship to insertase function unclear
  10. 2025 Medium

    Placed TMEM109 in a transcriptional circuit controlling glioblastoma ferroptosis, identifying ZBTB20 as a direct repressor.

    Evidence Dual-luciferase reporter, ChIP, gain/loss-of-function, and co-transfection rescue in GBM cells

    PMID:40999982

    Open questions at the time
    • Mechanism by which TMEM109 suppresses ferroptosis undefined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMEM109's two activities — SND-pathway membrane insertase and ER/SR cation channel — are coordinated within a single protein, and whether they share structural elements, remains unresolved.
  • No study reconciles the insertase fold with the channel pore
  • Whether the SND complex and channel oligomer are mutually exclusive states is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0005198 structural molecule activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005635 nuclear envelope 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9609507 Protein localization 2
Partners
CCDC47CRYABSEC61TRAPΑ
Complex memberships
SND3 ribosome-associated translocon (SND3-SEC61-CCDC47-TRAPα)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Snd3 (TMEM109 ortholog) functions as part of the SND (SRP-independent targeting) pathway in yeast, working together with Snd1 and Snd2 to target proteins to the ER in parallel with the SRP and GET pathways. Genetic epistasis showed that the SND proteins can synthetically compensate for loss of both SRP and GET pathways, acting as a backup ER targeting system. Systematic visual screen in S. cerevisiae, genetic epistasis (synthetic lethality/compensation with SRP and GET pathway mutants), loss-of-function targeting assays Nature High 27905431
2022 TMEM109 was characterized as hSnd3, the human ortholog of yeast Snd3 and a component of the human SND ER-targeting pathway. Depletion of hSnd2 from HeLa cells combined with proteomic analysis identified TMEM109/hSnd3 as a novel component of the SND pathway. SND pathway clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals, distinct from SRP and TRC pathway substrates. siRNA knockdown of hSnd2 in HeLa cells, quantitative proteomics, differential protein abundance analysis Cells Medium 36139500
2025 SND3 (TMEM109 ortholog) is a membrane insertase with an atypical fold that promotes integral membrane protein (IMP) insertion via a membrane-embedded hydrophilic groove that disrupts the lipid bilayer. Cryo-EM structure of a ribosome-associated SND3 translocon complex revealed it comprises SND3, the complete SEC61 translocon, CCDC47, and TRAPα. Within this complex, the SEC61β N-terminus works together with CCDC47 to prevent substrate access to the SEC61 translocon, redirecting substrates to SND3. Cryo-electron microscopy structure determination, molecular dynamics simulations, structural and sequence comparisons Nature Communications High 41162385
2025 SND3 (TMEM109 ortholog from Chaetomium thermophilum) is a membrane insertase of novel fold that disrupts the lipid bilayer via a membrane-embedded hydrophilic groove to promote co-translational IMP insertion. The SND3 translocon complex includes SEC61 translocon, CCDC47, and TRAPα. Structural comparisons indicate this is a distinct multipass translocon for insertion of multipass IMPs in fungi and euglenozoan parasites. Cryo-EM structure determination, molecular dynamics simulations, structural and sequence comparisons bioRxivpreprint High
2011 MG23 (TMEM109) has three transmembrane segments and forms homo-oligomeric, bowl-shaped assemblies with a central pore. After reconstitution into planar phospholipid bilayers, purified MG23 functions as a voltage-dependent, cation-conducting channel permeable to both K+ and Ca2+, with multiple channels gating together. Hydropathicity profiling, limited proteolysis, chemical cross-linking, single-particle 3D cryo-EM reconstruction, reconstitution into planar phospholipid bilayers, electrophysiology Biochemistry High 21381722
2017 MG23 (TMEM109) is a Zn2+-regulated Ca2+-permeable channel in the sarcoplasmic reticulum. Elevating cytosolic Zn2+ to 1 nM increased MG23 activity in SR vesicles incorporated into phospholipid bilayers. The full-open state current amplitude of MG23 is consistent with that previously attributed to RyR2 sub-conductance gating, suggesting MG23 contributes to SR Ca2+ leakage in heart failure. MG23 expression is increased in H9C2 cells under ischemic conditions coinciding with elevated intracellular Zn2+. Planar phospholipid bilayer electrophysiology with cardiac SR vesicles, voltage-clamp, H9C2 cell ischemia model, Western blot The Journal of biological chemistry High 28630041
2010 MG23 (TMEM109) overexpression in HEK293T cells specifically enhanced apoptosis triggered by etoposide (a DNA-damaging drug). Genetic deletion of MG23 in mice reduced susceptibility of thymocytes to DNA damage-induced apoptosis after whole-body irradiation, with attenuated p53 induction in MG23-knockout thymocytes. Overexpression in HEK293T cells, MG23 knockout mouse model, whole-body irradiation, flow cytometry apoptosis assay, Western blot for p53 Biochemical and biophysical research communications Medium 20060811
2013 MG23 (TMEM109) protects against UVC-induced cell death. Knockdown of MG23 enhanced UVC-induced apoptosis. The small heat shock protein αB-crystallin (αBC) was identified as a MG23 binding molecule, and expression of ER-anchored αBC lowered UVC sensitivity, suggesting MG23 acts by accumulating αBC near the ER. siRNA knockdown, co-immunoprecipitation/binding assay to identify αBC as MG23 partner, overexpression of ER-anchored αBC, UVC cell death assay FEBS letters Medium 23542032
2026 MG23 (TMEM109) knockout in mice protects against angiotensin II-induced pressure overload cardiac hypertrophy and dysfunction. AngII treatment increased MG23 protein expression in WT hearts. Mg23-KO cardiomyocytes displayed altered Ca2+-spark profiles consistent with reduced SR Ca2+ leak. Overexpression of MG23 in H9C2 cells reduced SR Ca2+ store levels. No alteration in expression of key Ca2+-handling proteins was found in Mg23-KO hearts. Mg23 knockout mouse model, AngII osmotic pump infusion, pressure-volume catheter measurements in vivo, Western blot, histology/immunofluorescence, live-cell Ca2+ imaging with Fluo-4, H9C2 overexpression FASEB journal Medium 41568959
2021 Yeast Snd3 (TMEM109 ortholog) is an ER protein that is central to nucleus-vacuole junction (NVJ) formation. Snd3 interacts with NVJ tethers and supports their targeting to contact sites. Upon glucose exhaustion, Snd3 relocalizes from the ER to NVJs and promotes NVJ expansion regulated by central glucose signaling pathways. Glucose replenishment induces rapid dissociation of Snd3 from NVJs preceding slow NVJ disassembly. Fluorescence microscopy (live imaging and colocalization), co-immunoprecipitation, genetic deletion, glucose signaling pathway analysis in S. cerevisiae Cell reports Medium 33472077
2025 ZBTB20 transcriptionally represses TMEM109 expression in glioblastoma cells, as demonstrated by dual-luciferase reporter assay and chromatin immunoprecipitation. TMEM109 overexpression inhibits ferroptosis while TMEM109 knockdown promotes ferroptosis in GBM cells. Co-transfection showed TMEM109 overexpression can reverse the pro-ferroptotic effect of ZBTB20. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), gain- and loss-of-function (overexpression and knockdown), co-transfection rescue experiment International journal of oncology Medium 40999982

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 The SND proteins constitute an alternative targeting route to the endoplasmic reticulum. Nature 170 27905431
2007 Review of studies of androgen treatment of female-to-male transsexuals: effects and risks of administration of androgens to females. The journal of sexual medicine 79 17971101
2014 New and notable ion-channels in the sarcoplasmic/endoplasmic reticulum: do they support the process of intracellular Ca²⁺ release? The Journal of physiology 60 26228553
1985 Examination of irreversible platelet-fibrinogen interactions. The American journal of physiology 51 3158213
2023 Banana MaNAC1 activates secondary cell wall cellulose biosynthesis to enhance chilling resistance in fruit. Plant biotechnology journal 34 37816143
2021 Snd3 controls nucleus-vacuole junctions in response to glucose signaling. Cell reports 28 33472077
2017 Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. The Journal of biological chemistry 24 28630041
1999 Isolation of a specific DNA fragment and development of a PCR-based method for the detection of Mycobacterium genavense. FEMS immunology and medical microbiology 23 10219597
2011 Mitsugumin 23 forms a massive bowl-shaped assembly and cation-conducting channel. Biochemistry 19 21381722
2022 Proteomics Identifies Substrates and a Novel Component in hSnd2-Dependent ER Protein Targeting. Cells 16 36139500
2013 Protective role of the endoplasmic reticulum protein mitsugumin23 against ultraviolet C-induced cell death. FEBS letters 16 23542032
2010 Facilitation of DNA damage-induced apoptosis by endoplasmic reticulum protein mitsugumin23. Biochemical and biophysical research communications 11 20060811
2006 [Study on sini decoction in treatment of intestinal ischemia-reperfusion injury in rats: mechanism relating to oxygen radical and bcl-2 protein]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 3 16706028
2026 Bone marrow proteomic profiling reveals TMEM109 as a biomarker for relapse in thrombotic thrombocytopenic purpura. Journal of thrombosis and haemostasis : JTH 1 41617037
2025 ZBTB20 promotes ferroptosis through inhibiting TMEM109 expression in glioblastoma cells. International journal of oncology 1 40999982
2025 SND3 is the membrane insertase within a distinct SEC61 translocon complex. Nature communications 1 41162385
2026 Knockout of the Intracellular Calcium Conducting Ion Channel Mitsugumin 23 (MG23) Protects Against Pressure Overload Induced Left Ventricular Hypertrophy and Cardiac Dysfunction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41568959
2025 Predicted Role of Mitsugumin 23 in Skeletal and Cardiac Muscle. Cells 0 41439978

Missed literature

Know a paper Affinage missed for TMEM109? Flag it for the maintainers and the community.

No submissions yet.