- Topology
- Multi-pass membrane protein (p=1.00): four transmembrane helices with a large (~260-residue) perinuclear-space domain; likely homo-oligomeric (p=0.99).
- Disease Map
- Three Mendelian diseases, mapped. S358L (lethal cardiomyopathy, ARVC5) sits in TM3; the Emery-Dreifuss variants in the luminal domain; the auditory-neuropathy truncation at the C-terminal helix.
- Predicted Pocket
- Pocket in the luminal domain (0.74). A residue-level cavity (~124–167) in the large perinuclear-space region — a candidate ligand / interaction site.
- Function
- Non-enzyme (p=1.00); a proposed pH-sensing cation channel (preprint only) — treat as a hypothesis.
- Clean Signal
- Low disorder (~10%); no amyloid signal.
Model-reported confidence for the headline calls (amber = the load-bearing prediction the rest of the profile builds on). These are model-estimated probabilities that rank and gate each call — not calibrated rates of experimental success.
The Gap
Why This Target Is Still Dark
Few dark proteins carry a clinical burden like TMEM43. The single variant p.Ser358Leu causes arrhythmogenic right-ventricular cardiomyopathy type 5 (ARVC5) — a fully penetrant, lethal arrhythmia. Other variants cause Emery-Dreifuss muscular dystrophy and autosomal-dominant auditory neuropathy (AUNA3). TMEM43 (LUMA) is an inner-nuclear-membrane protein, and was recently proposed — in a preprint — to act as a pH-sensing cation channel. Yet for all this clinical weight it has no experimental structure in the PDB and remains understudied at the molecular level (IDG Tbio).
That combination — three Mendelian diseases, near-zero structural information — is exactly where prediction earns its keep: everything below is computed from the canonical 400-residue sequence and derived structural predictions, with no experimental TMEM43 structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| N-terminus | 1–31 | Short cytosolic / nuclear N-terminus; predicted N-terminal acetylation. |
| TM1 | 32–52 | First transmembrane helix. |
| Perinuclear-space domain | 53–313 | Large (~260-residue) luminal domain; a coherent, foldable unit; carries the predicted pocket (124–167) and the Emery-Dreifuss variants (85/91). |
| TM2–TM4 | 314–334, 346–366, 369–389 | C-terminal cluster of three transmembrane helices; S358L (ARVC5) sits in TM3; the AUNA3 truncation begins at TM4 (372). |
The Predicted Pocket
The Predicted Pocket
A residue-level cavity (0.74) in the large luminal domain — a candidate ligand / interaction site, not a demonstrated ion-conduction pore. As a control, the same predictors recover known topology and pocket sites on membrane proteins whose structures are solved.
Site: Luminal (perinuclear-space) domain, ~124–167
Post-Translational & Structural Features
Specific, Testable Residues
- Homo-oligomer (p=0.99). TMEM43 is predicted to self-associate — consistent with reports that Emery-Dreifuss variants perturb its complexes and partner localisation.
- S358L (ARVC5) in TM3. The lethal cardiomyopathy variant sits in a transmembrane helix — a helix-packing / membrane-interface hypothesis.
- Emery-Dreifuss variants (85/91) in the perinuclear-space domain. Predicted to perturb partner localisation while oligomerisation is largely retained.
- **Arg372* (AUNA3) at TM4.** A truncation at the C-terminal helix with reduced protein stability.
- Low disorder, no amyloid. A well-folded protein (~10% disorder) — the luminal domain in particular is a coherent, foldable unit worth expressing on its own.
- N-terminal acetylation. A predicted co-translational modification consistent with a stable cytosolic / nuclear N-terminus.
Recommended Experimental Follow-Up
An Orphan Sequence, Turned Into a Ranked Plan
Each prediction is paired with the experiment that would test it and the readout to watch for.
| Prediction | Experiment | Readout |
|---|---|---|
| S358L in TM3 | Membrane-insertion / oligomer assay, S358L vs WT | A structural mechanism for ARVC5 |
| Luminal domain is foldable (53–313) | Express the luminal domain alone | A crystallisable / assayable fragment |
| Predicted pocket (124–167) | Fragment screen / docking at the pocket | A ligand or interaction hypothesis |
| Homo-oligomer | Cross-linking / native-PAGE ± disease variants | Oligomer state and its disruption |
| Proposed channel role | Electrophysiology on purified protein | Confirm (or refute) channel activity |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a substitute for a structure or an assay. No result here has been validated in the wet lab.
- The channel role is unproven. TMEM43's proposed pH-sensing cation-channel activity rests on a single preprint; the predicted pocket is in the luminal domain, not a demonstrated ion-conduction pore.
- Variant interpretation. The structural placements above are hypotheses for how each variant acts; the Emery-Dreifuss variants perturb localisation while oligomerisation is largely retained.
All predictions were generated with Orbion's Astra suite from the canonical TMEM43 sequence (UniProt Q9BTV4), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q9BTV4 (TMEM43, human). uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. TMEM43 target record — Tbio. pharos.nih.gov/targets/Q9BTV4.
- [3]Merner N.D., Hodgkinson K.A., Haywood A.F.M., et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am. J. Hum. Genet. 82(4), 809–821 (2008). https://doi.org/10.1016/j.ajhg.2008.01.010
- [4]Liang W.-C., Mitsuhashi H., Keduka E., et al. TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy. Ann. Neurol. 69(6), 1005–1013 (2011). https://doi.org/10.1002/ana.22338
- [5]Jang M.W., Oh D.-Y., Yi E., et al. A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. Proc. Natl. Acad. Sci. USA 118(21), e2019681118 (2021). https://doi.org/10.1073/pnas.2019681118
- [6]Jang M.W., Kim H.M., Lee C.J., et al. Characterization of TMEM43 as a novel pH-sensing cation channel. bioRxiv 2022.11.08.515259 (2022; preprint). https://doi.org/10.1101/2022.11.08.515259