- Fold
- Seven predicted transmembrane helices; a multi-pass ER-membrane channel that assembles as a trimer (TRIC family).
- Allosteric Pocket
- AstraBIND allosteric-candidate hypothesis (confidence 0.85) at the helix interface — a residue-level starting point for mutagenesis; no validated ligand.
- Flexible Regions
- Elevated predicted disorder in the cytoplasmic C-tail (232–289) — the natural truncation boundary for construct design.
- Clean Signal
- Aggregation-prone segment flagged (max 0.57) — worth screening in construct design.
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
Most tractable protein families have been structurally explored. Trimeric intracellular cation channel type B has not: an IDG Tbio target with no experimental structure in the PDB and only a handful of functional studies. UniProt summarises it as: “Intracellular monovalent cation channel required for maintenance of rapid intracellular calcium release. Acts as a potassium counter-ion channel that functions in synchronization with calcium release…” Interest is real (Osteogenesis Imperfecta), but there is almost nothing to look up.
That combination — genuine interest, near-zero structural information — is where prediction earns its keep: everything below is computed from the canonical 291-residue sequence, with no experimental TMEM38B structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Transmembrane Helices | 7 predicted | Boundaries: 20–33; 51–70; 83–99; 105–121; 140–156; 180–195; 208–227. |
The Predicted Pocket
A Predicted Allosteric Pocket
A residue-level hypothesis from AstraBIND. TMEM38B has no ligand-bound relative to retrieve from, so this is a low-confidence, structure-based prediction; the residues neighbour one of the two UniProt-annotated PIP₂-binding positions (122) but miss the other (118). Treat it as an exploratory pore / interface surface, not a validated pocket or a druggable site.
Site: Predicted pore / gating interface
Post-Translational & Structural Features
Specific, Testable Residues
- PIP₂-binding residues (118, 122). UniProt-annotated phosphatidylinositol-4,5-bisphosphate (PIP₂) binding sites — a lipid-regulation input to the channel and a direct mutagenesis handle.
- Aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.57) — worth screening in construct design.
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 |
|---|---|---|
| Predicted Allosteric Pocket + PIP₂-Binding Residues (118 / 122) | Alanine scan + ER Ca²⁺-release / K⁺-flux readout | Altered counter-ion flux or lipid regulation — tests the predicted site |
| Disordered C-Tail (232–289) | C-terminal truncation | Improved expression / thermostability for cryo-EM |
| Predicted Trimeric Assembly (TRIC Family) | Cross-linking / native mass-spec on the expressed protein | Confirm the oligomeric state |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a structure or an assay. Nothing here is wet-lab validated.
- The pocket is predicted; the ligand is not named. AstraBIND is retrieval-based; the honest output is a residue-level hypothesis, not a proven druggable site or a validated binder.
- Thin biology. TRIC-B's contribution is framed by recessive osteogenesis-imperfecta genetics and its reported role as an ER K⁺ counter-ion channel supporting calcium release; the structural and mechanistic detail remains sparsely characterised. Treat mechanism as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical TMEM38B sequence (UniProt Q9NVV0), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q9NVV0 (TMEM38B, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). TMEM38B target record — Tbio. pharos.nih.gov.
- [3]Shaheen R et al. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. (2012). https://doi.org/10.1136/jmedgenet-2012-101142
- [4]Volodarsky M et al. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. (2013). https://doi.org/10.1002/humu.22274
- [5]Cabral WA et al. Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta. (2016). https://doi.org/10.1371/journal.pgen.1006156