- Topology
- Multi-pass membrane protein (p=1.00): ~ten transmembrane helices forming a large channel-like domain — the TMC-family architecture.
- Pore Cavity
- High-confidence pocket (0.74). A residue-level cavity in the TM4–TM5 region — the pore / modulator site a docking or mutagenesis campaign needs, and the one thing a fold alone will not give you.
- Function
- Predicted cation channel; its best-defined role is as an inhibitory modulator of PIEZO2 in sensory neurons.
- Modifications
- Extracellular N-glycosylation (N24, N84, N96, N259, N638); an intracellular phosphosite (S89).
- Clean Signal
- Short disordered N-terminus only; 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
The transmembrane channel-like (TMC) family has one famous pair and six unknowns. TMC1 and TMC2 are the mechanotransduction channels of inner-ear hair cells; TMC3–TMC8 remain largely uncharacterised. TMC7 (subfamily C) is among the darkest: a predicted multi-pass cation channel with no confirmed conductance of its own, a thin literature (IDG Tdark), and no experimental structure in the PDB. Its best-defined role is indirect but important — in mouse dorsal-root-ganglion neurons, TMC7 acts as an inhibitory modulator ("suppressor") of PIEZO2, and its loss enhances mechanotransduction and mechanical hypersensitivity. So TMC7 sits on the touch / mechanical-pain axis, yet is structurally a blank.
That combination — a mechanosensory channel with no structure — is exactly where prediction earns its keep: everything below is computed from the canonical 723-residue sequence and derived structural predictions, with no experimental TMC7 structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| N-terminus | N-terminal region | Short disordered N-terminus; carries an intracellular phosphosite (S89). |
| Transmembrane core | ~10 helices | About ten transmembrane helices (~30% of the chain) form the large channel-like domain. |
| Pore-lining helices | TM4–TM6 | Contribute residues to the predicted pore-lining cavity in the TM4–TM5 region. |
| Extracellular loops | N24, N84, N96, N259, N638 | N-glycosylation sites on the extracellular side. |
The Predicted Pocket
The Predicted Pore-Lining Cavity
No known binder — a genuine orphan cavity. These residues are the first testable hypothesis for the permeation path and for any small molecule that would tune TMC7's effect on PIEZO2; as a control, the same detection recovers known pore/ligand sites on channels whose structures are solved (e.g. the C. elegans TMC-1 complex).
Site: Pore-lining cavity in the TM4–TM5 region
Post-Translational & Structural Features
Specific, Testable Residues
- Extracellular N-glycosylation (N24, N84, N96, N259, N638). The expected surface modification for a multi-pass plasma-membrane channel — and a set of handles for surface-expression and trafficking assays.
- Intracellular phosphorylation (S89). A candidate regulatory site in the disordered N-terminal region.
- Low disorder, no amyloid. A well-folded channel; the ordered TM core is the region for structural work.
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 |
|---|---|---|
| Pore-lining cavity (TM4–TM5) | Alanine scan at the cavity + electrophysiology | Change in conductance / PIEZO2 modulation |
| ~ten-TM topology | Surface-labelling / glycosylation mapping | Confirmed topology and orientation |
| PIEZO2-suppressor role | Cavity-mutant rescue of the PIEZO2 phenotype | Which residues carry the modulation |
| Predicted cation-channel function | Reconstitution / patch on purified TMC7 | Confirm (or refute) intrinsic conductance |
| N-glycosylation sites | N→Q mutants | Trafficking / surface-expression change |
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.
- Channel activity is predicted. An intrinsic TMC7 conductance has not been demonstrated; its established role is as a modulator of PIEZO2. The pore-lining cavity is a residue-level hypothesis, not a proven permeation path.
- Biology caveats. The PIEZO2-modulation data are from mouse sensory neurons; a human physiological role is inferred, not established.
All predictions were generated with Orbion's Astra suite from the canonical TMC7 sequence (UniProt Q7Z402), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q7Z402 (TMC7, human). uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. TMC7 target record — Tdark. pharos.nih.gov/targets/Q7Z402.
- [3]Zhang X., Shao J., Wang C., et al. TMC7 functions as a suppressor of Piezo2 in primary sensory neurons blunting peripheral mechanotransduction. Cell Rep. 43(4), 114014 (2024). https://doi.org/10.1016/j.celrep.2024.114014