Polytopic membrane protein of the transmembrane channel-like (TMC) family and the pore-forming subunit of the mechanoelectrical transduction (MET) channel at the tips of the shorter-row stereocilia of cochlear and vestibular hair cells. TMC1 assembles as a dimer with a TMEM16-like fold and, together with the auxiliary subunits TMIE, LHFPL5, CIB2/CIB3 and TOMT and the tip-link protein PCDH15, forms the complex that converts hair-bundle deflection into a cation current. The channel is gated by mechanical force transmitted through the tip link rather than by membrane voltage, is non-selective among cations and is highly permeable to calcium; deafness-causing point mutations in the pore region change single-channel conductance, calcium permeability and reversal potential. TMC2 is co-expressed transiently in the neonatal cochlea and persistently in vestibular hair cells, which is why TMC1 loss in humans causes deafness (DFNA36, DFNB7/11) without vestibular failure while loss of both proteins abolishes mechanotransduction entirely. Whether TMC1 additionally performs lipid scrambling is unsettled: hair cells require TMC1 or TMC2 for phosphatidylserine externalisation, and reconstituted TMC1 translocates phospholipids in a cholesterol-dependent manner, but the distinction between an essential permissive role and direct lipid translocation by TMC1 itself has not been resolved in peer-reviewed work.
Definition: A cation channel complex located at the tip of a hair-cell stereocilium that opens in response to tension applied through the tip link, composed of pore-forming transmembrane channel-like subunits together with auxiliary subunits.
Justification: There is no cellular-component term for the hair-cell MET complex. The nearest available term is GO:0034703 cation channel complex, which does not distinguish this assembly from any other cation channel. The complex has a defined and conserved composition (TMC1 or TMC2, TMIE, LHFPL5, CIB2 or CIB3, with TOMT required for trafficking and PCDH15 forming the tip link), and its subunits are individually annotated in GOA without a shared complex term to attach them to.
Parent term: cation channel complex
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: TMC1 is an integral protein of the hair-cell plasma membrane and conducts there. Reason: Correct, although the stereocilium tip (GO:0032426) annotation carried by this gene states the site of action far more usefully. |
| GO:0005245 voltage-gated calcium channel activity | IBA GO_REF:0000033 | MODIFY | Summary: The gating stimulus is wrong. TMC1 is gated by tension delivered through the tip link, not by membrane potential; the calcium permeability that the underlying experiments measured is a permeation property of a mechanically gated channel. Reason: Traced to the mouse source annotation: MGI carries `enables GO:0005245` for Tmc1 from PMID:23871232, a paper that measured calcium permeability and single-channel currents of the hair-cell MET channel and made no claim of voltage gating. The same paper supports GO:0005262 calcium channel activity, which mouse Tmc1 also carries. GO:0005245 is a child of GO:0005262 that adds a gating mechanism the data do not support, so the specificity is spurious rather than merely generous. Replace with the mechanosensitive cation channel term plus the plain calcium channel term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2151016 Β· Tmc1 (mouse) SOURCE BAD Carries enables GO:0005245 from PMID:23871232, which demonstrates calcium permeability of a mechanically gated channel, not voltage gating. PANTHER:PTN002761439 Β· TMC1/TMC2 ancestral node SUPPORTS SOURCE BUT NOT TARGET The node correctly groups the vertebrate MET-channel TMCs; only the term chosen at the node encodes the wrong gating mechanism. Proposed replacements: mechanosensitive monoatomic cation channel activity calcium channel activity Supporting Evidence: PMID:23871232 Cells that expressed Tmc2 had high calcium permeability and large single-channel currents, while cells with mutant Tmc1 had reduced calcium permeability and reduced single-channel currents. PMID:39674179 Deafness-related TMC1 mutations altered the reversal potential of TMC1, indicating that TMC1/2 are pore-forming mechanotransduction channels. |
| GO:0050910 detection of mechanical stimulus involved in sensory perception of sound | IBA GO_REF:0000033 | ACCEPT | Summary: This is the process the TMC1 channel carries out - conversion of hair-bundle deflection into a receptor current. Reason: Core biological process, grounded in mouse knockouts that lack all mechanotransduction and in human deafness alleles. Supporting Evidence: PMID:22105175 Tmc1(Ξ)Tmc2(Ξ) mice had profound vestibular dysfunction, deafness, and structurally normal hair cells that lacked all mechanotransduction activity |
| GO:0060005 vestibular reflex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Organismal reflex behaviour downstream of vestibular hair-cell transduction. Reason: Real but distal. TMC1 contributes to vestibular transduction only where TMC2 is absent or reduced; human TMC1 mutations cause deafness without vestibular dysfunction because TMC2 persists in vestibular hair cells. A reflex arc is not something the TMC1 protein executes. |
| GO:0008381 mechanosensitive monoatomic ion channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: The core molecular function, asserted at the family node. Pore-lining residues of TMC1 set the permeation properties of the hair-cell MET current. Reason: Core molecular function, independently supported by cysteine-modification pore mapping in mouse hair cells and by direct poke- and stretch-activated recordings from plasma-membrane-localised human TMC1. The more specific GO:0140135 (cation) would fit the mammalian MET channel better, but the generic parent is the defensible assertion at a node that also spans invertebrate TMCs, so it is left as the phylogenetic curator placed it. Supporting Evidence: PMID:30138589 The data provide compelling evidence that TMC1 is a pore-forming component of sensory transduction channels in auditory and vestibular hair cells. PMID:39674179 our study provides evidence that human TMC1/2 are pore-forming, mechanically activated ion channels, supporting their roles as mechanotransduction channels in hair cells. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: TMC1 is an integral protein of the hair-cell plasma membrane and conducts there. Reason: Correct, although the stereocilium tip (GO:0032426) annotation carried by this gene states the site of action far more usefully. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: True but uninformative - it says only that TMC1 is a membrane protein. Reason: A far more specific compartment is established for this protein and is already used by other rows of this annotation set. Proposed replacements: stereocilium membrane |
| GO:0034220 monoatomic ion transmembrane transport | IEA GO_REF:0000108 | MODIFY | Summary: Correct in kind but under-specific; the MET current is a cation current, with no measurable anion component. Reason: The channel is non-selective among cations and highly calcium permeable; the cation-specific child states this and is consistent with the calcium ion transmembrane transport row. Proposed replacements: monoatomic cation transmembrane transport |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000120 | ACCEPT | Summary: Calcium entry through the MET channel is a direct consequence of the channel activity and is the flux that pore mutations perturb. Reason: Core biological process. Supporting Evidence: PMID:23871232 Cells that expressed Tmc2 had high calcium permeability and large single-channel currents, while cells with mutant Tmc1 had reduced calcium permeability and reduced single-channel currents. |
| GO:0005245 voltage-gated calcium channel activity | IEA GO_REF:0000107 | MODIFY | Summary: The gating stimulus is wrong. TMC1 is gated by tension delivered through the tip link, not by membrane potential. Reason: Orthology transfer of the same mouse annotation reviewed above. The underlying measurement is calcium permeability of a mechanically gated channel; the voltage-gating claim is an artefact of term choice at the source. Proposed replacements: mechanosensitive monoatomic cation channel activity calcium channel activity |
| GO:0005262 calcium channel activity | IEA GO_REF:0000107 | ACCEPT | Summary: The MET channel formed by TMC1 is highly calcium permeable, and TMC1 pore mutations change that permeability. Reason: Correct and experimentally grounded in the mouse orthologue; calcium entry through this channel is what pore-region deafness alleles disrupt. Supporting Evidence: PMID:36191207 Transmembrane channel-like protein 1 (TMC1) is thought to form the ion-conducting pore of the mechanoelectrical transducer (MET) channel in auditory hair cells. |
| GO:0008381 mechanosensitive monoatomic ion channel activity | IEA GO_REF:0000107 | ACCEPT | Summary: The core molecular function, transferred from the mouse orthologue with the contributes_to qualifier appropriate to a subunit of a multi-protein channel complex. Reason: Core molecular function. TMC1 lines the pore but the functional MET channel also requires TMIE, LHFPL5 and CIB2/CIB3, so contributes_to is the better-argued qualifier of the two used in this annotation set. Supporting Evidence: PMID:34089643 CIB2 and CIB3 bind to TMC1/2 through a domain in TMC1/2 flanked by transmembrane domains 2 and 3. |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer of an experimental mouse localisation (MGI IDA, PMID:16455951). TMC1 is a polytopic protein with cytoplasmic termini, so the term sits awkwardly with the topology. Reason: Retained rather than removed - the source is an experimental curator call whose full text has not been read here, and detection of an extracellular-facing epitope is a plausible basis for it. But the term is normally used for proteins displayed on the outer face of the membrane, and it adds nothing beyond the stereocilium tip and plasma membrane annotations. |
| GO:0032420 stereocilium | IEA GO_REF:0000107 | ACCEPT | Summary: TMC1 traffics into stereocilia, a step that requires TOMT. Reason: Correct location; the stereocilium tip row is the more specific statement. |
| GO:0032426 stereocilium tip | IEA GO_REF:0000107 | ACCEPT | Summary: GFP-tagged TMC proteins localise near stereocilia tips, the site of the MET channel and of the lower tip-link insertion. Reason: Core location - this is where the channel acts. Supporting Evidence: PMID:22105175 We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: TMC1 is an integral protein of the hair-cell plasma membrane and conducts there. Reason: Correct, although the stereocilium tip (GO:0032426) annotation carried by this gene states the site of action far more usefully. |
| GO:0032420 stereocilium | ISS GO_REF:0000024 | ACCEPT | Summary: TMC1 traffics into stereocilia, a step that requires TOMT. Reason: Correct location; the stereocilium tip row is the more specific statement. |
| GO:0005262 calcium channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: The MET channel formed by TMC1 is highly calcium permeable, and TMC1 pore mutations change that permeability. Reason: Correct and experimentally grounded in the mouse orthologue; calcium entry through this channel is what pore-region deafness alleles disrupt. |
| GO:0008381 mechanosensitive monoatomic ion channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-judged sequence-similarity transfer of the core molecular function from mouse Tmc1, now independently confirmed for the human protein in a heterologous system. Reason: Core molecular function. Human TMC1 forced to the plasma membrane by a CRISPRi screen responds to poking and stretch and yields resolvable single-channel currents, so the human assertion no longer rests on similarity alone. Supporting Evidence: PMID:39674179 Further, whole-genome CRISPRi screening enabled wild-type human TMC1/2 localization in the plasma membrane, where they responded robustly to poking stimuli. |
| GO:0017121 plasma membrane phospholipid scrambling | IMP PMID:40073458 Mammalian TMC1 or 2 are necessary for scramblase activity in... | NEW | Summary: Proposed new annotation. Auditory hair cells require TMC1 or TMC2 for phosphatidylserine externalisation - double knockouts show none at all, and virally expressed human TMC1 restores it - so TMC1 is genetically required for plasma-membrane phospholipid scrambling in hair cells. Reason: This is deliberately the involved_in process term and NOT the molecular function GO:0017128 phospholipid scramblase activity. The peer-reviewed genetics establishes necessity, and the authors themselves decline to conclude that TMC1 performs the translocation. Direct translocation by purified TMC1 has so far been shown only in a preprint (PMID:40631239, reconstituted proteoliposomes plus MD). "Necessary for" is not "performs", so the process is asserted and the activity is not. Supporting Evidence: PMID:40073458 We found that expression of either TMC1 or TMC2, was essential for PS externalization. PMID:40073458 Tmc1/Tmc2 knockout mice and Tmie mutant mice lacked PS externalization completely. PMID:40073458 However, it remains unclear whether TMC1 and TMC2 have a direct role in lipid scrambling or an essential but indirect role, perhaps by providing a signal or environment that enables lipid scrambling. |
| GO:0034703 cation channel complex | IDA PMID:34089643 CIB2 and CIB3 are auxiliary subunits of the mechanotransduct... | NEW | Summary: Proposed new annotation. TMC1 does not act alone: the functional mechanoelectrical transduction channel is an assembly of a TMC1 (or TMC2) dimer with TMIE, LHFPL5 and CIB2/CIB3, and GOA currently gives TMC1 no complex membership at all. Reason: Two of this gene's molecular-function rows already carry the contributes_to qualifier, which presupposes a complex that the annotation set never names. GO:0034703 is the closest existing term; a dedicated mechanoelectrical transduction channel complex term is proposed separately. Supporting Evidence: PMID:34089643 CIB2 and CIB3 bind to TMC1/2 through a domain in TMC1/2 flanked by transmembrane domains 2 and 3. PMID:34089643 We conclude that CIB2 and CIB3 are MET channel auxiliary subunits with striking similarity to Kv4 channel auxiliary subunits. |
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Download this section (compressed HTML)Q: Is TMC1 itself a lipid scramblase, or only necessary for scrambling that another protein performs? The peer-reviewed hair-cell genetics establishes necessity but the authors explicitly leave the mechanism open, and the only direct translocation assay is in a preprint. Two distinguishing experiments are already implied by the published work: does a TMC1 pore mutant that preserves ion conduction abolish scrambling (and vice versa), and does the correlation between FM1-43 permeation and PS externalisation survive separation of the two pathways?
Q: Should channel activity and scramblase activity be annotated as one dual-function protein, as they now are for TMEM63B, or should TMC1 be handled differently? The TMEM16 and TMEM63/OSCA precedents both allow a single groove to pass ions and lipids with separate bottleneck residues, so a dual annotation is not inherently contradictory - what is missing for TMC1 is replication of the direct assay outside one laboratory and outside a preprint.
Q: Is phosphatidylserine externalisation in hair cells a physiological process or a pathological one? It is triggered by blocking transduction and by deafness alleles, which suggests it reports hair-cell distress rather than normal function; if so, GO:0017121 on TMC1 describes a disease mechanism rather than a normal biological role.
Q: The human GOA carries GO:0009897 external side of plasma membrane by orthology from a mouse IDA. For a ten-transmembrane protein with cytoplasmic termini, what observation does that annotation encode, and is it distinguishable from detection of an extracellular loop epitope?
Experiment: Purify human TMC1 with TMIE and CIB2, reconstitute into proteoliposomes of defined cholesterol content, and measure ion conduction and phospholipid translocation on the same preparation, in a laboratory independent of the group that reported the preprint result. A dual measurement on one preparation is what distinguishes genuine dual function from an assay-specific artefact.
Experiment: Engineer TMC1 pore mutations that separate the two activities - a conduction-dead but scrambling-competent mutant and its converse - and knock them into mice, following the strategy that resolved the equivalent question for TMEM63B disease variants. If no such separation can be engineered, that is itself informative about a shared pathway.
Experiment: Record from plasma-membrane-localised human TMC1 in the CRISPRi-modified heterologous system while simultaneously imaging annexin-V binding, to test whether scrambling accompanies mechanical gating in a cell that contains no other hair-cell-specific machinery.
Experiment: Test whether TMC1-dependent PS externalisation occurs in unstressed hair cells in vivo at physiological sound levels, rather than only after pharmacological block or in deafness-allele carriers, to decide whether the process is physiological or pathological.
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