{"gene":"TMC2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2013,"finding":"TMC1 and TMC2 are components of the mechanosensitive ion channel in inner ear hair cells. Cells expressing TMC2 alone showed high calcium permeability and large single-channel currents; cells expressing mutant TMC1 showed reduced calcium permeability and smaller single-channel currents. Cells co-expressing both TMC1 and TMC2 displayed a broad range of single-channel conductances, suggesting heteromeric channel assemblies. TMC2 and TMC1 thus contribute to the permeation properties of the hair cell transduction channel.","method":"Whole-cell and single-channel patch-clamp recordings from mouse hair cells expressing Tmc1, Tmc2, or mutant Tmc1 (including Tmc1/Tmc2 knockout mice)","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct electrophysiological recordings in defined genetic backgrounds (KO mice), multiple channel properties measured, independently reproduced in subsequent studies","pmids":["23871232"],"is_preprint":false},{"year":2015,"finding":"TMC1 and TMC2 localize to the tips of stereocilia (the site of mechanotransduction) in mature hair cells, and both are absent from the tips of the tallest stereocilia row where MET activity is undetectable. In immature hair cells both proteins distribute along the full stereocilia length. Fluorescent-tagged TMC1-mCherry and TMC2-AcGFP rescued MET currents and hearing in Tmc1Δ/Δ;Tmc2Δ/Δ mice, confirming functionality of the localization data.","method":"Transgenic knock-in mice expressing TMC1-mCherry and TMC2-AcGFP; transgenic rescue of MET currents; immunofluorescence of endogenous proteins; live-cell imaging","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional rescue validation, endogenous protein confirmation, multiple orthogonal methods","pmids":["26321635"],"is_preprint":false},{"year":2014,"finding":"Tip-link protein PCDH15 physically interacts with TMC1 and TMC2. A membrane-based two-hybrid screen identified interaction between zebrafish Pcdh15a and TMC2a N-terminal fragment; yeast two-hybrid and co-immunoprecipitation confirmed interaction between mouse PCDH15-CD3 isoform and TMC1 or TMC2. Overexpression of the Tmc2a N terminus in zebrafish hair cells mislocalized Pcdh15a within bundles and significantly reduced mechanosensitive responses, demonstrating functional relevance of the complex.","method":"Membrane-based two-hybrid screen, yeast two-hybrid assay, co-immunoprecipitation (mouse), overexpression of dominant-negative Tmc2a N-terminus in zebrafish with electrophysiological readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction shown by multiple orthogonal methods (membrane two-hybrid, yeast two-hybrid, Co-IP) with in vivo functional validation","pmids":["25114259"],"is_preprint":false},{"year":2017,"finding":"Calcium and integrin-binding protein 2 (CIB2) physically binds TMC1 and TMC2, and this interaction is disrupted by deafness-causing CIB2 mutations. Loss of CIB2 abolishes mechanotransduction in auditory hair cells despite intact tip links, establishing CIB2 as required for normal operation of the TMC-containing MET channel complex.","method":"Co-immunoprecipitation of CIB2 with TMC1/TMC2; characterization of Cib2 knockout and deafness-mutation knock-in mouse lines; electrophysiological recording of MET currents","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic mouse models with electrophysiology, multiple orthogonal approaches in single study","pmids":["28663585"],"is_preprint":false},{"year":2017,"finding":"TMC2 modifies the pore properties of the MET channel in early postnatal cochlear outer hair cells (OHCs). In Tmc2 knockout OHCs, the channel blocker dihydrostreptomycin (DHS) had higher affinity (both extracellularly and intracellularly), and aminoglycoside entry was reduced during the first postnatal week. These pore-property changes implicate TMC2 as a pore-forming contributor to the neonatal MET channel.","method":"Whole-cell patch-clamp recordings of MET currents from Tmc2 knockout and heterozygous mice; pharmacological block with dihydrostreptomycin; aminoglycoside uptake assay","journal":"Frontiers in Molecular Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined pharmacological/pore phenotype, single lab, multiple measurements supporting same conclusion","pmids":["29093662"],"is_preprint":false},{"year":2019,"finding":"Purified and liposome-reconstituted TMC2 protein (from budgerigar, MuTMC2) possesses intrinsic ion channel activity and responds directly to applied pressure (mechanical stimuli), demonstrating that TMC2 is itself a pore-forming subunit of a mechanosensitive ion channel without requiring additional hair-cell-specific proteins.","method":"Heterologous expression in insect cells, protein purification, liposome reconstitution, single-channel electrophysiology, pressurized proteoliposome recordings","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with purified protein in liposomes, mechanical gating demonstrated, single rigorous study with multiple orthogonal methods","pmids":["31761710"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of the native C. elegans TMC-2 complex shows it assembles as a dimer of TMC-2 pore-forming subunits together with the calcium and integrin binding protein CALM-1 and the transmembrane inner ear protein TMIE. Conserved protein-lipid interactions and a π-helical motif in the pore-forming helices are proposed as mechanistically important features. Comparison with the C. elegans TMC-1 complex reveals differences in subunit composition alongside conserved structural features.","method":"Single-particle cryo-electron microscopy of native TMC-2 complex isolated from C. elegans","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution cryo-EM structure of native complex, ortholog study with strong mechanistic context; single lab but rigorous structural method","pmids":["38354260"],"is_preprint":false},{"year":2018,"finding":"TMC2 can partially substitute for TMC1 in vestibular hair cells but not in mature cochlear hair cells. Cre-inducible transgenic expression of Tmc2 in Tmc1-null mice restored sensory transduction in vestibular hair cells and transiently in cochlear hair cells, rescuing balance but not auditory function, indicating TMC1 has distinct functional requirements in mature cochlear hair cells not fulfilled by TMC2.","method":"Cre-inducible Tmc2 knock-in mouse model; electrophysiological recording of hair cell MET currents; auditory brainstem responses; vestibular behavioral assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment with electrophysiology and behavioral readouts, single lab, clear functional distinction between TMC1 and TMC2 established","pmids":["30108254"],"is_preprint":false},{"year":2018,"finding":"Persistent transgenic Tmc2 expression driven by the Tmc1 promoter in mature cochlear hair cells of Tmc1-null mice only slightly and transiently restored hearing, and outer hair cells eventually lost stereocilia, demonstrating that TMC2 cannot fully substitute for TMC1 in mature cochlear function and that TMC1 has a distinct requirement in this context.","method":"Transgenic mouse line Tg[PTmc1::Tmc2]; auditory brainstem response and DPOAE hearing tests; electrophysiological recordings; histological analysis of hair cells","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation experiment with multiple functional readouts, single lab, orthogonal physiological and histological methods","pmids":["30108230"],"is_preprint":false},{"year":2025,"finding":"Full-length mouse TMC2, when directed to the plasma membrane via a Fyn lipidation tag (bypassing ER retention), functions as a mechanosensitive ion channel in heterologous cells. TMIE robustly potentiates TMC2 channel activity by modulating gating. Palmitoylation at TMIE residues C76/C77 is required for TMIE stimulation of TMC2 gating. TMC2 + TMIE reconstitute 24 pS single channels with biophysical and pharmacological properties resembling the native MET channel.","method":"Heterologous expression with Fyn lipidation tag; whole-cell and single-channel patch-clamp electrophysiology; co-expression with TMIE and TMIE mutants (N-terminal deletion, C76A/C77A palmitoylation site mutants)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional reconstitution of full-length mammalian TMC2 with mutagenesis of regulatory partners, single-channel recordings, multiple orthogonal approaches in one rigorous study","pmids":["39999170"],"is_preprint":false},{"year":2025,"finding":"TMC1 and TMC2 function as cholesterol-regulated lipid scramblases in addition to ion channels. Using reconstituted proteoliposomes and molecular dynamics simulations, both proteins facilitate phospholipid translocation across bilayers; activity is tuned by cholesterol and enhanced by deafness-causing TMC1 mutations. In murine auditory hair cells, TMC1-dependent phosphatidylserine externalization and membrane blebbing were observed, linking TMC-dependent membrane homeostasis dysregulation to hair cell pathology.","method":"Proteoliposome reconstitution scramblase assay, molecular dynamics simulations, phosphatidylserine externalization assay in murine auditory hair cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with MD simulations and cell-based validation, but preprint/single lab, novel claim not yet peer-reviewed","pmids":["40631239"],"is_preprint":true},{"year":2024,"finding":"TMC2 (and TMC1) function as mechanosensitive scramblases in auditory hair cell stereocilia, with scramblase activity dependent on MET channel opening. Blocking scramblase activity unmasked a second process increasing effective membrane viscosity independently of the MET machinery, revealing dynamic regulation of stereocilia membrane properties.","method":"BODIPY 1c viscosity sensor, genetic (Tmc2 KO), electrophysiological, and pharmacological approaches in hair cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, novel assay (BODIPY viscosity sensor) without independent replication; mechanistic interpretation partially indirect","pmids":[],"is_preprint":true}],"current_model":"TMC2 is a pore-forming subunit of the mechanosensitive mechanoelectrical transduction (MET) ion channel complex in inner ear hair cells: it localizes to stereocilia tips, physically interacts with the tip-link protein PCDH15 and the auxiliary proteins CIB2 and TMIE (which potentiates its gating via palmitoylation), contributes to channel permeation properties (including calcium permeability and single-channel conductance), and, in reconstituted liposomes, directly gates in response to mechanical force; additionally, emerging evidence indicates TMC2 possesses cholesterol-regulated lipid scramblase activity that modulates stereocilia membrane homeostasis."},"narrative":{"mechanistic_narrative":"TMC2 is a pore-forming subunit of the mechanoelectrical transduction (MET) channel that mediates mechanosensation in inner ear hair cells [PMID:23871232, PMID:31761710]. Genetic and electrophysiological analysis established that TMC2, together with TMC1, sets the permeation properties of the hair cell transduction channel, conferring high calcium permeability and large single-channel conductances and assembling into heteromeric channels of variable conductance [PMID:23871232]; in early postnatal outer hair cells TMC2 shapes pore pharmacology, including affinity for the blocker dihydrostreptomycin and aminoglycoside entry [PMID:29093662]. TMC2 localizes to stereocilia tips, the site of MET activity, and tagged TMC2 rescues MET currents and hearing in Tmc1/Tmc2-null mice [PMID:26321635]. Within the transduction apparatus TMC2 physically engages the tip-link protein PCDH15 [PMID:25114259] and the auxiliary subunit CIB2 (and its ortholog CALM-1), whose binding is required for normal channel operation [PMID:28663585, PMID:38354260]. Reconstitution of purified TMC2 in liposomes demonstrated that the protein is intrinsically a mechanically gated ion channel that does not require additional hair-cell proteins [PMID:31761710], and full-length mammalian TMC2 forms 24 pS channels resembling the native MET channel when co-expressed with TMIE, which potentiates gating in a manner dependent on palmitoylation of TMIE residues C76/C77 [PMID:39999170]. Cryo-EM of the native C. elegans TMC-2 complex shows a dimer of pore-forming TMC-2 subunits assembled with CALM-1 and TMIE, with conserved protein-lipid interactions and a π-helical pore motif [PMID:38354260]. Despite this overlapping role, TMC2 cannot fully substitute for TMC1 in mature cochlear hair cells, rescuing balance but only transiently restoring hearing [PMID:30108254, PMID:30108230]. Beyond ion conduction, TMC2 additionally functions as a cholesterol-regulated, MET-coupled lipid scramblase that translocates phospholipids and modulates stereocilia membrane homeostasis [PMID:40631239].","teleology":[{"year":2013,"claim":"Established that TMC2 is not merely associated with the MET channel but contributes directly to its ion permeation properties, distinguishing it from a purely structural role.","evidence":"Whole-cell and single-channel patch-clamp from mouse hair cells expressing Tmc1, Tmc2, or mutant Tmc1 in KO backgrounds","pmids":["23871232"],"confidence":"High","gaps":["Did not resolve whether TMC2 itself forms the pore or requires partner subunits","Stoichiometry of TMC1/TMC2 heteromers not defined"]},{"year":2014,"claim":"Answered how the MET channel is physically coupled to the force-conveying tip link by showing TMC2 directly binds the tip-link protein PCDH15.","evidence":"Membrane and yeast two-hybrid, Co-IP, and dominant-negative N-terminus overexpression in zebrafish with electrophysiology","pmids":["25114259"],"confidence":"High","gaps":["Binding interface and affinity not quantified","Whether interaction is constitutive or force-dependent unknown"]},{"year":2015,"claim":"Localized TMC2 to stereocilia tips and confirmed functional relevance, placing the protein precisely at the site of mechanotransduction.","evidence":"Knock-in mice expressing TMC2-AcGFP with functional MET/hearing rescue, immunofluorescence, live imaging","pmids":["26321635"],"confidence":"High","gaps":["Mechanism targeting TMC2 to tips not defined","Developmental redistribution of the protein not mechanistically explained"]},{"year":2017,"claim":"Identified CIB2 as an obligate auxiliary subunit, showing the TMC channel requires this partner for function and that deafness mutations disrupt the interaction.","evidence":"Co-IP of CIB2 with TMC1/TMC2, Cib2 KO and knock-in deafness mutants, MET electrophysiology","pmids":["28663585"],"confidence":"High","gaps":["How CIB2 binding enables gating is unresolved","CIB2 binding site on TMC2 not mapped"]},{"year":2017,"claim":"Refined TMC2's contribution to neonatal channel pharmacology, showing it shapes blocker affinity and aminoglycoside permeation in early postnatal outer hair cells.","evidence":"Patch-clamp of Tmc2 KO/het mice with dihydrostreptomycin block and aminoglycoside uptake assays","pmids":["29093662"],"confidence":"Medium","gaps":["Single-lab pore phenotype","Does not separate TMC2 pore contribution from heteromer effects"]},{"year":2018,"claim":"Defined the functional non-equivalence of TMC1 and TMC2, showing TMC2 rescues vestibular but not mature cochlear transduction.","evidence":"Cre-inducible and promoter-driven transgenic Tmc2 expression in Tmc1-null mice with ABR, DPOAE, electrophysiology, and histology","pmids":["30108254","30108230"],"confidence":"Medium","gaps":["Molecular basis of TMC1-specific cochlear requirement unknown","Why outer hair cells lose stereocilia with TMC2 substitution unexplained"]},{"year":2019,"claim":"Demonstrated TMC2 is intrinsically a mechanosensitive pore-forming channel, settling whether it forms the pore by reconstituting purified protein that gates to mechanical force without hair-cell-specific accessory proteins.","evidence":"Purified budgerigar TMC2 reconstituted into liposomes with single-channel and pressurized proteoliposome recordings","pmids":["31761710"],"confidence":"High","gaps":["Used an avian ortholog rather than mammalian TMC2","Native gating regulation by partners not addressed in minimal system"]},{"year":2024,"claim":"Provided the structural architecture of the TMC-2 complex, showing a dimer of pore-forming subunits with CALM-1/CIB2 and TMIE and identifying conserved lipid contacts and a π-helical pore motif.","evidence":"Single-particle cryo-EM of native C. elegans TMC-2 complex","pmids":["38354260"],"confidence":"High","gaps":["Structure is of an invertebrate ortholog","Open/closed conformational transitions during gating not captured"]},{"year":2025,"claim":"Reconstituted full-length mammalian TMC2 as a native-like MET channel and defined TMIE palmitoylation as a gating-potentiating mechanism.","evidence":"Fyn-lipidation-tag plasma membrane targeting in heterologous cells, single-channel recordings, TMIE deletion and C76A/C77A mutants","pmids":["39999170"],"confidence":"High","gaps":["How palmitoylated TMIE physically modulates the pore is not resolved","Contribution of PCDH15/CIB2 to gating in this system not tested"]},{"year":2025,"claim":"Revealed a second, non-conductive activity: TMC2 acts as a cholesterol-regulated, MET-coupled lipid scramblase regulating stereocilia membrane homeostasis.","evidence":"Proteoliposome scramblase assays, MD simulations, phosphatidylserine externalization and membrane viscosity assays in hair cells (preprints)","pmids":["40631239"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed and single lab","Physiological role of scramblase activity in hearing not established","Coupling between channel gating and lipid translocation mechanistically unclear"]},{"year":null,"claim":"How TMC2 channel gating, the auxiliary subunit network (PCDH15, CIB2, TMIE), and the newly described scramblase activity are mechanistically integrated within a single physiological transduction event remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mammalian high-resolution structure of the assembled complex","Force-transmission path from tip link to pore not defined","Functional significance of dual ion-channel/scramblase activity in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,5,9]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[0,1]}],"complexes":["mechanoelectrical transduction (MET) channel complex"],"partners":["TMC1","PCDH15","CIB2","TMIE"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TDI7","full_name":"Transmembrane channel-like protein 2","aliases":["Transmembrane cochlear-expressed protein 2"],"length_aa":906,"mass_kda":102.6,"function":"Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system (PubMed:11850618). The MET complex is composed of two dimeric pore-forming ion-conducting transmembrane TMC (TMC1 or TMC2) subunits, and aided by several auxiliary proteins including LHFPL5, TMIE, CIB2/3 and TOMT, and the tip-link PCDH15. MET channel is activated by tension in the tip-link extending from the side wall of one stereocilium to the tip of the adjacent shorter stereocilium, where the channel is located (By similarity). TMC2 MET channel is highly permeable to calcium and likely transports monovalent cations. Also involved in vestibular hair cell transduction current of the mammalian inner ear (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TDI7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMC2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMC2","total_profiled":1310},"omim":[{"mim_id":"617198","title":"TRANSMEMBRANE CHANNEL-LIKE PROTEIN 7; TMC7","url":"https://www.omim.org/entry/617198"},{"mim_id":"617197","title":"TRANSMEMBRANE CHANNEL-LIKE PROTEIN 5; TMC5","url":"https://www.omim.org/entry/617197"},{"mim_id":"617196","title":"TRANSMEMBRANE CHANNEL-LIKE PROTEIN 3; TMC3","url":"https://www.omim.org/entry/617196"},{"mim_id":"617181","title":"TRANSMEMBRANE CHANNEL-LIKE PROTEIN 4; TMC4","url":"https://www.omim.org/entry/617181"},{"mim_id":"606707","title":"TRANSMEMBRANE CHANNEL-LIKE PROTEIN 2; TMC2","url":"https://www.omim.org/entry/606707"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":2.7}],"url":"https://www.proteinatlas.org/search/TMC2"},"hgnc":{"alias_symbol":["dJ686C3.3"],"prev_symbol":["C20orf145"]},"alphafold":{"accession":"Q8TDI7","domains":[{"cath_id":"-","chopping":"236-283_326-544_574-720","consensus_level":"medium","plddt":81.0164,"start":236,"end":720},{"cath_id":"1.20.5","chopping":"776-807","consensus_level":"medium","plddt":76.7606,"start":776,"end":807}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDI7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDI7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDI7-F1-predicted_aligned_error_v6.png","plddt_mean":67.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMC2","jax_strain_url":"https://www.jax.org/strain/search?query=TMC2"},"sequence":{"accession":"Q8TDI7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TDI7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TDI7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDI7"}},"corpus_meta":[{"pmid":"23871232","id":"PMC_23871232","title":"TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear.","date":"2013","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/23871232","citation_count":344,"is_preprint":false},{"pmid":"26321635","id":"PMC_26321635","title":"TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26321635","citation_count":155,"is_preprint":false},{"pmid":"28663585","id":"PMC_28663585","title":"CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28663585","citation_count":149,"is_preprint":false},{"pmid":"25114259","id":"PMC_25114259","title":"Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25114259","citation_count":138,"is_preprint":false},{"pmid":"31761710","id":"PMC_31761710","title":"TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels.","date":"2019","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/31761710","citation_count":130,"is_preprint":false},{"pmid":"18259073","id":"PMC_18259073","title":"TMC1 but not TMC2 is responsible for autosomal recessive nonsyndromic hearing impairment in Tunisian families.","date":"2008","source":"Audiology & neuro-otology","url":"https://pubmed.ncbi.nlm.nih.gov/18259073","citation_count":52,"is_preprint":false},{"pmid":"29093662","id":"PMC_29093662","title":"TMC2 Modifies Permeation Properties of the Mechanoelectrical Transducer Channel in Early Postnatal Mouse Cochlear Outer Hair Cells.","date":"2017","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29093662","citation_count":30,"is_preprint":false},{"pmid":"38354260","id":"PMC_38354260","title":"The structure of the Caenorhabditis elegans TMC-2 complex suggests roles of lipid-mediated subunit contacts in mechanosensory transduction.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38354260","citation_count":29,"is_preprint":false},{"pmid":"30108254","id":"PMC_30108254","title":"Transgenic Tmc2 expression preserves inner ear hair cells and vestibular function in mice lacking Tmc1.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30108254","citation_count":25,"is_preprint":false},{"pmid":"30108230","id":"PMC_30108230","title":"Tmc2 expression partially restores auditory function in a mouse model of DFNB7/B11 deafness caused by loss of Tmc1 function.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30108230","citation_count":25,"is_preprint":false},{"pmid":"39999170","id":"PMC_39999170","title":"Ectopic mouse TMC1 and TMC2 alone form mechanosensitive channels that are potently modulated by TMIE.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39999170","citation_count":8,"is_preprint":false},{"pmid":"40280017","id":"PMC_40280017","title":"TMC1 and TMC2 function as the mechano-electrical transduction ion channel in hearing.","date":"2025","source":"Current opinion in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40280017","citation_count":7,"is_preprint":false},{"pmid":"40631239","id":"PMC_40631239","title":"TMC1 and TMC2 are cholesterol-dependent scramblases that regulate membrane homeostasis in auditory hair cells.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40631239","citation_count":3,"is_preprint":false},{"pmid":"37645790","id":"PMC_37645790","title":"Structure of C. elegans TMC-2 complex suggests roles of lipid-mediated subunit contacts in mechanosensory transduction.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37645790","citation_count":3,"is_preprint":false},{"pmid":"36568409","id":"PMC_36568409","title":"Functional consequences of Genetics variant in TMC1 and TMC2 within a United Arab Emirates family with Pre-lingual hearing loss.","date":"2022","source":"Saudi journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36568409","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.27.615395","title":"Dynamic modulation of auditory hair cell stereocilia membrane mechanics by the scrambling mechanotransduction complex","date":"2024-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.27.615395","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9571,"output_tokens":3464,"usd":0.040336,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11125,"output_tokens":3573,"usd":0.072475,"stage2_stop_reason":"end_turn"},"total_usd":0.112811,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TMC1 and TMC2 are components of the mechanosensitive ion channel in inner ear hair cells. Cells expressing TMC2 alone showed high calcium permeability and large single-channel currents; cells expressing mutant TMC1 showed reduced calcium permeability and smaller single-channel currents. Cells co-expressing both TMC1 and TMC2 displayed a broad range of single-channel conductances, suggesting heteromeric channel assemblies. TMC2 and TMC1 thus contribute to the permeation properties of the hair cell transduction channel.\",\n      \"method\": \"Whole-cell and single-channel patch-clamp recordings from mouse hair cells expressing Tmc1, Tmc2, or mutant Tmc1 (including Tmc1/Tmc2 knockout mice)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct electrophysiological recordings in defined genetic backgrounds (KO mice), multiple channel properties measured, independently reproduced in subsequent studies\",\n      \"pmids\": [\"23871232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMC1 and TMC2 localize to the tips of stereocilia (the site of mechanotransduction) in mature hair cells, and both are absent from the tips of the tallest stereocilia row where MET activity is undetectable. In immature hair cells both proteins distribute along the full stereocilia length. Fluorescent-tagged TMC1-mCherry and TMC2-AcGFP rescued MET currents and hearing in Tmc1Δ/Δ;Tmc2Δ/Δ mice, confirming functionality of the localization data.\",\n      \"method\": \"Transgenic knock-in mice expressing TMC1-mCherry and TMC2-AcGFP; transgenic rescue of MET currents; immunofluorescence of endogenous proteins; live-cell imaging\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional rescue validation, endogenous protein confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"26321635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tip-link protein PCDH15 physically interacts with TMC1 and TMC2. A membrane-based two-hybrid screen identified interaction between zebrafish Pcdh15a and TMC2a N-terminal fragment; yeast two-hybrid and co-immunoprecipitation confirmed interaction between mouse PCDH15-CD3 isoform and TMC1 or TMC2. Overexpression of the Tmc2a N terminus in zebrafish hair cells mislocalized Pcdh15a within bundles and significantly reduced mechanosensitive responses, demonstrating functional relevance of the complex.\",\n      \"method\": \"Membrane-based two-hybrid screen, yeast two-hybrid assay, co-immunoprecipitation (mouse), overexpression of dominant-negative Tmc2a N-terminus in zebrafish with electrophysiological readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction shown by multiple orthogonal methods (membrane two-hybrid, yeast two-hybrid, Co-IP) with in vivo functional validation\",\n      \"pmids\": [\"25114259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Calcium and integrin-binding protein 2 (CIB2) physically binds TMC1 and TMC2, and this interaction is disrupted by deafness-causing CIB2 mutations. Loss of CIB2 abolishes mechanotransduction in auditory hair cells despite intact tip links, establishing CIB2 as required for normal operation of the TMC-containing MET channel complex.\",\n      \"method\": \"Co-immunoprecipitation of CIB2 with TMC1/TMC2; characterization of Cib2 knockout and deafness-mutation knock-in mouse lines; electrophysiological recording of MET currents\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic mouse models with electrophysiology, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"28663585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TMC2 modifies the pore properties of the MET channel in early postnatal cochlear outer hair cells (OHCs). In Tmc2 knockout OHCs, the channel blocker dihydrostreptomycin (DHS) had higher affinity (both extracellularly and intracellularly), and aminoglycoside entry was reduced during the first postnatal week. These pore-property changes implicate TMC2 as a pore-forming contributor to the neonatal MET channel.\",\n      \"method\": \"Whole-cell patch-clamp recordings of MET currents from Tmc2 knockout and heterozygous mice; pharmacological block with dihydrostreptomycin; aminoglycoside uptake assay\",\n      \"journal\": \"Frontiers in Molecular Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined pharmacological/pore phenotype, single lab, multiple measurements supporting same conclusion\",\n      \"pmids\": [\"29093662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Purified and liposome-reconstituted TMC2 protein (from budgerigar, MuTMC2) possesses intrinsic ion channel activity and responds directly to applied pressure (mechanical stimuli), demonstrating that TMC2 is itself a pore-forming subunit of a mechanosensitive ion channel without requiring additional hair-cell-specific proteins.\",\n      \"method\": \"Heterologous expression in insect cells, protein purification, liposome reconstitution, single-channel electrophysiology, pressurized proteoliposome recordings\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with purified protein in liposomes, mechanical gating demonstrated, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"31761710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the native C. elegans TMC-2 complex shows it assembles as a dimer of TMC-2 pore-forming subunits together with the calcium and integrin binding protein CALM-1 and the transmembrane inner ear protein TMIE. Conserved protein-lipid interactions and a π-helical motif in the pore-forming helices are proposed as mechanistically important features. Comparison with the C. elegans TMC-1 complex reveals differences in subunit composition alongside conserved structural features.\",\n      \"method\": \"Single-particle cryo-electron microscopy of native TMC-2 complex isolated from C. elegans\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution cryo-EM structure of native complex, ortholog study with strong mechanistic context; single lab but rigorous structural method\",\n      \"pmids\": [\"38354260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMC2 can partially substitute for TMC1 in vestibular hair cells but not in mature cochlear hair cells. Cre-inducible transgenic expression of Tmc2 in Tmc1-null mice restored sensory transduction in vestibular hair cells and transiently in cochlear hair cells, rescuing balance but not auditory function, indicating TMC1 has distinct functional requirements in mature cochlear hair cells not fulfilled by TMC2.\",\n      \"method\": \"Cre-inducible Tmc2 knock-in mouse model; electrophysiological recording of hair cell MET currents; auditory brainstem responses; vestibular behavioral assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment with electrophysiology and behavioral readouts, single lab, clear functional distinction between TMC1 and TMC2 established\",\n      \"pmids\": [\"30108254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Persistent transgenic Tmc2 expression driven by the Tmc1 promoter in mature cochlear hair cells of Tmc1-null mice only slightly and transiently restored hearing, and outer hair cells eventually lost stereocilia, demonstrating that TMC2 cannot fully substitute for TMC1 in mature cochlear function and that TMC1 has a distinct requirement in this context.\",\n      \"method\": \"Transgenic mouse line Tg[PTmc1::Tmc2]; auditory brainstem response and DPOAE hearing tests; electrophysiological recordings; histological analysis of hair cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation experiment with multiple functional readouts, single lab, orthogonal physiological and histological methods\",\n      \"pmids\": [\"30108230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Full-length mouse TMC2, when directed to the plasma membrane via a Fyn lipidation tag (bypassing ER retention), functions as a mechanosensitive ion channel in heterologous cells. TMIE robustly potentiates TMC2 channel activity by modulating gating. Palmitoylation at TMIE residues C76/C77 is required for TMIE stimulation of TMC2 gating. TMC2 + TMIE reconstitute 24 pS single channels with biophysical and pharmacological properties resembling the native MET channel.\",\n      \"method\": \"Heterologous expression with Fyn lipidation tag; whole-cell and single-channel patch-clamp electrophysiology; co-expression with TMIE and TMIE mutants (N-terminal deletion, C76A/C77A palmitoylation site mutants)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro functional reconstitution of full-length mammalian TMC2 with mutagenesis of regulatory partners, single-channel recordings, multiple orthogonal approaches in one rigorous study\",\n      \"pmids\": [\"39999170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMC1 and TMC2 function as cholesterol-regulated lipid scramblases in addition to ion channels. Using reconstituted proteoliposomes and molecular dynamics simulations, both proteins facilitate phospholipid translocation across bilayers; activity is tuned by cholesterol and enhanced by deafness-causing TMC1 mutations. In murine auditory hair cells, TMC1-dependent phosphatidylserine externalization and membrane blebbing were observed, linking TMC-dependent membrane homeostasis dysregulation to hair cell pathology.\",\n      \"method\": \"Proteoliposome reconstitution scramblase assay, molecular dynamics simulations, phosphatidylserine externalization assay in murine auditory hair cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with MD simulations and cell-based validation, but preprint/single lab, novel claim not yet peer-reviewed\",\n      \"pmids\": [\"40631239\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMC2 (and TMC1) function as mechanosensitive scramblases in auditory hair cell stereocilia, with scramblase activity dependent on MET channel opening. Blocking scramblase activity unmasked a second process increasing effective membrane viscosity independently of the MET machinery, revealing dynamic regulation of stereocilia membrane properties.\",\n      \"method\": \"BODIPY 1c viscosity sensor, genetic (Tmc2 KO), electrophysiological, and pharmacological approaches in hair cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, novel assay (BODIPY viscosity sensor) without independent replication; mechanistic interpretation partially indirect\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TMC2 is a pore-forming subunit of the mechanosensitive mechanoelectrical transduction (MET) ion channel complex in inner ear hair cells: it localizes to stereocilia tips, physically interacts with the tip-link protein PCDH15 and the auxiliary proteins CIB2 and TMIE (which potentiates its gating via palmitoylation), contributes to channel permeation properties (including calcium permeability and single-channel conductance), and, in reconstituted liposomes, directly gates in response to mechanical force; additionally, emerging evidence indicates TMC2 possesses cholesterol-regulated lipid scramblase activity that modulates stereocilia membrane homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMC2 is a pore-forming subunit of the mechanoelectrical transduction (MET) channel that mediates mechanosensation in inner ear hair cells [#0, #5]. Genetic and electrophysiological analysis established that TMC2, together with TMC1, sets the permeation properties of the hair cell transduction channel, conferring high calcium permeability and large single-channel conductances and assembling into heteromeric channels of variable conductance [#0]; in early postnatal outer hair cells TMC2 shapes pore pharmacology, including affinity for the blocker dihydrostreptomycin and aminoglycoside entry [#4]. TMC2 localizes to stereocilia tips, the site of MET activity, and tagged TMC2 rescues MET currents and hearing in Tmc1/Tmc2-null mice [#1]. Within the transduction apparatus TMC2 physically engages the tip-link protein PCDH15 [#2] and the auxiliary subunit CIB2 (and its ortholog CALM-1), whose binding is required for normal channel operation [#3, #6]. Reconstitution of purified TMC2 in liposomes demonstrated that the protein is intrinsically a mechanically gated ion channel that does not require additional hair-cell proteins [#5], and full-length mammalian TMC2 forms 24 pS channels resembling the native MET channel when co-expressed with TMIE, which potentiates gating in a manner dependent on palmitoylation of TMIE residues C76/C77 [#9]. Cryo-EM of the native C. elegans TMC-2 complex shows a dimer of pore-forming TMC-2 subunits assembled with CALM-1 and TMIE, with conserved protein-lipid interactions and a π-helical pore motif [#6]. Despite this overlapping role, TMC2 cannot fully substitute for TMC1 in mature cochlear hair cells, rescuing balance but only transiently restoring hearing [#7, #8]. Beyond ion conduction, TMC2 additionally functions as a cholesterol-regulated, MET-coupled lipid scramblase that translocates phospholipids and modulates stereocilia membrane homeostasis [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that TMC2 is not merely associated with the MET channel but contributes directly to its ion permeation properties, distinguishing it from a purely structural role.\",\n      \"evidence\": \"Whole-cell and single-channel patch-clamp from mouse hair cells expressing Tmc1, Tmc2, or mutant Tmc1 in KO backgrounds\",\n      \"pmids\": [\"23871232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether TMC2 itself forms the pore or requires partner subunits\", \"Stoichiometry of TMC1/TMC2 heteromers not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Answered how the MET channel is physically coupled to the force-conveying tip link by showing TMC2 directly binds the tip-link protein PCDH15.\",\n      \"evidence\": \"Membrane and yeast two-hybrid, Co-IP, and dominant-negative N-terminus overexpression in zebrafish with electrophysiology\",\n      \"pmids\": [\"25114259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface and affinity not quantified\", \"Whether interaction is constitutive or force-dependent unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Localized TMC2 to stereocilia tips and confirmed functional relevance, placing the protein precisely at the site of mechanotransduction.\",\n      \"evidence\": \"Knock-in mice expressing TMC2-AcGFP with functional MET/hearing rescue, immunofluorescence, live imaging\",\n      \"pmids\": [\"26321635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism targeting TMC2 to tips not defined\", \"Developmental redistribution of the protein not mechanistically explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified CIB2 as an obligate auxiliary subunit, showing the TMC channel requires this partner for function and that deafness mutations disrupt the interaction.\",\n      \"evidence\": \"Co-IP of CIB2 with TMC1/TMC2, Cib2 KO and knock-in deafness mutants, MET electrophysiology\",\n      \"pmids\": [\"28663585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CIB2 binding enables gating is unresolved\", \"CIB2 binding site on TMC2 not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined TMC2's contribution to neonatal channel pharmacology, showing it shapes blocker affinity and aminoglycoside permeation in early postnatal outer hair cells.\",\n      \"evidence\": \"Patch-clamp of Tmc2 KO/het mice with dihydrostreptomycin block and aminoglycoside uptake assays\",\n      \"pmids\": [\"29093662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pore phenotype\", \"Does not separate TMC2 pore contribution from heteromer effects\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the functional non-equivalence of TMC1 and TMC2, showing TMC2 rescues vestibular but not mature cochlear transduction.\",\n      \"evidence\": \"Cre-inducible and promoter-driven transgenic Tmc2 expression in Tmc1-null mice with ABR, DPOAE, electrophysiology, and histology\",\n      \"pmids\": [\"30108254\", \"30108230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of TMC1-specific cochlear requirement unknown\", \"Why outer hair cells lose stereocilia with TMC2 substitution unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated TMC2 is intrinsically a mechanosensitive pore-forming channel, settling whether it forms the pore by reconstituting purified protein that gates to mechanical force without hair-cell-specific accessory proteins.\",\n      \"evidence\": \"Purified budgerigar TMC2 reconstituted into liposomes with single-channel and pressurized proteoliposome recordings\",\n      \"pmids\": [\"31761710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Used an avian ortholog rather than mammalian TMC2\", \"Native gating regulation by partners not addressed in minimal system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural architecture of the TMC-2 complex, showing a dimer of pore-forming subunits with CALM-1/CIB2 and TMIE and identifying conserved lipid contacts and a π-helical pore motif.\",\n      \"evidence\": \"Single-particle cryo-EM of native C. elegans TMC-2 complex\",\n      \"pmids\": [\"38354260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure is of an invertebrate ortholog\", \"Open/closed conformational transitions during gating not captured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reconstituted full-length mammalian TMC2 as a native-like MET channel and defined TMIE palmitoylation as a gating-potentiating mechanism.\",\n      \"evidence\": \"Fyn-lipidation-tag plasma membrane targeting in heterologous cells, single-channel recordings, TMIE deletion and C76A/C77A mutants\",\n      \"pmids\": [\"39999170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How palmitoylated TMIE physically modulates the pore is not resolved\", \"Contribution of PCDH15/CIB2 to gating in this system not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a second, non-conductive activity: TMC2 acts as a cholesterol-regulated, MET-coupled lipid scramblase regulating stereocilia membrane homeostasis.\",\n      \"evidence\": \"Proteoliposome scramblase assays, MD simulations, phosphatidylserine externalization and membrane viscosity assays in hair cells (preprints)\",\n      \"pmids\": [\"40631239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed and single lab\", \"Physiological role of scramblase activity in hearing not established\", \"Coupling between channel gating and lipid translocation mechanistically unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMC2 channel gating, the auxiliary subunit network (PCDH15, CIB2, TMIE), and the newly described scramblase activity are mechanistically integrated within a single physiological transduction event remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mammalian high-resolution structure of the assembled complex\", \"Force-transmission path from tip link to pore not defined\", \"Functional significance of dual ion-channel/scramblase activity in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"mechanoelectrical transduction (MET) channel complex\"],\n    \"partners\": [\"TMC1\", \"PCDH15\", \"CIB2\", \"TMIE\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}