{"gene":"LHFPL5","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2005,"finding":"TMHS (LHFPL5) is a tetraspan integral membrane protein localized to the apical membrane (hair bundles) of inner and outer cochlear hair cells; loss-of-function missense mutation (C→F) causes disorganized hair bundles and deafness in hurry-scurry mice, implicating TMHS in hair bundle morphogenesis.","method":"Positional cloning, immunohistochemistry with polyclonal antibodies, scanning electron microscopy of cochleae in hscy mutant mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization established by antibody staining with functional link to hair bundle morphogenesis via loss-of-function, single lab","pmids":["15905332"],"is_preprint":false},{"year":2007,"finding":"Targeted null mutation of Tmhs (Lhfpl5) produces identical deafness/vestibular phenotype to the hscy missense allele, confirming that TMHS loss of function causes deafness; lacZ reporter shows expression peaks around P0 and is absent by P15, consistent with a role during stereocilia development.","method":"Targeted gene knockout (null allele), lacZ reporter knock-in, beta-galactosidase activity assay","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null allele with defined phenotype, lacZ reporter for temporal expression, single lab","pmids":["17876667"],"is_preprint":false},{"year":2012,"finding":"TMHS (LHFPL5) is an integral component of the hair cell mechanotransduction machinery: it binds to the tip-link component PCDH15, regulates tip-link assembly, controls transducer channel conductance, and is required for fast channel adaptation. Deafness-causing Tmhs mutations disrupt tip-link assembly and PCDH15 binding.","method":"Electrophysiology (mechanotransduction recordings), co-immunoprecipitation (TMHS–PCDH15 interaction), knockout mouse analysis, tip-link assembly assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction assays combined with electrophysiology and knockout phenotype; independently corroborated by structural work","pmids":["23217710"],"is_preprint":false},{"year":2017,"finding":"LHFPL5 localizes to ranked stereocilia tips (site of tip links) from P0, peaks at P3, and becomes restricted to shorter stereocilia rows by P12. In PCDH15-deficient mice at P3, LHFPL5 is mislocalized away from tips to unranked stereocilia and lateral links, demonstrating that PCDH15 is required for LHFPL5 tip localization.","method":"Immunofluorescence and immunogold transmission electron microscopy in wild-type and Pcdh15-knockout mice across developmental time points","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by immunogold TEM with functional validation via PCDH15 knockout, multiple time points and orthogonal imaging methods","pmids":["29069081"],"is_preprint":false},{"year":2018,"finding":"Crystal/cryo-EM structure of the PCDH15–LHFPL5 complex reveals a heterotetrameric assembly (2:2 stoichiometry with 2-fold symmetry) in which LHFPL5 forms extensive interactions with PCDH15 transmembrane helices and stabilizes the overall assembly; the extracellular cadherin domains form a mobile tether coupled to a rigid 'collar' near the membrane.","method":"Structural biology (cryo-EM/X-ray crystallography), analytical ultracentrifugation (sedimentation), structure-based mapping of deafness mutations","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution structure with biochemical validation of complex stoichiometry and deafness mutation mapping","pmids":["30070639"],"is_preprint":false},{"year":2019,"finding":"TMC1 and LHFPL5 co-localize at the tips of shorter stereocilia rows in both neonatal and adult outer hair cells; LHFPL5 persists in the hair bundle after P7, confirming it is a permanent component of the mechanotransduction complex. In adult inner hair cells, TMC1 distributes uniformly across both tallest and shorter rows while LHFPL5 remains in shorter rows.","method":"Immunofluorescence, confocal microscopy, super-resolution microscopy in neonatal and adult mouse cochlea","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by multiple imaging approaches at distinct developmental stages, single lab","pmids":["30808210"],"is_preprint":false},{"year":2020,"finding":"LHFPL5 physically interacts with and stabilizes TMC1 protein in heterologous cells and in native hair cell soma and hair bundles; the deafness mutation D572N in human TMC1 (D569N in mouse) disrupts LHFPL5 binding and destabilizes TMC1 expression.","method":"Single-molecule pull-down (SiMPull microbead assay), co-immunoprecipitation in heterologous expression systems and native hair cells, western blot for protein stability","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction demonstrated by multiple orthogonal methods (SiMPull + Co-IP) in both heterologous and native cells, with mutagenesis validation","pmids":["33168709"],"is_preprint":false},{"year":2020,"finding":"In zebrafish, LHFPL5 localization to stereocilia tips requires the tip-link cadherins Pcdh15a and Cdh23, as well as the motor protein Myo7aa; however, localization of TMC1 and TMC2b to stereocilia does not depend on Lhfpl5 (negative finding for Lhfpl5-dependent TMC trafficking in zebrafish).","method":"GFP-Lhfpl5a stable transgene imaging, lhfpl5a/b mutant zebrafish analysis, co-localization studies with Pcdh15, Cdh23, and Myo7aa knockouts","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live transgene imaging in genetic knockouts, multiple orthogonal lines; note contradiction with mouse data regarding TMC localization dependence","pmids":["32009898"],"is_preprint":false},{"year":2023,"finding":"The N-terminal cytoplasmic domain of LHFPL5 directly binds to an amphipathic helix in TMC1 that is a critical gating domain conserved among MET channels; mutations in either the amphipathic helix of TMC1 or the N-terminus of LHFPL5 that disrupt this interaction impair mechanical force responses of the MET channel, supporting a tether model for tip-link gating.","method":"Binding assays, site-directed mutagenesis of LHFPL5 N-terminus and TMC1 amphipathic helix, electrophysiology in mutant mice, evolutionary conservation analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of both interaction partners with functional electrophysiology readout; mechanistic pathway placement supported by multiple methods","pmids":["36917610"],"is_preprint":false},{"year":2023,"finding":"A region within extracellular loop 1 of LHFPL5 (which interacts with PCDH15) prevents trafficking of LHFPL5 to the plasma membrane in heterologous cells, suggesting an endoplasmic reticulum retention signal that is masked by PCDH15 binding.","method":"Aquaporin 3-tGFP plasma membrane reporter (AGR) assay in heterologous cell lines with LHFPL5 truncation/deletion constructs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay in heterologous cells identifies a trafficking-blocking region, single lab, no direct ER-retention mechanism confirmed","pmids":["36781873"],"is_preprint":false},{"year":2024,"finding":"LHFPL5 is a principal component of the gating spring of the MET channel: Lhfpl5 knockout doubles the MET working range (52→123 nm), more than halves the single-channel gating force (0.34→0.13 pN), and virtually abolishes gating stiffness (~40% of total bundle stiffness in wild type vs. ~0 in knockout), establishing LHFPL5 as the primary mechanical link transmitting tip-link tension to the TMC channel.","method":"Patch-clamp electrophysiology in Lhfpl5-/- and Lhfpl5+/- outer hair cells; bundle stiffness measurements; tip-link destruction assays; comparison with Tmc1 D569N mutant mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative biophysical measurements of gating force and spring stiffness in genetic knockout with multiple controls and allelic series","pmids":["38194445"],"is_preprint":false},{"year":2025,"finding":"An LHFPL5 mutant lacking three N-terminal amino acids causes recessive deafness with drastically impaired MET; resting open probability of MET channels is increased, but unitary channel conductance, adaptation, and tonotopic properties remain normal. Crucially, MET channel proteins still localize normally to stereocilia, demonstrating that the N-terminus of LHFPL5 is specifically required for maximal mechanical activation of MET channels rather than for channel trafficking.","method":"Knock-in mouse model (3 N-terminal amino acid deletion), patch-clamp electrophysiology, immunofluorescence localization of MET complex proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse with precise mutation, electrophysiology with multiple channel parameters measured, localization controls separating trafficking from gating function","pmids":["41187086"],"is_preprint":false},{"year":2026,"finding":"Native PCDH15–LHFPL5 complexes isolated from mouse cochlea and utricle are heterotetrameric (2 PCDH15 : 2 LHFPL5) as determined by single-molecule stoichiometry; single-molecule pull-down and single-molecule array assays can detect and quantify amol-level native MET complex proteins.","method":"Single-molecule pull-down (SiMPull) and single-molecule array (SiMoA) with native protein from mouse cochlea/utricle; stoichiometry counting","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct stoichiometry measured on native complex by two orthogonal single-molecule methods, single lab","pmids":["41668373"],"is_preprint":false}],"current_model":"LHFPL5 (TMHS) is a tetraspan transmembrane auxiliary subunit of the hair cell mechanoelectrical transduction (MET) channel that forms a heterotetrameric complex (2:2) with the tip-link protein PCDH15 via its extracellular loop and transmembrane helices, and directly couples tip-link tension to the TMC1 pore-forming subunit via a N-terminal cytoplasmic domain interaction with TMC1's amphipathic gating helix, thereby constituting the principal component of the gating spring and enabling maximal force sensitivity and fast adaptation of the MET channel in cochlear hair cells."},"narrative":{"mechanistic_narrative":"LHFPL5 (TMHS) is a tetraspan integral membrane protein of cochlear and vestibular hair cell stereocilia that serves as the central auxiliary subunit coupling tip-link tension to the mechanoelectrical transduction (MET) channel [PMID:15905332, PMID:23217710]. Loss of LHFPL5 function—whether by missense mutation or genetic null—causes disorganized hair bundles and deafness with vestibular dysfunction, establishing its requirement for hair bundle integrity and transduction [PMID:15905332, PMID:17876667]. LHFPL5 physically binds the tip-link cadherin PCDH15, forming a heterotetrameric 2:2 complex in which LHFPL5 engages PCDH15 transmembrane helices to stabilize the assembly; this interaction governs tip-link assembly and is needed to deliver and retain LHFPL5 at stereocilia tips [PMID:23217710, PMID:29069081, PMID:30070639, PMID:41668373]. On the channel side, LHFPL5 stabilizes the pore-forming subunit TMC1 and links the two via its N-terminal cytoplasmic domain, which binds a conserved amphipathic gating helix in TMC1; deafness mutations that disrupt either side of this interface impair force responses [PMID:33168709, PMID:36917610]. Biophysically, LHFPL5 constitutes the principal component of the MET gating spring: its loss roughly doubles the working range, more than halves the single-channel gating force, and abolishes gating stiffness, while a precise three-residue N-terminal deletion impairs maximal mechanical activation without altering channel conductance, adaptation, or trafficking—demonstrating a dedicated mechanical-coupling role distinct from channel localization [PMID:38194445, PMID:41187086].","teleology":[{"year":2005,"claim":"Establishing that an uncharacterized tetraspan membrane protein matters for hearing, positional cloning tied TMHS to hair bundle morphogenesis and deafness.","evidence":"Positional cloning, immunohistochemistry, and SEM of hurry-scurry mutant mouse cochleae","pmids":["15905332"],"confidence":"Medium","gaps":["Molecular function beyond bundle morphology unknown","No interacting partners identified","Single missense allele studied"]},{"year":2007,"claim":"A targeted null allele confirmed that loss of TMHS function, not a neomorphic effect of the missense allele, causes the deafness/vestibular phenotype, and timed its expression to stereocilia development.","evidence":"Targeted gene knockout and lacZ reporter knock-in temporal expression assay in mice","pmids":["17876667"],"confidence":"Medium","gaps":["Did not define molecular role within the bundle","Transient developmental expression seemingly conflicted with a permanent structural role"]},{"year":2012,"claim":"Resolving whether TMHS is structural or part of the transduction apparatus, it was shown to bind PCDH15, regulate tip-link assembly, and control channel conductance and fast adaptation.","evidence":"Co-immunoprecipitation, mechanotransduction electrophysiology, and knockout analysis in mice","pmids":["23217710"],"confidence":"High","gaps":["Pore-forming channel partner not yet identified","Stoichiometry and structural basis of PCDH15 binding unknown"]},{"year":2017,"claim":"Addressing how LHFPL5 reaches its functional site, immunogold imaging localized it to ranked stereocilia tips and showed PCDH15 is required for that targeting.","evidence":"Immunofluorescence and immunogold TEM in wild-type and Pcdh15-knockout mice across development","pmids":["29069081"],"confidence":"High","gaps":["Trafficking signal sequence not mapped","Mechanism of PCDH15-dependent retention unresolved"]},{"year":2018,"claim":"Defining the architecture of the LHFPL5–PCDH15 unit, the structure revealed a 2:2 heterotetramer with LHFPL5 clamping PCDH15 transmembrane helices and a membrane-proximal rigid collar.","evidence":"Cryo-EM/crystallography, analytical ultracentrifugation, and structure-based deafness mutation mapping","pmids":["30070639"],"confidence":"High","gaps":["TMC channel not included in the structure","How the complex couples to the gate not shown"]},{"year":2019,"claim":"Reconciling transient developmental expression with a transduction role, LHFPL5 and TMC1 were shown to co-localize at shorter-row tips and persist into adulthood as permanent complex components.","evidence":"Immunofluorescence, confocal, and super-resolution microscopy in neonatal and adult mouse cochlea","pmids":["30808210"],"confidence":"Medium","gaps":["Direct LHFPL5–TMC1 physical interaction not yet demonstrated here","Functional consequence of differential IHC TMC1 distribution unclear"]},{"year":2020,"claim":"Establishing a direct link to the pore subunit, LHFPL5 was shown to bind and stabilize TMC1, with a human deafness mutation disrupting this interaction.","evidence":"Single-molecule pull-down, co-IP in heterologous and native cells, and western blot stability assays with mutagenesis","pmids":["33168709"],"confidence":"High","gaps":["Interacting domains not yet mapped","Whether stabilization vs. gating is the primary function unresolved"]},{"year":2020,"claim":"Testing cross-species requirements, zebrafish work confirmed PCDH15/CDH23/Myo7aa-dependent LHFPL5 tip localization but found TMC trafficking independent of Lhfpl5, exposing a species difference.","evidence":"GFP-Lhfpl5a transgene imaging in lhfpl5, pcdh15, cdh23, and myo7aa mutant zebrafish","pmids":["32009898"],"confidence":"Medium","gaps":["Contradicts mouse evidence for LHFPL5-dependent TMC stabilization","Mechanism of the species difference unexplained"]},{"year":2023,"claim":"Identifying the molecular coupling element, the LHFPL5 N-terminal cytoplasmic domain was shown to bind a conserved TMC1 amphipathic gating helix, with interface mutations impairing force responses.","evidence":"Binding assays, mutagenesis of both partners, electrophysiology in mutant mice, conservation analysis","pmids":["36917610"],"confidence":"High","gaps":["No structure of the N-terminus–helix interface","Quantitative contribution to gating not yet measured"]},{"year":2023,"claim":"Probing trafficking control, a region within LHFPL5 extracellular loop 1 was found to block plasma membrane delivery, consistent with PCDH15-masked ER retention.","evidence":"Plasma membrane GFP reporter (AGR) assay with LHFPL5 truncation/deletion constructs in heterologous cells","pmids":["36781873"],"confidence":"Medium","gaps":["Direct ER-retention mechanism not confirmed","Reporter assay in heterologous cells, not native hair cells","Retention motif not precisely defined"]},{"year":2024,"claim":"Quantifying its mechanical role, biophysics established LHFPL5 as the principal gating-spring component transmitting tip-link tension to the channel.","evidence":"Patch-clamp, bundle stiffness measurements, and tip-link destruction in Lhfpl5 allelic-series outer hair cells","pmids":["38194445"],"confidence":"High","gaps":["Molecular identity of residual gating stiffness in knockout unresolved","Direct mapping of elastic element within the complex not shown"]},{"year":2025,"claim":"Separating mechanical activation from trafficking, a three-residue N-terminal deletion impaired maximal MET activation while leaving conductance, adaptation, and complex localization intact.","evidence":"Knock-in mouse, patch-clamp of multiple channel parameters, immunofluorescence localization of MET proteins","pmids":["41187086"],"confidence":"High","gaps":["Structural basis of the N-terminal effect on open probability not resolved","Whether the deleted residues directly contact TMC1 not directly shown"]},{"year":2026,"claim":"Confirming complex stoichiometry in vivo, native cochlear and utricular PCDH15–LHFPL5 complexes were counted as 2:2 heterotetramers by single-molecule methods.","evidence":"Single-molecule pull-down and single-molecule array stoichiometry counting of native mouse tissue protein","pmids":["41668373"],"confidence":"Medium","gaps":["Stoichiometry of the full LHFPL5–PCDH15–TMC1 assembly not measured","Single lab determination"]},{"year":null,"claim":"How the elastic gating-spring element is physically embodied within the LHFPL5–PCDH15–TMC1 assembly and how N-terminal binding converts tip-link tension into pore opening remain to be resolved at structural and quantitative levels.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the complete MET complex including TMC1","Physical seat of elasticity within the complex unknown","Species differences in TMC dependence unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,10,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,6,8]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[2,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,8]}],"complexes":["PCDH15-LHFPL5 heterotetramer","hair cell mechanoelectrical transduction (MET) channel complex"],"partners":["PCDH15","TMC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAF8","full_name":"LHFPL tetraspan subfamily member 5 protein","aliases":["Lipoma HMGIC fusion partner-like 5 protein","Tetraspan membrane protein of hair cell stereocilia"],"length_aa":219,"mass_kda":24.2,"function":"Auxiliary subunit of the mechanotransducer (MET) non-specific cation channel complex located at the tips of the shorter stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system. 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. Functionally couples PCDH15 to the transduction channel","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TAF8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LHFPL5","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LHFPL5","total_profiled":1310},"omim":[{"mim_id":"614218","title":"WD REPEAT-CONTAINING PROTEIN 81; WDR81","url":"https://www.omim.org/entry/614218"},{"mim_id":"610265","title":"DEAFNESS, AUTOSOMAL RECESSIVE 67; DFNB67","url":"https://www.omim.org/entry/610265"},{"mim_id":"610240","title":"LHFPL TETRASPAN SUBFAMILY, MEMBER 4; LHFPL4","url":"https://www.omim.org/entry/610240"},{"mim_id":"610185","title":"CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 2; CAMRQ2","url":"https://www.omim.org/entry/610185"},{"mim_id":"609427","title":"LHFPL TETRASPAN SUBFAMILY, MEMBER 5; LHFPL5","url":"https://www.omim.org/entry/609427"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":17.2},{"tissue":"epididymis","ntpm":11.6}],"url":"https://www.proteinatlas.org/search/LHFPL5"},"hgnc":{"alias_symbol":["MGC33835","dJ510O8.8","Tmhs"],"prev_symbol":["DFNB67"]},"alphafold":{"accession":"Q8TAF8","domains":[{"cath_id":"1.20.140.150","chopping":"47-205","consensus_level":"medium","plddt":93.1394,"start":47,"end":205}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAF8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAF8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAF8-F1-predicted_aligned_error_v6.png","plddt_mean":89.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LHFPL5","jax_strain_url":"https://www.jax.org/strain/search?query=LHFPL5"},"sequence":{"accession":"Q8TAF8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAF8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAF8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAF8"}},"corpus_meta":[{"pmid":"23217710","id":"PMC_23217710","title":"TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23217710","citation_count":207,"is_preprint":false},{"pmid":"15905332","id":"PMC_15905332","title":"A missense mutation in the previously undescribed gene Tmhs underlies deafness in hurry-scurry (hscy) mice.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15905332","citation_count":83,"is_preprint":false},{"pmid":"16459341","id":"PMC_16459341","title":"Mutations of human TMHS cause recessively inherited non-syndromic hearing loss.","date":"2006","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16459341","citation_count":74,"is_preprint":false},{"pmid":"30070639","id":"PMC_30070639","title":"Structure of mouse protocadherin 15 of the stereocilia tip link in complex with LHFPL5.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30070639","citation_count":66,"is_preprint":false},{"pmid":"16752389","id":"PMC_16752389","title":"Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16752389","citation_count":54,"is_preprint":false},{"pmid":"33168709","id":"PMC_33168709","title":"Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33168709","citation_count":29,"is_preprint":false},{"pmid":"36917610","id":"PMC_36917610","title":"The tetraspan LHFPL5 is critical to establish maximal force sensitivity of the mechanotransduction channel of cochlear hair cells.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36917610","citation_count":25,"is_preprint":false},{"pmid":"32009898","id":"PMC_32009898","title":"The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish.","date":"2020","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32009898","citation_count":25,"is_preprint":false},{"pmid":"29069081","id":"PMC_29069081","title":"Spatiotemporal changes in the distribution of LHFPL5 in mice cochlear hair bundles during development and in the absence of PCDH15.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29069081","citation_count":25,"is_preprint":false},{"pmid":"30808210","id":"PMC_30808210","title":"Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental 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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/40340224","citation_count":0,"is_preprint":false},{"pmid":"41668373","id":"PMC_41668373","title":"The protocadherin-15-LHFPL5 tip link complex is a heterotetrameric assembly in hair cell stereocilia.","date":"2026","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41668373","citation_count":0,"is_preprint":false},{"pmid":"41400044","id":"PMC_41400044","title":"LHFPL5 splice site variant in a cat with deafness and vestibular dysfunction.","date":"2025","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41400044","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.25.678357","title":"The longer transmembrane helices of class I viral fusion proteins may facilitate viral fusion","date":"2025-09-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.25.678357","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12854,"output_tokens":3404,"usd":0.044811,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10918,"output_tokens":3957,"usd":0.076758,"stage2_stop_reason":"end_turn"},"total_usd":0.121569,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"TMHS (LHFPL5) is a tetraspan integral membrane protein localized to the apical membrane (hair bundles) of inner and outer cochlear hair cells; loss-of-function missense mutation (C→F) causes disorganized hair bundles and deafness in hurry-scurry mice, implicating TMHS in hair bundle morphogenesis.\",\n      \"method\": \"Positional cloning, immunohistochemistry with polyclonal antibodies, scanning electron microscopy of cochleae in hscy mutant mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization established by antibody staining with functional link to hair bundle morphogenesis via loss-of-function, single lab\",\n      \"pmids\": [\"15905332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Targeted null mutation of Tmhs (Lhfpl5) produces identical deafness/vestibular phenotype to the hscy missense allele, confirming that TMHS loss of function causes deafness; lacZ reporter shows expression peaks around P0 and is absent by P15, consistent with a role during stereocilia development.\",\n      \"method\": \"Targeted gene knockout (null allele), lacZ reporter knock-in, beta-galactosidase activity assay\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null allele with defined phenotype, lacZ reporter for temporal expression, single lab\",\n      \"pmids\": [\"17876667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TMHS (LHFPL5) is an integral component of the hair cell mechanotransduction machinery: it binds to the tip-link component PCDH15, regulates tip-link assembly, controls transducer channel conductance, and is required for fast channel adaptation. Deafness-causing Tmhs mutations disrupt tip-link assembly and PCDH15 binding.\",\n      \"method\": \"Electrophysiology (mechanotransduction recordings), co-immunoprecipitation (TMHS–PCDH15 interaction), knockout mouse analysis, tip-link assembly assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction assays combined with electrophysiology and knockout phenotype; independently corroborated by structural work\",\n      \"pmids\": [\"23217710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LHFPL5 localizes to ranked stereocilia tips (site of tip links) from P0, peaks at P3, and becomes restricted to shorter stereocilia rows by P12. In PCDH15-deficient mice at P3, LHFPL5 is mislocalized away from tips to unranked stereocilia and lateral links, demonstrating that PCDH15 is required for LHFPL5 tip localization.\",\n      \"method\": \"Immunofluorescence and immunogold transmission electron microscopy in wild-type and Pcdh15-knockout mice across developmental time points\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by immunogold TEM with functional validation via PCDH15 knockout, multiple time points and orthogonal imaging methods\",\n      \"pmids\": [\"29069081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal/cryo-EM structure of the PCDH15–LHFPL5 complex reveals a heterotetrameric assembly (2:2 stoichiometry with 2-fold symmetry) in which LHFPL5 forms extensive interactions with PCDH15 transmembrane helices and stabilizes the overall assembly; the extracellular cadherin domains form a mobile tether coupled to a rigid 'collar' near the membrane.\",\n      \"method\": \"Structural biology (cryo-EM/X-ray crystallography), analytical ultracentrifugation (sedimentation), structure-based mapping of deafness mutations\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution structure with biochemical validation of complex stoichiometry and deafness mutation mapping\",\n      \"pmids\": [\"30070639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMC1 and LHFPL5 co-localize at the tips of shorter stereocilia rows in both neonatal and adult outer hair cells; LHFPL5 persists in the hair bundle after P7, confirming it is a permanent component of the mechanotransduction complex. In adult inner hair cells, TMC1 distributes uniformly across both tallest and shorter rows while LHFPL5 remains in shorter rows.\",\n      \"method\": \"Immunofluorescence, confocal microscopy, super-resolution microscopy in neonatal and adult mouse cochlea\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by multiple imaging approaches at distinct developmental stages, single lab\",\n      \"pmids\": [\"30808210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LHFPL5 physically interacts with and stabilizes TMC1 protein in heterologous cells and in native hair cell soma and hair bundles; the deafness mutation D572N in human TMC1 (D569N in mouse) disrupts LHFPL5 binding and destabilizes TMC1 expression.\",\n      \"method\": \"Single-molecule pull-down (SiMPull microbead assay), co-immunoprecipitation in heterologous expression systems and native hair cells, western blot for protein stability\",\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 demonstrated by multiple orthogonal methods (SiMPull + Co-IP) in both heterologous and native cells, with mutagenesis validation\",\n      \"pmids\": [\"33168709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish, LHFPL5 localization to stereocilia tips requires the tip-link cadherins Pcdh15a and Cdh23, as well as the motor protein Myo7aa; however, localization of TMC1 and TMC2b to stereocilia does not depend on Lhfpl5 (negative finding for Lhfpl5-dependent TMC trafficking in zebrafish).\",\n      \"method\": \"GFP-Lhfpl5a stable transgene imaging, lhfpl5a/b mutant zebrafish analysis, co-localization studies with Pcdh15, Cdh23, and Myo7aa knockouts\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live transgene imaging in genetic knockouts, multiple orthogonal lines; note contradiction with mouse data regarding TMC localization dependence\",\n      \"pmids\": [\"32009898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The N-terminal cytoplasmic domain of LHFPL5 directly binds to an amphipathic helix in TMC1 that is a critical gating domain conserved among MET channels; mutations in either the amphipathic helix of TMC1 or the N-terminus of LHFPL5 that disrupt this interaction impair mechanical force responses of the MET channel, supporting a tether model for tip-link gating.\",\n      \"method\": \"Binding assays, site-directed mutagenesis of LHFPL5 N-terminus and TMC1 amphipathic helix, electrophysiology in mutant mice, evolutionary conservation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of both interaction partners with functional electrophysiology readout; mechanistic pathway placement supported by multiple methods\",\n      \"pmids\": [\"36917610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A region within extracellular loop 1 of LHFPL5 (which interacts with PCDH15) prevents trafficking of LHFPL5 to the plasma membrane in heterologous cells, suggesting an endoplasmic reticulum retention signal that is masked by PCDH15 binding.\",\n      \"method\": \"Aquaporin 3-tGFP plasma membrane reporter (AGR) assay in heterologous cell lines with LHFPL5 truncation/deletion constructs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay in heterologous cells identifies a trafficking-blocking region, single lab, no direct ER-retention mechanism confirmed\",\n      \"pmids\": [\"36781873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LHFPL5 is a principal component of the gating spring of the MET channel: Lhfpl5 knockout doubles the MET working range (52→123 nm), more than halves the single-channel gating force (0.34→0.13 pN), and virtually abolishes gating stiffness (~40% of total bundle stiffness in wild type vs. ~0 in knockout), establishing LHFPL5 as the primary mechanical link transmitting tip-link tension to the TMC channel.\",\n      \"method\": \"Patch-clamp electrophysiology in Lhfpl5-/- and Lhfpl5+/- outer hair cells; bundle stiffness measurements; tip-link destruction assays; comparison with Tmc1 D569N mutant mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative biophysical measurements of gating force and spring stiffness in genetic knockout with multiple controls and allelic series\",\n      \"pmids\": [\"38194445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An LHFPL5 mutant lacking three N-terminal amino acids causes recessive deafness with drastically impaired MET; resting open probability of MET channels is increased, but unitary channel conductance, adaptation, and tonotopic properties remain normal. Crucially, MET channel proteins still localize normally to stereocilia, demonstrating that the N-terminus of LHFPL5 is specifically required for maximal mechanical activation of MET channels rather than for channel trafficking.\",\n      \"method\": \"Knock-in mouse model (3 N-terminal amino acid deletion), patch-clamp electrophysiology, immunofluorescence localization of MET complex proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse with precise mutation, electrophysiology with multiple channel parameters measured, localization controls separating trafficking from gating function\",\n      \"pmids\": [\"41187086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Native PCDH15–LHFPL5 complexes isolated from mouse cochlea and utricle are heterotetrameric (2 PCDH15 : 2 LHFPL5) as determined by single-molecule stoichiometry; single-molecule pull-down and single-molecule array assays can detect and quantify amol-level native MET complex proteins.\",\n      \"method\": \"Single-molecule pull-down (SiMPull) and single-molecule array (SiMoA) with native protein from mouse cochlea/utricle; stoichiometry counting\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct stoichiometry measured on native complex by two orthogonal single-molecule methods, single lab\",\n      \"pmids\": [\"41668373\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LHFPL5 (TMHS) is a tetraspan transmembrane auxiliary subunit of the hair cell mechanoelectrical transduction (MET) channel that forms a heterotetrameric complex (2:2) with the tip-link protein PCDH15 via its extracellular loop and transmembrane helices, and directly couples tip-link tension to the TMC1 pore-forming subunit via a N-terminal cytoplasmic domain interaction with TMC1's amphipathic gating helix, thereby constituting the principal component of the gating spring and enabling maximal force sensitivity and fast adaptation of the MET channel in cochlear hair cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LHFPL5 (TMHS) is a tetraspan integral membrane protein of cochlear and vestibular hair cell stereocilia that serves as the central auxiliary subunit coupling tip-link tension to the mechanoelectrical transduction (MET) channel [#0, #2]. Loss of LHFPL5 function—whether by missense mutation or genetic null—causes disorganized hair bundles and deafness with vestibular dysfunction, establishing its requirement for hair bundle integrity and transduction [#0, #1]. LHFPL5 physically binds the tip-link cadherin PCDH15, forming a heterotetrameric 2:2 complex in which LHFPL5 engages PCDH15 transmembrane helices to stabilize the assembly; this interaction governs tip-link assembly and is needed to deliver and retain LHFPL5 at stereocilia tips [#2, #3, #4, #12]. On the channel side, LHFPL5 stabilizes the pore-forming subunit TMC1 and links the two via its N-terminal cytoplasmic domain, which binds a conserved amphipathic gating helix in TMC1; deafness mutations that disrupt either side of this interface impair force responses [#6, #8]. Biophysically, LHFPL5 constitutes the principal component of the MET gating spring: its loss roughly doubles the working range, more than halves the single-channel gating force, and abolishes gating stiffness, while a precise three-residue N-terminal deletion impairs maximal mechanical activation without altering channel conductance, adaptation, or trafficking—demonstrating a dedicated mechanical-coupling role distinct from channel localization [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that an uncharacterized tetraspan membrane protein matters for hearing, positional cloning tied TMHS to hair bundle morphogenesis and deafness.\",\n      \"evidence\": \"Positional cloning, immunohistochemistry, and SEM of hurry-scurry mutant mouse cochleae\",\n      \"pmids\": [\"15905332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function beyond bundle morphology unknown\", \"No interacting partners identified\", \"Single missense allele studied\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A targeted null allele confirmed that loss of TMHS function, not a neomorphic effect of the missense allele, causes the deafness/vestibular phenotype, and timed its expression to stereocilia development.\",\n      \"evidence\": \"Targeted gene knockout and lacZ reporter knock-in temporal expression assay in mice\",\n      \"pmids\": [\"17876667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define molecular role within the bundle\", \"Transient developmental expression seemingly conflicted with a permanent structural role\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolving whether TMHS is structural or part of the transduction apparatus, it was shown to bind PCDH15, regulate tip-link assembly, and control channel conductance and fast adaptation.\",\n      \"evidence\": \"Co-immunoprecipitation, mechanotransduction electrophysiology, and knockout analysis in mice\",\n      \"pmids\": [\"23217710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pore-forming channel partner not yet identified\", \"Stoichiometry and structural basis of PCDH15 binding unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Addressing how LHFPL5 reaches its functional site, immunogold imaging localized it to ranked stereocilia tips and showed PCDH15 is required for that targeting.\",\n      \"evidence\": \"Immunofluorescence and immunogold TEM in wild-type and Pcdh15-knockout mice across development\",\n      \"pmids\": [\"29069081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking signal sequence not mapped\", \"Mechanism of PCDH15-dependent retention unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining the architecture of the LHFPL5–PCDH15 unit, the structure revealed a 2:2 heterotetramer with LHFPL5 clamping PCDH15 transmembrane helices and a membrane-proximal rigid collar.\",\n      \"evidence\": \"Cryo-EM/crystallography, analytical ultracentrifugation, and structure-based deafness mutation mapping\",\n      \"pmids\": [\"30070639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TMC channel not included in the structure\", \"How the complex couples to the gate not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconciling transient developmental expression with a transduction role, LHFPL5 and TMC1 were shown to co-localize at shorter-row tips and persist into adulthood as permanent complex components.\",\n      \"evidence\": \"Immunofluorescence, confocal, and super-resolution microscopy in neonatal and adult mouse cochlea\",\n      \"pmids\": [\"30808210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LHFPL5–TMC1 physical interaction not yet demonstrated here\", \"Functional consequence of differential IHC TMC1 distribution unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing a direct link to the pore subunit, LHFPL5 was shown to bind and stabilize TMC1, with a human deafness mutation disrupting this interaction.\",\n      \"evidence\": \"Single-molecule pull-down, co-IP in heterologous and native cells, and western blot stability assays with mutagenesis\",\n      \"pmids\": [\"33168709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interacting domains not yet mapped\", \"Whether stabilization vs. gating is the primary function unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Testing cross-species requirements, zebrafish work confirmed PCDH15/CDH23/Myo7aa-dependent LHFPL5 tip localization but found TMC trafficking independent of Lhfpl5, exposing a species difference.\",\n      \"evidence\": \"GFP-Lhfpl5a transgene imaging in lhfpl5, pcdh15, cdh23, and myo7aa mutant zebrafish\",\n      \"pmids\": [\"32009898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contradicts mouse evidence for LHFPL5-dependent TMC stabilization\", \"Mechanism of the species difference unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying the molecular coupling element, the LHFPL5 N-terminal cytoplasmic domain was shown to bind a conserved TMC1 amphipathic gating helix, with interface mutations impairing force responses.\",\n      \"evidence\": \"Binding assays, mutagenesis of both partners, electrophysiology in mutant mice, conservation analysis\",\n      \"pmids\": [\"36917610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the N-terminus–helix interface\", \"Quantitative contribution to gating not yet measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Probing trafficking control, a region within LHFPL5 extracellular loop 1 was found to block plasma membrane delivery, consistent with PCDH15-masked ER retention.\",\n      \"evidence\": \"Plasma membrane GFP reporter (AGR) assay with LHFPL5 truncation/deletion constructs in heterologous cells\",\n      \"pmids\": [\"36781873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ER-retention mechanism not confirmed\", \"Reporter assay in heterologous cells, not native hair cells\", \"Retention motif not precisely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Quantifying its mechanical role, biophysics established LHFPL5 as the principal gating-spring component transmitting tip-link tension to the channel.\",\n      \"evidence\": \"Patch-clamp, bundle stiffness measurements, and tip-link destruction in Lhfpl5 allelic-series outer hair cells\",\n      \"pmids\": [\"38194445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of residual gating stiffness in knockout unresolved\", \"Direct mapping of elastic element within the complex not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Separating mechanical activation from trafficking, a three-residue N-terminal deletion impaired maximal MET activation while leaving conductance, adaptation, and complex localization intact.\",\n      \"evidence\": \"Knock-in mouse, patch-clamp of multiple channel parameters, immunofluorescence localization of MET proteins\",\n      \"pmids\": [\"41187086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the N-terminal effect on open probability not resolved\", \"Whether the deleted residues directly contact TMC1 not directly shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirming complex stoichiometry in vivo, native cochlear and utricular PCDH15–LHFPL5 complexes were counted as 2:2 heterotetramers by single-molecule methods.\",\n      \"evidence\": \"Single-molecule pull-down and single-molecule array stoichiometry counting of native mouse tissue protein\",\n      \"pmids\": [\"41668373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of the full LHFPL5–PCDH15–TMC1 assembly not measured\", \"Single lab determination\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the elastic gating-spring element is physically embodied within the LHFPL5–PCDH15–TMC1 assembly and how N-terminal binding converts tip-link tension into pore opening remain to be resolved at structural and quantitative levels.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the complete MET complex including TMC1\", \"Physical seat of elasticity within the complex unknown\", \"Species differences in TMC dependence unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 6, 8]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"complexes\": [\n      \"PCDH15-LHFPL5 heterotetramer\",\n      \"hair cell mechanoelectrical transduction (MET) channel complex\"\n    ],\n    \"partners\": [\n      \"PCDH15\",\n      \"TMC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}