TOMT

TOMT (LRTOMT2) is a Golgi-enriched, methyltransferase-homology protein in cochlear and vestibular hair cells that functions as a trafficking factor required to deliver the mechanotransduction (MET) channel subunits TMC1/2 into the stereocilia hair bundle, thereby enabling hair-cell mechanotransduction (PMID:28534737, PMID:28504928). In tomt-deficient hair cells, Tmc1/2 are specifically excluded from the hair bundle while other MET complex proteins still localize correctly, abolishing mechanotransduction (PMID:28534737). TOMT directly binds TMC1, an interaction modulated by His183, providing a physical basis for its role in channel transport (PMID:28534737, PMID:28504928). This chaperone/trafficking function is independent of catalytic methyltransferase activity: methyltransferase-dead TOMT retains function in hair cells, and the catecholamine methyltransferase paralog COMT cannot substitute for it (PMID:28504928). The gene arose in primates from fusion of two ancestral genes (Lrrc51 and Tomt) that remain separate in rodents, with LRTOMT2 corresponding to the methyltransferase-homology product (PMID:18953341).

1. 2008 Medium

   Established the gene's identity and architecture, defining LRTOMT2 as a putative methyltransferase product and clarifying the primate-specific gene fusion underlying the locus.

   Evidence Protein blot analysis, positional cloning, and evolutionary genomic analysis

   PMID:18953341

   Open questions at the time

   • No functional reconstitution of methyltransferase activity
   • No cellular role assigned at this stage
2. 2017 High

   Resolved what TOMT does at the cellular level, showing it is Golgi-localized and selectively required to traffic Tmc1/2 into the hair bundle to enable mechanotransduction.

   Evidence Zebrafish tomt mutant with GFP-tagged Tomt live imaging, Tmc1/2 immunofluorescence, and mechanotransduction functional assays

   PMID:28534737

   Open questions at the time

   • Mechanism of cargo selectivity for Tmc1/2 over other MET components unknown
   • How TOMT exits the Golgi and whether it accompanies cargo not defined
3. 2017 Medium

   Provided a physical basis for the trafficking role by demonstrating a direct TOMT-TMC1 interaction dependent on His183.

   Evidence Co-immunoprecipitation in HEK 293 cells with His183 site-directed mutagenesis

   PMID:28534737

   Open questions at the time

   • Heterologous system; not validated in native hair cells
   • Structural basis of the His183-dependent interface not determined
4. 2017 High

   Separated TOMT's hair-cell function from its enzymatic homology, showing the trafficking role is independent of methyltransferase catalysis and not interchangeable with the COMT paralog.

   Evidence Knock-in mice with methyltransferase-dead TOMT and COMT substitution, plus Co-IP and immunofluorescence in cochlear hair cells

   PMID:28504928

   Open questions at the time

   • Whether TOMT retains any enzymatic substrate in vivo is unresolved
   • Full set of MET components bound by TOMT not defined

• How TOMT achieves selective recognition and Golgi-to-stereocilia delivery of TMC1/2, and whether its methyltransferase fold has any residual biochemical activity, remain open.
• No structural model of the TOMT-TMC1 complex
• Mechanism distinguishing Tmc1/2 cargo from other MET proteins unknown
• No identified enzymatic substrate