TOMT_MOUSE
ID TOMT_MOUSE Reviewed; 258 AA.
AC A1Y9I9;
DT 16-DEC-2008, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 1.
DT 03-AUG-2022, entry version 99.
DE RecName: Full=Transmembrane O-methyltransferase homolog {ECO:0000305};
DE Short=mTOMT {ECO:0000303|PubMed:28504928};
DE EC=2.1.1.6 {ECO:0000269|PubMed:18794526};
DE AltName: Full=Catechol O-methyltransferase 2 {ECO:0000303|PubMed:18794526};
GN Name=Tomt {ECO:0000312|MGI:MGI:3769724};
GN Synonyms=Comt2 {ECO:0000303|PubMed:18794526};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP DEVELOPMENTAL STAGE.
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=18953341; DOI=10.1038/ng.245;
RA Ahmed Z.M., Masmoudi S., Kalay E., Belyantseva I.A., Mosrati M.A.,
RA Collin R.W.J., Riazuddin S., Hmani-Aifa M., Venselaar H., Kawar M.N.,
RA Tlili A., van der Zwaag B., Khan S.Y., Ayadi L., Riazuddin S.A.,
RA Morell R.J., Griffith A.J., Charfedine I., Caylan R., Oostrik J.,
RA Karaguzel A., Ghorbel A., Riazuddin S., Friedman T.B., Ayadi H., Kremer H.;
RT "Mutations of LRTOMT, a fusion gene with alternative reading frames, cause
RT nonsyndromic deafness in humans.";
RL Nat. Genet. 40:1335-1340(2008).
RN [2] {ECO:0000305, ECO:0000312|EMBL:ABI37014.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF ARG-48.
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:ABI37014.1};
RC TISSUE=Brain {ECO:0000312|EMBL:ABI37014.1};
RX PubMed=18794526; DOI=10.1073/pnas.0807219105;
RA Du X., Schwander M., Moresco E.M.Y., Viviani P., Haller C.,
RA Hildebrand M.S., Pak K., Tarantino L., Roberts A., Richardson H., Koob G.,
RA Najmabadi H., Ryan A.F., Smith R.J.H., Mueller U., Beutler B.;
RT "A catechol-O-methyltransferase that is essential for auditory function in
RT mice and humans.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:14609-14614(2008).
RN [3]
RP FUNCTION, INTERACTION WITH LHFPL5; PCDH15; TMC1; TMC2 AND TMIE, SUBCELLULAR
RP LOCATION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF 22-HIS--ARG-25; ARG-48
RP AND TYR-108.
RX PubMed=28504928; DOI=10.7554/elife.24318;
RA Cunningham C.L., Wu Z., Jafari A., Zhao B., Schrode K., Harkins-Perry S.,
RA Lauer A., Mueller U.;
RT "The murine catecholamine methyltransferase mTOMT is essential for
RT mechanotransduction by cochlear hair cells.";
RL Elife 6:0-0(2017).
RN [4]
RP INTERACTION WITH TMC1, AND MUTAGENESIS OF HIS-183.
RX PubMed=28534737; DOI=10.7554/elife.28474;
RA Erickson T., Morgan C.P., Olt J., Hardy K., Busch-Nentwich E., Maeda R.,
RA Clemens R., Krey J.F., Nechiporuk A., Barr-Gillespie P.G., Marcotti W.,
RA Nicolson T.;
RT "Integration of Tmc1/2 into the mechanotransduction complex in zebrafish
RT hair cells is regulated by Transmembrane O-methyltransferase (Tomt).";
RL Elife 6:0-0(2017).
CC -!- FUNCTION: Catalyzes the O-methylation, and thereby the inactivation, of
CC catecholamine neurotransmitters and catechol hormones
CC (PubMed:18794526). Required for auditory function (PubMed:18794526,
CC PubMed:28504928). Component of the cochlear hair cell's
CC mechanotransduction (MET) machinery. Involved in the assembly of the
CC asymmetric tip-link MET complex. Required for transportation of TMC1
CC and TMC2 proteins into the mechanically sensitive stereocilia of the
CC hair cells. The function in MET is independent of the enzymatic
CC activity (PubMed:28504928). {ECO:0000269|PubMed:18794526,
CC ECO:0000269|PubMed:28504928}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a catechol + S-adenosyl-L-methionine = a guaiacol + H(+) + S-
CC adenosyl-L-homocysteine; Xref=Rhea:RHEA:17877, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:33566, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:134251; EC=2.1.1.6;
CC Evidence={ECO:0000269|PubMed:18794526};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17878;
CC Evidence={ECO:0000305|PubMed:18794526};
CC -!- SUBUNIT: Interacts with LHFPL5, PCDH15, TMC1, TMC2 and TMIE
CC (PubMed:28504928). The interaction of TOMT with TMC1 and TMC2 is
CC required for the transportation of TMC1/2 into the stereocilia of hair
CC cells (PubMed:28504928, PubMed:28534737). Interacts directly with TMC1
CC (PubMed:28534737). {ECO:0000269|PubMed:28504928,
CC ECO:0000269|PubMed:28534737}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18953341,
CC ECO:0000269|PubMed:28504928}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:28504928}. Note=Localized to the cell body of the
CC cochlear hair cells, but is not present in the stereocilia. Present but
CC not restricted to the apical cistern, Hensen's body and the subsurface
CC cistern. {ECO:0000269|PubMed:28504928}.
CC -!- TISSUE SPECIFICITY: Widely expressed with high levels in outer and
CC inner hair cells of the cochlea and vestibule.
CC {ECO:0000269|PubMed:18794526, ECO:0000269|PubMed:18953341}.
CC -!- DEVELOPMENTAL STAGE: Not detected in the embryo at 12.5 dpc. At 14.5
CC dpc, expressed in the developing inner ear. At 16.5 dpc, expressed in
CC the utricle and saccule. At 18.5 dpc, expressed specifically in the
CC region of the sensory cells of the cochlea, utricle, saccule and crista
CC ampullaris. {ECO:0000269|PubMed:18953341}.
CC -!- DISRUPTION PHENOTYPE: Absence of auditory brain stem response (ABR) to
CC click stimuli demonstrates that the mice are profoundly deaf. Normal
CC hair bundle morphology as at postnatal day (P) 5 the sensory epithelia
CC are patterned into three rows of outer hair cells (OHCs) and one row of
CC inner hair cells (IHCs). The bundles of OHCs appear similar in size to
CC those of wild-type mice and form a normal staircase pattern. Hair cells
CC are maintained in the presence of gentamicin, an aminoglycoside
CC antibiotic that enters hair cells through their transduction channels
CC and normally causes hair cell death. No difference in the expression or
CC localization of tip link proteins CDH23 and PCDH15 or ATP2B2, MYO7A,
CC ESPN and WHRN proteins at P5-P8 in hair bundles of hair cells. Normal
CC localization of LHFPL5 and TMIE in OHCs, but TMC1 and TMC2 are absent
CC from the hair bundles of OHCs. {ECO:0000269|PubMed:28504928}.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC superfamily. Cation-dependent O-methyltransferase family.
CC {ECO:0000255|PROSITE-ProRule:PRU01019}.
CC -!- CAUTION: Despite its name, the murine TOMT protein does not contain a
CC transmembrane region in contrast to primate orthologs. {ECO:0000305}.
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DR EMBL; EU627091; ACF40901.1; -; mRNA.
DR EMBL; DQ854743; ABI37014.1; -; mRNA.
DR CCDS; CCDS40044.1; -.
DR RefSeq; NP_001075148.1; NM_001081679.1.
DR RefSeq; NP_001269017.1; NM_001282088.1.
DR RefSeq; XP_017167892.1; XM_017312403.1.
DR AlphaFoldDB; A1Y9I9; -.
DR SMR; A1Y9I9; -.
DR STRING; 10090.ENSMUSP00000102582; -.
DR iPTMnet; A1Y9I9; -.
DR PhosphoSitePlus; A1Y9I9; -.
DR PaxDb; A1Y9I9; -.
DR PRIDE; A1Y9I9; -.
DR Ensembl; ENSMUST00000106969; ENSMUSP00000102582; ENSMUSG00000078630.
DR Ensembl; ENSMUST00000106970; ENSMUSP00000102583; ENSMUSG00000078630.
DR GeneID; 791260; -.
DR KEGG; mmu:791260; -.
DR UCSC; uc009ipu.1; mouse.
DR CTD; 120356740; -.
DR MGI; MGI:3769724; Tomt.
DR VEuPathDB; HostDB:ENSMUSG00000078630; -.
DR eggNOG; KOG1663; Eukaryota.
DR GeneTree; ENSGT00940000161220; -.
DR HOGENOM; CLU_050461_5_0_1; -.
DR InParanoid; A1Y9I9; -.
DR OMA; YVLTHST; -.
DR OrthoDB; 1274244at2759; -.
DR PhylomeDB; A1Y9I9; -.
DR TreeFam; TF329140; -.
DR Reactome; R-MMU-379397; Enzymatic degradation of dopamine by COMT.
DR SABIO-RK; A1Y9I9; -.
DR BioGRID-ORCS; 791260; 1 hit in 71 CRISPR screens.
DR PRO; PR:A1Y9I9; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; A1Y9I9; protein.
DR Bgee; ENSMUSG00000078630; Expressed in morula and 44 other tissues.
DR GO; GO:0045177; C:apical part of cell; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0016206; F:catechol O-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0102084; F:L-dopa O-methyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0008171; F:O-methyltransferase activity; IBA:GO_Central.
DR GO; GO:0102938; F:orcinol O-methyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0060117; P:auditory receptor cell development; IMP:UniProtKB.
DR GO; GO:0042424; P:catecholamine catabolic process; IDA:UniProtKB.
DR GO; GO:0032502; P:developmental process; IBA:GO_Central.
DR GO; GO:0042417; P:dopamine metabolic process; IBA:GO_Central.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0042135; P:neurotransmitter catabolic process; IEA:UniProtKB-KW.
DR GO; GO:1904591; P:positive regulation of protein import; IMP:UniProtKB.
DR GO; GO:0007605; P:sensory perception of sound; IMP:UniProtKB.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR002935; SAM_O-MeTrfase.
DR InterPro; IPR033025; TOMT.
DR PANTHER; PTHR43836:SF1; PTHR43836:SF1; 1.
DR Pfam; PF01596; Methyltransf_3; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51682; SAM_OMT_I; 1.
PE 1: Evidence at protein level;
KW Catecholamine metabolism; Cytoplasm; Deafness; Endoplasmic reticulum;
KW Hearing; Methyltransferase; Neurotransmitter degradation;
KW Reference proteome; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..258
FT /note="Transmembrane O-methyltransferase homolog"
FT /id="PRO_0000354094"
FT BINDING 104
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 106..107
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 112
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 130
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT BINDING 160
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01019"
FT MUTAGEN 22..25
FT /note="Missing: Absence of auditory brain stem response
FT (ABR) to click stimuli demonstrates that the mice are
FT profoundly deaf. Distortion product otoacoustic emissions
FT (DPOAEs) are absent at 4 weeks of age at all frequencies
FT tested. Normal hair bundle morphology as at postnatal day
FT (P) 5 the sensory epithelia are patterned into three rows
FT of outer hair cells (OHCs) and one row of inner hair cells
FT (IHCs). The bundles of OHCs appear similar in size to those
FT of wild-type mice and form a normal staircase pattern."
FT /evidence="ECO:0000269|PubMed:28504928"
FT MUTAGEN 48
FT /note="R->L: In add; reduces methyltransferase activity;
FT causes hyperkinesis, circling, head-tossing, aggression,
FT progressive degeneration of the organ of Corti, hair cell
FT defects and profound deafness. Distortion product
FT otoacoustic emissions (DPOAEs) are absent at 4 weeks of age
FT at all frequencies tested. At postnatal day (P) 5 the
FT sensory epithelia are patterned into three rows of outer
FT hair cells (OHCs) and one row of inner hair cells (IHCs)
FT with no obvious structural abnormalities. The bundles of
FT OHCs appear similar in size to those of wild-type mice and
FT form a normal staircase pattern. The hair bundles of OHCs
FT have a slightly more rounded morphology, especially in
FT basal regions of the cochlea. The morphology of IHCs is not
FT significantly altered. Hair cells are maintained in the
FT presence of gentamicin, an aminoglycoside antibiotic that
FT enters hair cells through their transduction channels and
FT normally causes hair cell death. Mechanotransduction
FT currents are very small in P4 hair cells and completely
FT absent in P7 hair cells. Membrane potential, outward-evoked
FT currents and nonlinear capacitance are normal in OHCs. No
FT difference in the expression or localization of tip link
FT proteins CDH23 and PCDH15 or ATP2B2, MYO7A, ESPN and WHRN
FT proteins at P5-P8 in hair bundles of hair cells. No
FT difference in the number of tip links in IHCs and OHCs at
FT P7-P8. No difference in the levels of catecholamines,
FT including norepinephrine, homovanillic acid (HVA) and
FT norepinephrine, or serotonin levels in the inner ear. Loss
FT of reverse polarity currents."
FT /evidence="ECO:0000269|PubMed:18794526,
FT ECO:0000269|PubMed:28504928"
FT MUTAGEN 108
FT /note="Y->A: Is able to rescue the mechanotransduction
FT defect of L-48."
FT /evidence="ECO:0000269|PubMed:28504928"
FT MUTAGEN 183
FT /note="H->A: Enhanced interaction with TMC1."
FT /evidence="ECO:0000269|PubMed:28534737"
SQ SEQUENCE 258 AA; 28846 MW; 393954F017C67E0C CRC64;
MSPAIALAFL PLVVTLLVRY RHHFRLLVRT VLLRGFRDCL SGLRIEERAF SYVLTHALPG
DPGHILTTLD HWSSCCEYLS HMGPVKGQIL MRLVEEKAPA CVLELGTYCG YSTLLIARAL
PPGSRLLTVE RDSRTAAVAE KVIRLAGFDE QMVELIAGSS EEVIPRLRAQ HQLNRADLVL
LAHRPRYYLR DLQLLEAHAL LPHGATVLAD HVLFPGAPRF LQYTKSCGRY RCRLHHTSLP
DFPAIKDGIA QLTYTGPG
