TGM3L_HUMAN
ID TGM3L_HUMAN Reviewed; 706 AA.
AC O95932; Q5JXU4; Q5JXU5; Q719M2; Q719M3; Q9Y4U8;
DT 10-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 16-AUG-2005, sequence version 3.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Protein-glutamine gamma-glutamyltransferase 6;
DE EC=2.3.2.13;
DE AltName: Full=Transglutaminase Y;
DE Short=TGY;
DE Short=TGase Y;
DE AltName: Full=Transglutaminase-3-like;
DE Short=TGase-3-like;
DE AltName: Full=Transglutaminase-6;
DE Short=TG6;
DE Short=TGase-6;
GN Name=TGM6; Synonyms=TGM3L;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANT VAL-58.
RC TISSUE=Lung;
RA Thomas H., Aeschlimann D.;
RT "A novel transglutaminase expressed in the nervous system.";
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [3]
RP VARIANTS SCA35 GLY-327 AND TRP-517.
RX PubMed=21106500; DOI=10.1093/brain/awq323;
RA Wang J.L., Yang X., Xia K., Hu Z.M., Weng L., Jin X., Jiang H., Zhang P.,
RA Shen L., Guo J.F., Li N., Li Y.R., Lei L.F., Zhou J., Du J., Zhou Y.F.,
RA Pan Q., Wang J., Wang J., Li R.Q., Tang B.S.;
RT "TGM6 identified as a novel causative gene of spinocerebellar ataxias using
RT exome sequencing.";
RL Brain 133:3510-3518(2010).
RN [4]
RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS SCA35 GLY-327 AND
RP TRP-517.
RX PubMed=23206699; DOI=10.1016/j.bbrc.2012.11.069;
RA Guan W.J., Wang J.L., Liu Y.T., Ma Y.T., Zhou Y., Jiang H., Shen L.,
RA Guo J.F., Xia K., Li J.D., Tang B.S.;
RT "Spinocerebellar ataxia type 35 (SCA35)-associated transglutaminase 6
RT mutants sensitize cells to apoptosis.";
RL Biochem. Biophys. Res. Commun. 430:780-786(2013).
RN [5]
RP VARIANT SCA35 HIS-510.
RX PubMed=22554020; DOI=10.1111/j.1399-0004.2012.01895.x;
RA Li M., Pang S.Y., Song Y., Kung M.H., Ho S.L., Sham P.C.;
RT "Whole exome sequencing identifies a novel mutation in the transglutaminase
RT 6 gene for spinocerebellar ataxia in a Chinese family.";
RL Clin. Genet. 83:269-273(2013).
RN [6]
RP SUBCELLULAR LOCATION, VARIANT SCA35 ASN-426, AND CHARACTERIZATION OF
RP VARIANT SCA35 ASN-426.
RX PubMed=29053796; DOI=10.1093/brain/awx251;
RA Nibbeling E.A.R., Duarri A., Verschuuren-Bemelmans C.C., Fokkens M.R.,
RA Karjalainen J.M., Smeets C.J.L.M., de Boer-Bergsma J.J., van der Vries G.,
RA Dooijes D., Bampi G.B., van Diemen C., Brunt E., Ippel E., Kremer B.,
RA Vlak M., Adir N., Wijmenga C., van de Warrenburg B.P.C., Franke L.,
RA Sinke R.J., Verbeek D.S.;
RT "Exome sequencing and network analysis identifies shared mechanisms
RT underlying spinocerebellar ataxia.";
RL Brain 140:2860-2878(2017).
RN [7]
RP VARIANTS SCA35 CYS-111; HIS-510 AND GLU-574 DEL, CHARACTERIZATION OF
RP VARIANTS SCA35 CYS-111; HIS-510 AND GLU-574 DEL, AND SUBCELLULAR LOCATION.
RX PubMed=25253745; DOI=10.1212/wnl.0000000000000909;
RA Guo Y.C., Lin J.J., Liao Y.C., Tsai P.C., Lee Y.C., Soong B.W.;
RT "Spinocerebellar ataxia 35: Novel mutations in TGM6 with clinical and
RT genetic characterization.";
RL Neurology 83:1554-1561(2014).
CC -!- FUNCTION: Catalyzes the cross-linking of proteins and the conjugation
CC of polyamines to proteins. {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-
CC lysyl-N(6)-5-L-glutamyl-[protein] + NH4(+); Xref=Rhea:RHEA:54816,
CC Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:14005,
CC ChEBI:CHEBI:28938, ChEBI:CHEBI:29969, ChEBI:CHEBI:30011,
CC ChEBI:CHEBI:138370; EC=2.3.2.13; Evidence={ECO:0000255|PROSITE-
CC ProRule:PRU10024};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000250};
CC Note=Binds up to 3 Ca(2+) cations per subunit. {ECO:0000250};
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23206699,
CC ECO:0000269|PubMed:25253745, ECO:0000269|PubMed:29053796}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Long;
CC IsoId=O95932-1; Sequence=Displayed;
CC Name=2; Synonyms=Short;
CC IsoId=O95932-2; Sequence=VSP_015103, VSP_015104;
CC -!- DISEASE: Spinocerebellar ataxia 35 (SCA35) [MIM:613908]: A form of
CC spinocerebellar ataxia, a clinically and genetically heterogeneous
CC group of cerebellar disorders. Patients show progressive incoordination
CC of gait and often poor coordination of hands, speech and eye movements,
CC due to degeneration of the cerebellum with variable involvement of the
CC brainstem and spinal cord. SCA35 patients commonly show upper limb
CC involvement and torticollis. There is no cognitive impairment.
CC {ECO:0000269|PubMed:21106500, ECO:0000269|PubMed:22554020,
CC ECO:0000269|PubMed:23206699, ECO:0000269|PubMed:25253745,
CC ECO:0000269|PubMed:29053796}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the transglutaminase superfamily.
CC Transglutaminase family. {ECO:0000305}.
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DR EMBL; AF540969; AAQ10751.1; -; mRNA.
DR EMBL; AF540970; AAQ10752.1; -; mRNA.
DR EMBL; AL049650; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL031678; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS13025.1; -. [O95932-1]
DR CCDS; CCDS58761.1; -. [O95932-2]
DR RefSeq; NP_001241663.1; NM_001254734.1. [O95932-2]
DR RefSeq; NP_945345.2; NM_198994.2. [O95932-1]
DR AlphaFoldDB; O95932; -.
DR SMR; O95932; -.
DR BioGRID; 131269; 1.
DR IntAct; O95932; 1.
DR STRING; 9606.ENSP00000202625; -.
DR BindingDB; O95932; -.
DR ChEMBL; CHEMBL2079852; -.
DR DrugBank; DB00130; L-Glutamine.
DR DrugBank; DB01956; Taurine.
DR iPTMnet; O95932; -.
DR PhosphoSitePlus; O95932; -.
DR BioMuta; TGM6; -.
DR PaxDb; O95932; -.
DR PeptideAtlas; O95932; -.
DR PRIDE; O95932; -.
DR ProteomicsDB; 51132; -. [O95932-1]
DR ProteomicsDB; 51133; -. [O95932-2]
DR TopDownProteomics; O95932-1; -. [O95932-1]
DR Antibodypedia; 23168; 68 antibodies from 22 providers.
DR DNASU; 343641; -.
DR Ensembl; ENST00000202625.7; ENSP00000202625.2; ENSG00000166948.10. [O95932-1]
DR Ensembl; ENST00000381423.1; ENSP00000370831.1; ENSG00000166948.10. [O95932-2]
DR GeneID; 343641; -.
DR KEGG; hsa:343641; -.
DR MANE-Select; ENST00000202625.7; ENSP00000202625.2; NM_198994.3; NP_945345.2.
DR UCSC; uc002wfy.1; human. [O95932-1]
DR CTD; 343641; -.
DR DisGeNET; 343641; -.
DR GeneCards; TGM6; -.
DR HGNC; HGNC:16255; TGM6.
DR HPA; ENSG00000166948; Not detected.
DR MalaCards; TGM6; -.
DR MIM; 613900; gene.
DR MIM; 613908; phenotype.
DR neXtProt; NX_O95932; -.
DR OpenTargets; ENSG00000166948; -.
DR Orphanet; 319465; Inherited acute myeloid leukemia.
DR Orphanet; 276193; Spinocerebellar ataxia type 35.
DR PharmGKB; PA38098; -.
DR VEuPathDB; HostDB:ENSG00000166948; -.
DR eggNOG; ENOG502QVH4; Eukaryota.
DR GeneTree; ENSGT01050000244866; -.
DR HOGENOM; CLU_013435_2_2_1; -.
DR InParanoid; O95932; -.
DR OMA; AAHHTQD; -.
DR OrthoDB; 297055at2759; -.
DR PhylomeDB; O95932; -.
DR TreeFam; TF324278; -.
DR BRENDA; 2.3.2.13; 2681.
DR PathwayCommons; O95932; -.
DR SignaLink; O95932; -.
DR BioGRID-ORCS; 343641; 7 hits in 1062 CRISPR screens.
DR ChiTaRS; TGM6; human.
DR GenomeRNAi; 343641; -.
DR Pharos; O95932; Tchem.
DR PRO; PR:O95932; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; O95932; protein.
DR Bgee; ENSG00000166948; Expressed in colonic epithelium and 36 other tissues.
DR Genevisible; O95932; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0003810; F:protein-glutamine gamma-glutamyltransferase activity; IDA:MGI.
DR GO; GO:0018149; P:peptide cross-linking; IBA:GO_Central.
DR Gene3D; 2.60.40.10; -; 3.
DR Gene3D; 3.90.260.10; -; 1.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR002931; Transglutaminase-like.
DR InterPro; IPR036985; Transglutaminase-like_sf.
DR InterPro; IPR023608; Transglutaminase_animal.
DR InterPro; IPR013808; Transglutaminase_AS.
DR InterPro; IPR008958; Transglutaminase_C.
DR InterPro; IPR036238; Transglutaminase_C_sf.
DR InterPro; IPR001102; Transglutaminase_N.
DR Pfam; PF00927; Transglut_C; 2.
DR Pfam; PF01841; Transglut_core; 1.
DR Pfam; PF00868; Transglut_N; 1.
DR PIRSF; PIRSF000459; TGM_EBP42; 1.
DR SMART; SM00460; TGc; 1.
DR SUPFAM; SSF49309; SSF49309; 2.
DR SUPFAM; SSF54001; SSF54001; 1.
DR SUPFAM; SSF81296; SSF81296; 1.
DR PROSITE; PS00547; TRANSGLUTAMINASES; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Alternative splicing; Calcium; Cytoplasm; Disease variant;
KW Metal-binding; Neurodegeneration; Reference proteome;
KW Spinocerebellar ataxia; Transferase.
FT CHAIN 1..706
FT /note="Protein-glutamine gamma-glutamyltransferase 6"
FT /id="PRO_0000213715"
FT ACT_SITE 274
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10024"
FT ACT_SITE 333
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10024"
FT ACT_SITE 356
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10024"
FT BINDING 223
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255"
FT BINDING 226
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255"
FT BINDING 228
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255"
FT BINDING 303
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 305
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 307
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 309
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 327
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 396
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 417
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 445
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 450
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT VAR_SEQ 612..625
FT /note="VLGPAMVGVAVTVE -> RAYPGASGEGLSPV (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_015103"
FT VAR_SEQ 626..706
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_015104"
FT VARIANT 58
FT /note="M -> V (in dbSNP:rs2076405)"
FT /evidence="ECO:0000269|Ref.1"
FT /id="VAR_013250"
FT VARIANT 111
FT /note="R -> C (in SCA35; impairs transglutaminase activity;
FT dbSNP:rs372250159)"
FT /evidence="ECO:0000269|PubMed:25253745"
FT /id="VAR_072179"
FT VARIANT 327
FT /note="D -> G (in SCA35; decreased transglutaminase
FT activity; decreased protein stability; dbSNP:rs387907098)"
FT /evidence="ECO:0000269|PubMed:21106500,
FT ECO:0000269|PubMed:23206699"
FT /id="VAR_065360"
FT VARIANT 426
FT /note="T -> N (in SCA35; decreased protein stability)"
FT /evidence="ECO:0000269|PubMed:29053796"
FT /id="VAR_080737"
FT VARIANT 510
FT /note="D -> H (in SCA35; impairs transglutaminase activity;
FT dbSNP:rs201964784)"
FT /evidence="ECO:0000269|PubMed:22554020,
FT ECO:0000269|PubMed:25253745"
FT /id="VAR_072180"
FT VARIANT 517
FT /note="L -> W (in SCA35; decreased transglutaminase
FT activity; decreased protein stability; dbSNP:rs387907097)"
FT /evidence="ECO:0000269|PubMed:21106500,
FT ECO:0000269|PubMed:23206699"
FT /id="VAR_065361"
FT VARIANT 574
FT /note="Missing (in SCA35; impairs transglutaminase
FT activity)"
FT /evidence="ECO:0000269|PubMed:25253745"
FT /id="VAR_072181"
SQ SEQUENCE 706 AA; 79312 MW; 97BBE2043C5FF834 CRC64;
MAGIRVTKVD WQRSRNGAAH HTQEYPCPEL VVRRGQSFSL TLELSRALDC EEILIFTMET
GPRASEALHT KAVFQTSELE RGEGWTAARE AQMEKTLTVS LASPPSAVIG RYLLSIRLSS
HRKHSNRRLG EFVLLFNPWC AEDDVFLASE EERQEYVLSD SGIIFRGVEK HIRAQGWNYG
QFEEDILNIC LSILDRSPGH QNNPATDVSC RHNPIYVTRV ISAMVNSNND RGVVQGQWQG
KYGGGTSPLH WRGSVAILQK WLKGRYKPVK YGQCWVFAGV LCTVLRCLGI ATRVVSNFNS
AHDTDQNLSV DKYVDSFGRT LEDLTEDSMW NFHVWNESWF ARQDLGPSYN GWQVLDATPQ
EESEGVFRCG PASVTAIREG DVHLAHDGPF VFAEVNADYI TWLWHEDESR ERVYSNTKKI
GRCISTKAVG SDSRVDITDL YKYPEGSRKE RQVYSKAVNR LFGVEASGRR IWIRRAGGRC
LWRDDLLEPA TKPSIAGKFK VLEPPMLGHD LRLALCLANL TSRAQRVRVN LSGATILYTR
KPVAEILHES HAVRLGPQEE KRIPITISYS KYKEDLTEDK KILLAAMCLV TKGEKLLVEK
DITLEDFITI KVLGPAMVGV AVTVEVTVVN PLIERVKDCA LMVEGSGLLQ EQLSIDVPTL
EPQERASVQF DITPSKSGPR QLQVDLVSPH FPDIKGFVIV HVATAK
