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   24-JAN-2024, entry version 184.
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   GlyGen; O95932; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; O95932; -.
DR   PhosphoSitePlus; O95932; -.
DR   BioMuta; TGM6; -.
DR   PaxDb; 9606-ENSP00000202625; -.
DR   PeptideAtlas; O95932; -.
DR   ProteomicsDB; 51132; -. [O95932-1]
DR   ProteomicsDB; 51133; -. [O95932-2]
DR   TopDownProteomics; O95932-1; -. [O95932-1]
DR   Antibodypedia; 23168; 85 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   AGR; HGNC:16255; -.
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; RVKDCVL; -.
DR   OrthoDB; 5344745at2759; -.
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 1140 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 37 other cell types or tissues.
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   Gene3D; 2.60.40.10; Immunoglobulins; 3.
DR   Gene3D; 3.90.260.10; Transglutaminase-like; 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   PANTHER; PTHR11590; PROTEIN-GLUTAMINE GAMMA-GLUTAMYLTRANSFERASE; 1.
DR   PANTHER; PTHR11590:SF50; PROTEIN-GLUTAMINE GAMMA-GLUTAMYLTRANSFERASE 6; 1.
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; SSF54001; Cysteine proteinases; 1.
DR   SUPFAM; SSF81296; E set domains; 1.
DR   SUPFAM; SSF49309; Transglutaminase, two C-terminal domains; 2.
DR   PROSITE; PS00547; TRANSGLUTAMINASES; 1.
DR   Genevisible; O95932; HS.
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
//