ID   IOD2_HUMAN              Reviewed;         273 AA.
AC   Q92813; B9EGK0; G3V315; Q6B0A3; Q9HCP7; Q9HCP8; Q9P1W4; Q9UDZ1;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   26-FEB-2008, sequence version 4.
DT   27-MAR-2024, entry version 193.
DE   RecName: Full=Type II iodothyronine deiodinase;
DE            EC=1.21.99.4;
DE   AltName: Full=5DII;
DE   AltName: Full=DIOII;
DE   AltName: Full=Type 2 DI;
DE   AltName: Full=Type-II 5'-deiodinase;
GN   Name=DIO2; Synonyms=ITDI2, TXDI2;
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] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX   PubMed=8755651; DOI=10.1172/jci118806;
RA   Croteau W., Davey J.C., Galton V.A., St Germain D.L.;
RT   "Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein
RT   differentially expressed and regulated in human and rat brain and other
RT   tissues.";
RL   J. Clin. Invest. 98:405-417(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=9837913; DOI=10.1074/jbc.273.50.33374;
RA   Buettner C., Harney J.W., Larsen P.R.;
RT   "The 3'-untranslated region of human type 2 iodothyronine deiodinase mRNA
RT   contains a functional selenocysteine insertion sequence element.";
RL   J. Biol. Chem. 273:33374-33378(1998).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), ALTERNATIVE SPLICING
RP   (ISOFORM 1), AND TISSUE SPECIFICITY.
RC   TISSUE=Umbilical vein;
RX   PubMed=11165050; DOI=10.1016/s0303-7207(00)00368-3;
RA   Ohba K., Yoshioka T., Muraki T.;
RT   "Identification of two novel splicing variants of human type II
RT   iodothyronine deiodinase mRNA.";
RL   Mol. Cell. Endocrinol. 172:169-175(2001).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Dickhoff R., Madan A., Qin S., Abbasi N., Dors M., Rowen L., Harrison G.,
RA   James R., Loretz C., Lasky S., Madan A., Prescott S., Ratcliffe A.,
RA   Shaffer T., Hood L.;
RT   "Sequencing of human chromosome 14q31 region.";
RL   Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12508121; DOI=10.1038/nature01348;
RA   Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA   Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA   Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA   Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA   Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA   Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA   Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA   Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA   Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA   Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA   Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA   Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA   Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA   Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA   Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA   Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA   Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA   Waterston R., Hood L., Weissenbach J.;
RT   "The DNA sequence and analysis of human chromosome 14.";
RL   Nature 421:601-607(2003).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Lung, and Testis;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   UBIQUITINATION, DEUBIQUITINATION BY USP20 AND USP33, AND INTERACTION WITH
RP   USP20 AND USP33.
RX   PubMed=12865408; DOI=10.1172/jci18348;
RA   Curcio-Morelli C., Zavacki A.M., Christofollete M., Gereben B.,
RA   de Freitas B.C., Harney J.W., Li Z., Wu G., Bianco A.C.;
RT   "Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau
RT   protein-interacting deubiquitinating enzymes regulates thyroid hormone
RT   activation.";
RL   J. Clin. Invest. 112:189-196(2003).
RN   [8]
RP   UBIQUITINATION BY MARCHF6, AND INTERACTION WITH MARCHF6.
RX   PubMed=19651899; DOI=10.1128/mcb.01498-08;
RA   Zavacki A.M., Arrojo E Drigo R., Freitas B.C., Chung M., Harney J.W.,
RA   Egri P., Wittmann G., Fekete C., Gereben B., Bianco A.C.;
RT   "The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine
RT   deiodinase.";
RL   Mol. Cell. Biol. 29:5339-5347(2009).
CC   -!- FUNCTION: Responsible for the deiodination of T4 (3,5,3',5'-
CC       tetraiodothyronine) into T3 (3,5,3'-triiodothyronine). Essential for
CC       providing the brain with appropriate levels of T3 during the critical
CC       period of development.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3,3',5-triiodo-L-thyronine + A + H(+) + iodide = AH2 + L-
CC         thyroxine; Xref=Rhea:RHEA:19745, ChEBI:CHEBI:13193,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:16382, ChEBI:CHEBI:17499,
CC         ChEBI:CHEBI:58448, ChEBI:CHEBI:533015; EC=1.21.99.4;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU10107};
CC   -!- SUBUNIT: Interacts with USP20 and USP33. Interacts with MARCHF6.
CC       {ECO:0000269|PubMed:12865408, ECO:0000269|PubMed:19651899}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass membrane
CC       protein {ECO:0000305}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=hDII-a;
CC         IsoId=Q92813-1; Sequence=Displayed;
CC       Name=2; Synonyms=hDII-b;
CC         IsoId=Q92813-2; Sequence=VSP_026154;
CC       Name=3; Synonyms=hDII-c;
CC         IsoId=Q92813-3; Sequence=VSP_060028, VSP_060029, VSP_060030;
CC   -!- TISSUE SPECIFICITY: Isoform 1 is expressed in the lung, trachea,
CC       kidney, heart, skeletal muscle, placenta, fetal brain and several
CC       regions of the adult brain (PubMed:8755651, PubMed:11165050). Isoform 2
CC       is expressed in the brain, heart, kidney and trachea (PubMed:11165050).
CC       {ECO:0000269|PubMed:11165050, ECO:0000269|PubMed:8755651}.
CC   -!- PTM: Ubiquitinated by MARCHF6, leading to its degradation by the
CC       proteasome. Deubiquitinated by USP20 and USP33.
CC       {ECO:0000269|PubMed:12865408, ECO:0000269|PubMed:19651899}.
CC   -!- MISCELLANEOUS: [Isoform 2]: Has a Sec in positions 90, 169 and 302.
CC       {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform 3]: Has a Sec in position 37. {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the iodothyronine deiodinase family.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAC95470.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/44390/DIO2";
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DR   EMBL; U53506; AAC50663.1; -; mRNA.
DR   EMBL; AF093774; AAC95470.1; ALT_INIT; mRNA.
DR   EMBL; AB041843; BAB16838.1; -; mRNA.
DR   EMBL; AB041844; BAB16839.1; -; mRNA.
DR   EMBL; AC007372; AAD45494.1; -; Genomic_DNA.
DR   EMBL; AC010849; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL049837; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC074882; AAH74882.1; -; mRNA.
DR   EMBL; BC136514; AAI36515.1; -; mRNA.
DR   CCDS; CCDS45146.1; -. [Q92813-1]
DR   RefSeq; NP_000784.2; NM_000793.5.
DR   RefSeq; NP_001007024.1; NM_001007023.4.
DR   RefSeq; NP_001229431.1; NM_001242502.2.
DR   RefSeq; NP_001229432.1; NM_001242503.2.
DR   RefSeq; NP_001311391.1; NM_001324462.1.
DR   RefSeq; NP_054644.1; NM_013989.4. [Q92813-1]
DR   BioGRID; 108078; 17.
DR   STRING; 9606.ENSP00000451419; -.
DR   ChEMBL; CHEMBL3542431; -.
DR   DrugBank; DB09100; Thyroid, porcine.
DR   BioMuta; DIO2; -.
DR   DMDM; 172045839; -.
DR   MassIVE; Q92813; -.
DR   PeptideAtlas; Q92813; -.
DR   Antibodypedia; 47379; 233 antibodies from 32 providers.
DR   DNASU; 1734; -.
DR   Ensembl; ENST00000438257.9; ENSP00000405854.5; ENSG00000211448.14. [Q92813-1]
DR   Ensembl; ENST00000557010.5; ENSP00000451419.1; ENSG00000211448.14. [Q92813-1]
DR   GeneID; 1734; -.
DR   KEGG; hsa:1734; -.
DR   MANE-Select; ENST00000438257.9; ENSP00000405854.5; NM_013989.5; NP_054644.1.
DR   UCSC; uc010asy.4; human. [Q92813-1]
DR   AGR; HGNC:2884; -.
DR   CTD; 1734; -.
DR   DisGeNET; 1734; -.
DR   GeneCards; DIO2; -.
DR   HGNC; HGNC:2884; DIO2.
DR   HPA; ENSG00000211448; Tissue enhanced (cervix, thyroid gland).
DR   MIM; 601413; gene.
DR   neXtProt; NX_Q92813; -.
DR   OpenTargets; ENSG00000211448; -.
DR   PharmGKB; PA27338; -.
DR   VEuPathDB; HostDB:ENSG00000211448; -.
DR   GeneTree; ENSGT00940000154482; -.
DR   HOGENOM; CLU_089345_1_0_1; -.
DR   InParanoid; Q92813; -.
DR   OMA; KSIWNSF; -.
DR   OrthoDB; 5405869at2759; -.
DR   PhylomeDB; Q92813; -.
DR   TreeFam; TF329721; -.
DR   BioCyc; MetaCyc:HS00008-MONOMER; -.
DR   BRENDA; 1.21.99.4; 2681.
DR   PathwayCommons; Q92813; -.
DR   Reactome; R-HSA-350864; Regulation of thyroid hormone activity.
DR   SABIO-RK; Q92813; -.
DR   SignaLink; Q92813; -.
DR   SIGNOR; Q92813; -.
DR   BioGRID-ORCS; 1734; 14 hits in 1139 CRISPR screens.
DR   ChiTaRS; DIO2; human.
DR   GeneWiki; DIO2; -.
DR   GenomeRNAi; 1734; -.
DR   Pharos; Q92813; Tbio.
DR   PRO; PR:Q92813; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; Q92813; Protein.
DR   Bgee; ENSG00000211448; Expressed in pharyngeal mucosa and 187 other cell types or tissues.
DR   ExpressionAtlas; Q92813; baseline and differential.
DR   GO; GO:0016020; C:membrane; IC:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0008430; F:selenium binding; TAS:ProtInc.
DR   GO; GO:0004800; F:thyroxine 5'-deiodinase activity; IDA:UniProtKB.
DR   GO; GO:0033798; F:thyroxine 5-deiodinase activity; IDA:ARUK-UCL.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR   GO; GO:0042446; P:hormone biosynthetic process; IEA:UniProtKB-KW.
DR   GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR   GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR   GO; GO:0001514; P:selenocysteine incorporation; NAS:UniProtKB.
DR   GO; GO:0006590; P:thyroid hormone generation; TAS:UniProtKB.
DR   GO; GO:0042403; P:thyroid hormone metabolic process; IDA:UniProtKB.
DR   Gene3D; 3.40.30.10; Glutaredoxin; 1.
DR   InterPro; IPR000643; Iodothyronine_deiodinase.
DR   InterPro; IPR008261; Iodothyronine_deiodinase_AS.
DR   InterPro; IPR036249; Thioredoxin-like_sf.
DR   PANTHER; PTHR11781; IODOTHYRONINE DEIODINASE; 1.
DR   PANTHER; PTHR11781:SF20; TYPE II IODOTHYRONINE DEIODINASE; 1.
DR   Pfam; PF00837; T4_deiodinase; 1.
DR   PIRSF; PIRSF001330; IOD; 1.
DR   SUPFAM; SSF52833; Thioredoxin-like; 1.
DR   PROSITE; PS01205; T4_DEIODINASE; 1.
DR   Genevisible; Q92813; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Membrane; Oxidoreductase; Reference proteome;
KW   Selenocysteine; Thyroid hormones biosynthesis; Transmembrane;
KW   Transmembrane helix; Ubl conjugation.
FT   CHAIN           1..273
FT                   /note="Type II iodothyronine deiodinase"
FT                   /id="PRO_0000154317"
FT   TRANSMEM        10..34
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        133
FT   NON_STD         133
FT                   /note="Selenocysteine"
FT   NON_STD         266
FT                   /note="Selenocysteine"
FT   VAR_SEQ         1..53
FT                   /note="Missing (in isoform 3)"
FT                   /id="VSP_060028"
FT   VAR_SEQ         74
FT                   /note="Q -> QLNCPPSGFSKDGHILCLVYEAYKSRLLVYSHLDLWM (in
FT                   isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:11165050"
FT                   /id="VSP_026154"
FT   VAR_SEQ         75..146
FT                   /note="VKLGEDAPNSSVVHVSSTEGGDNSGNGTQEKIAEGATCHLLDFASPERPLVV
FT                   NFGSATUPPFTSQLPAFRKL -> LNCPPSGFSKDGHILULVYEAYKSRLLVYSHLDLW
FT                   MTDSVVLTLNFPRQISLCFGKNSAAELYIVSKKEKVP (in isoform 3)"
FT                   /id="VSP_060029"
FT   VAR_SEQ         147..273
FT                   /note="Missing (in isoform 3)"
FT                   /id="VSP_060030"
FT   VARIANT         81
FT                   /note="A -> D (in dbSNP:rs2839859)"
FT                   /id="VAR_049640"
FT   VARIANT         92
FT                   /note="T -> A (in dbSNP:rs225014)"
FT                   /id="VAR_047549"
FT   CONFLICT        198
FT                   /note="L -> P (in Ref. 3; BAB16838)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   273 AA;  30552 MW;  88D68B9AA6CB2A42 CRC64;
     MGILSVDLLI TLQILPVFFS NCLFLALYDS VILLKHVVLL LSRSKSTRGE WRRMLTSEGL
     RCVWKSFLLD AYKQVKLGED APNSSVVHVS STEGGDNSGN GTQEKIAEGA TCHLLDFASP
     ERPLVVNFGS ATUPPFTSQL PAFRKLVEEF SSVADFLLVY IDEAHPSDGW AIPGDSSLSF
     EVKKHQNQED RCAAAQQLLE RFSLPPQCRV VADRMDNNAN IAYGVAFERV CIVQRQKIAY
     LGGKGPFSYN LQEVRHWLEK NFSKRUKKTR LAG
//