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Protein information

Protein name Type II iodothyronine deiodinase 
Synonyms EC
Type-II 5'-deiodinase
Type 2 DI
Gene name DIO2 , Synonyms: ITDI2, TXDI2 .
Source Homo sapiens (Human)
Expression system HEK-293, CHO-ts20 [ref. 2], Saccharomyces cerevisiae [ref. 3]
Full length  273
Precursor  no
Mature form length  273
Molecular weight (Da)  30552
Swiss-Prot Sequence Version  February 26, 2008 (Sequence version 4)
Comments  The type 2 iodothyronine deiodinase (D2) is an integral membrane ER-resident enzyme that activates the pro-hormone thyroxine (T4) and supplies most of the 3,5,3'-triiodothyronine (T3) that is essential for brain development. The protein contains selenocysteine in its active site and is active in a homodimeric form.



Ubiquitylation features

Ubiquitylation site  

Ubiquitylation type Multiple ubiquitylation
Features Deiodinase (D2) undergoes ubiquitylation in a substrate-inducible manner [1]. Ubiquitin attachment inactivates the enzyme by interfering with surfaces that are critical for dimerization and catalytic activity. This state of transient inactivity and change in dimer conformation persists until deubiquitylation [8]. Modification with multiubiquitin chain also leads to proteasomal degradation of deiodinase [1,2,3]. The COOH terminus is critical for the proteolysis of ubiquitylated D2 [2].

Ubiquitylation/deubiquitylation machinery

E2 UBC7 [6]; Ubc6p and Ubc7p [3]
E3 WSB1 [7]
E4/AP Not determined
DUB VDU1, VDU2 [4,5]
Comments WSB-1 is a SOCS-box-containing WD-40 protein that is induced by Hedgehog signaling. The WD-40 propeller of WSB-1 recognizes a novel 18-amino acid loop in D2 that confers metabolic instability, while the SOCS-box domain mediates its interaction with an ubiquitylating catalytic core complex, modeled as Elongin BC-Cul5-Rbx1 (ECS/WSB-1) [7]. Deiodinase dimer is continuously associated with WSB1, UBC7, and VDU1, even under conditions of minimal protein ubiquitylation, suggesting that D2 molecules can undergo multiple cycles of ubiquitylation and deubiquitylation before proteasomal degradation [8].


[1]Steinsapir J, Bianco AC, Buettner C, Harney J, Larsen PR.
Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme's active center. Endocrinology 141(3):1127-35 (2000).
[2]Gereben B, Goncalves C, Harney JW, Larsen PR, Bianco AC.
Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation. Mol Endocrinol. 14(11):1697-708 (2000).
[3]Botero D, Gereben B, Goncalves C, De Jesus LA, Harney JW, Bianco AC.
Ubc6p and ubc7p are required for normal and substrate-induced endoplasmic reticulum-associated degradation of the human selenoprotein type 2 iodothyronine monodeiodinase. Mol Endocrinol. 16(9):1999-2007 (2002).
[4]Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BC, Harney JW, Li Z, Wu G, Bianco AC.
Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. J Clin Invest. 112(2):189-96 (2003).
[5]Koenig RJ.
Ubiquitinated deiodinase: not dead yet. J Clin Invest. 112(2):145-7 (2003).
[6]Kim BW, Zavacki AM, Curcio-Morelli C, Dentice M, Harney JW, Larsen PR, Bianco AC.
Endoplasmic reticulum-associated degradation of the human type 2 iodothyronine deiodinase (D2) is mediated via an association between mammalian UBC7 and the carboxyl region of D2. Mol Endocrinol. 17(12):2603-12 (2003).
[7]Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA, Kim BW, Nissim S, Mornon JP, Zavacki AM, Ze?ld A, Capelo LP, Curcio-Morelli C, Ribeiro R, Harney JW, Tabin CJ, Bianco AC.
The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nat Cell Biol. 7(7):698-705 (2005).
[8]Sagar GD, Gereben B, Callebaut I, Mornon JP, Ze?ld A, da Silva WS, Luongo C, Dentice M, Tente SM, Freitas BC, Harney JW, Zavacki AM, Bianco AC.
Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. Mol Cell Biol. 27(13):4774-83 (2007).


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