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.
Deiodinase (D2) undergoes ubiquitylation in a substrate-inducible manner . 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 .
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 .
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) .
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 .
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