Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity

G. D Vivek Sagar, B. Gereben, Isabelle Callebaut, Jean Paul Mornon, A. Zeöld, Wagner S. Da Silva, Cristina Luongo, Monica Dentice, Susana M. Tente, Beatriz C G Freitas, John W. Harney, Ann Marie Zavacki, Antonio C. Bianco

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Ubiquitination is a critical posttranslational regulator of protein stability and/or subcellular localization. Here we show that ubiquitination can also regulate proteins by transiently inactivating enzymatic function through conformational change in a dimeric enzyme, which can be reversed upon deubiquitination. Our model system is the thyroid hormone-activating type 2 deiodinase (D2), an endoplasmic reticulum-resident type 1 integral membrane enzyme. D2 exists as a homodimer maintained by interacting surfaces at its transmembrane and globular cytosolic domains. The D2 dimer associates with the Hedgehog-inducible ubiquitin ligase WSB-1, the ubiquitin conjugase UBC-7, and VDU-1, a D2-specific deubiquitinase. Upon binding of T4, its natural substrate, D2 is ubiquitinated, which inactivates the enzyme by interfering with D2's globular interacting surfaces that are critical for dimerization and catalytic activity. This state of transient inactivity and change in dimer conformation persists until deubiquitination. The continuous association of D2 with this regulatory protein complex supports rapid cycles of deiodination, conjugation to ubiquitin, and enzyme reactivation by deubiquitination, allowing tight control of thyroid hormone action.

Original languageEnglish
Pages (from-to)4774-4783
Number of pages10
JournalMolecular and Cellular Biology
Volume27
Issue number13
DOIs
Publication statusPublished - Jul 2007

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Iodide Peroxidase
Ubiquitination
Ubiquitin
Enzymes
Thyroid Hormones
gamma-Glutamyl Hydrolase
Protein Stability
Dimerization
Ligases
Endoplasmic Reticulum
Proteins
Membranes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. / Sagar, G. D Vivek; Gereben, B.; Callebaut, Isabelle; Mornon, Jean Paul; Zeöld, A.; Da Silva, Wagner S.; Luongo, Cristina; Dentice, Monica; Tente, Susana M.; Freitas, Beatriz C G; Harney, John W.; Zavacki, Ann Marie; Bianco, Antonio C.

In: Molecular and Cellular Biology, Vol. 27, No. 13, 07.2007, p. 4774-4783.

Research output: Contribution to journalArticle

Sagar, GDV, Gereben, B, Callebaut, I, Mornon, JP, Zeöld, A, Da Silva, WS, Luongo, C, Dentice, M, Tente, SM, Freitas, BCG, Harney, JW, Zavacki, AM & Bianco, AC 2007, 'Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity', Molecular and Cellular Biology, vol. 27, no. 13, pp. 4774-4783. https://doi.org/10.1128/MCB.00283-07
Sagar, G. D Vivek ; Gereben, B. ; Callebaut, Isabelle ; Mornon, Jean Paul ; Zeöld, A. ; Da Silva, Wagner S. ; Luongo, Cristina ; Dentice, Monica ; Tente, Susana M. ; Freitas, Beatriz C G ; Harney, John W. ; Zavacki, Ann Marie ; Bianco, Antonio C. / Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 13. pp. 4774-4783.
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