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Molecular and Cellular Biology, July 2007, p. 4774-4783, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.00283-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ubiquitination-Induced Conformational Change within the Deiodinase Dimer Is a Switch Regulating Enzyme Activity{triangledown}

G. D. Vivek Sagar,1,{dagger} Balázs Gereben,2,{dagger} Isabelle Callebaut,3 Jean-Paul Mornon,3 Anikó Zeöld,2 Wagner S. da Silva,1 Cristina Luongo,1 Monica Dentice,1 Susana M. Tente,1 Beatriz C. G. Freitas,1 John W. Harney,1 Ann Marie Zavacki,1 and Antonio C. Bianco1*

Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary,2 Département de Biologie structurale, IMPMC, CNRS UMR7590, Universities Paris 6 and Paris 7, Paris 75252 Cedex 05, France3

Received 15 February 2007/ Returned for modification 11 April 2007/ Accepted 13 April 2007

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.

* Corresponding author. Mailing address: Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM Bldg. 643, Boston, MA 02115. Phone: (617) 525-5153. Fax: (617) 731-4718. E-mail: abianco{at}partners.org

{triangledown} Published ahead of print on 23 April 2007.

{dagger} These authors contributed equally to this paper.

Molecular and Cellular Biology, July 2007, p. 4774-4783, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.00283-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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