Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity
Open accessAbstract
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.
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T4 and rT3 inhibit DIO2 by promoting its ubiquitination, which inhibits DIO2 activity and targets it for proteasomal degradation, forming an incoherent feedforward motif with T3 as the output.
“T4 and rT3 also inhibit DIO2 by promoting its ubiquitination, which inhibits DIO2 activity and targets it for proteasomal degradation (37–40), forming an incoherent feedforward motif with T3 as the output.”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [40]
The introductory passage (page not provided) says T4 accelerates D2 ubiquitination, which inactivates D2 and targets it to the proteasome; the Results also report T4-induced loss of D2 activity. Our copy does not establish the same effect for rT3 (searched: rT3, reverse T3). The incoherent feedforward motif is the citing authors’ framing, not a finding attributed to this source. (LLM, conf=0.86)
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Cites
Deiodinases: implications of the local control of thyroid hormone action
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Research works printed but not linked: 2
- [8]8. Campos-Barros, A., L. L. Amma, J. S. Faris, R. Shailam, M. W. Kelley, and D. Forrest. 2000. Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing. Proc. Natl. Acad. Sci. USA 97: 1287-1292.
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Cited by
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Gereben, B., Zavacki, A. M., Ribich, S., Kim, B. W., Huang, S. A., Simonides, W. S., Zeöld, A., & Bianco, A. C. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0019 · Cited by 891 · see citing works
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Self-citationParadigms of dynamic control of thyroid hormone signaling
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Allosteric post-translational modification codes
Nussinov, R., Tsai, C.-J., Xin, F., & Radivojac, P. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.07.001 · Cited by 211 · see citing works
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Werneck de Castro, J. P., Fonseca, T. L., Ueta, C. B., McAninch, E. A., Abdalla, S., Wittmann, G., Lechan, R. M., Gereben, B., & Bianco, A. C. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77588 · Cited by 184 · see citing works
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de Vries, E. M., Fliers, E., & Boelen, A. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0133 · Cited by 192 · see citing works
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Jo, S., Fonseca, T. L., Bocco, B. M. L. C., Fernandes, G. W., McAninch, E. A., Bolin, A. P., Da Conceição, R. R., Werneck-de-Castro, J. P., Ignacio, D. L., Egri, P., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci123176 · Cited by 107 · see citing works
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Skeletal muscle deiodinase type 2 regulation during illness in mice
Kwakkel, J., van Beeren, H. C., Ackermans, M. T., Platvoet-ter Schiphorst, M. C., Fliers, E., Wiersinga, W. M., & Boelen, A. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0118 · Cited by 48 · see citing works
Coupling between Nutrient Availability and Thyroid Hormone Activation
Lartey, L. J., Werneck-de-Castro, J. P., O-Sullivan, I., Unterman, T. G., & Bianco, A. C. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.665505 · Cited by 41 · see citing works
Self-citationKwakkel, J., Chassande, O., van Beeren, H. C., Fliers, E., Wiersinga, W. M., & Boelen, A. (2010) · Endocrinology · doi:10.1210/en.2009-1049 · Cited by 34 · see citing works
Fekete, C., Freitas, B. C. G., Zeöld, A., Wittmann, G., Kádár, A., Liposits, Z., Christoffolete, M. A., Singru, P., Lechan, R. M., Bianco, A. C., et al. (2007) · Endocrinology · doi:10.1210/en.2007-0448 · Cited by 33 · see citing works
Self-citation
- Authors
- Sagar, G. D. V., Gereben, B., Callebaut, I., Mornon, J.-P., Zeöld, A., da Silva, W. S., Luongo, C., Dentice, M., Tente, S. M., Freitas, B. C. G., Harney, J. W., Zavacki, A. M., & Bianco, A. C.
- Affiliations
- Brigham and Women's Hospital (US)
- HUN-REN Institute of Experimental Medicine (HU)
- Centre National de la Recherche Scientifique (FR)
- Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
- Corresponding author
- Bianco, Antonio C.
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-07-01
- Volume
- 27
- Issue
- 13
- Pages
- 4774-4783
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1951476
- OpenAlex
- W2014871570
- Cited by
- 103
- References
- 2
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 7 · 2020: 3 · 2019: 4 · 2018: 9 · 2017: 2 · 2016: 6 · 2015: 11 · 2014: 7 · 2013: 5 · 2012: 3
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Fogarty International Center (TW006467, R03TW006467)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058538, DK 58538)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- ubiquitination, type 2 deiodinase, enzyme regulation, conformational change, dimerization, deubiquitination, thyroid hormone activation, post-translational regulation, thyroid hormone signaling
- MeSH terms
- Amino Acid Sequence, Animals, Catalysis, Cell Line, Humans, Iodide Peroxidase, Models, Molecular, Molecular Sequence Data, Protein Binding, Structure-Activity Relationship, Protein Structure, Secondary, Protein Structure, Tertiary, Dimerization, Holoenzymes, Catalytic Domain, Protein Structure, Quaternary, Ubiquitin, Mice
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