[Frontiers In Bioscience, Landmark, 24, 212-230, Jan 1, 2019]

Thyroid hormone binding motifs and iodination pattern of thyroglobulin

Salvatore Benvenga1,2,3, Fabrizio Guarneri4

1Department of Clinical and Experimental Medicine - Endocrinology, University of Messina, via Consolare Valeria, Gazzi, 98125 Messina, Italy, 2Master Program on Childhood, Adolescent and Women’s Endocrine Health, University of Messina, via Consolare Valeria, Gazzi, 98125 Messina, Italy, 3Interdepartmental Program on Molecular and Clinical Endocrinology and Women’s Endocrine Health, AOU Policlinico G. Martino, via Consolare Valeria, Gazzi, 98125 Messina, Italy, 4Department of Clinical and Experimental Medicine, Dermatology, University of Messina, via Consolare Valeria - Gazzi, 98125 Messina, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
4. Results
4.1. Perfect five-residue TH-binding motifs
4.2. Imperfect five-residue TH-binding motifs
4.3. Perfect/imperfect motifs in relation to tyrosines that, in both mTg and hTg, form solely MIT
4.4. Perfect/imperfect motifs in relation to tyrosines that, in both mTg and hTg, form solely DIT
4.5. Perfect/imperfect motifs in relation to tyrosines that, in both mTg and hTg, form only MIT and DIT
4.6. Perfect/imperfect motifs in relation to tyrosines that, in both mTg and hTg, form MIT, DIT, T4 and T3
4.7. Perfect/imperfect motifs in relation to tyrosines that are iodinated in Tg from one species but not iodinated in Tg from the other species
4.7.1. Forming solely MIT, and only in one species
4.7.2. Forming solely DIT in mTg but not iodinated in hTg, and vice versa
4.7.3. Forming MIT and DIT only in mTg, but not iodinated in hTg
4.7.4. Tyrosines that form both MIT and DIT in mTg, but only MIT in hTg
4.7.5. Tyrosines that form both MIT and DIT in mTg, but both MIT and T4 in hTg
4.7.6. Tyrosines that form MIT, DIT and T4 in mTg, but MIT, T4 and T3 in hTg
4.7.7. Tyrosines that form MIT, DIT, T4 and T3 in mTg, but MIT, T4 and T3 in hTg
4.7.8. Tyrosines that form MIT, DIT and T3 in mTg, but only MIT and DIT in hTg
4.7.9. Tyrosines that form only MIT in mTg, but only DIT in hTg
4.7.10. Summary
5. Discussion
6. References

1. ABSTRACT

A phylogenetically conserved 5-residue thyroid hormone (TH)- binding motif was originally found in a few TH plasma carriers and, more recently, in all known plasma and cell-associated proteins interacting with TH as well as in proteins involved in iodide uptake. Minor variations of the motif were found, depending on the particular class of those proteins. Since thyroglobulin (Tg) is the protein matrix for TH synthesis starting from iodination of a selected number of tyrosines (to form first monoiodotyrosine (MIT) and diiodotyrosine (DIT) and then T3 and T4), we hypothesized that by searching the presence of perfect or imperfect versions of that motif in two Tg species (human and murine) in which the iodinated tyrosines and pattern of iodotyrosine/iodothyronine formation are known, we could have found relevant explanations. Explanations, which are not furnished by the simple possession of tyrosine-iodination motifs and sequence of the iodination motif, concern why only some (but not other) tyrosine residues in one species are iodinated and why they have a particular iodination pattern. In this bioinformatics study, we provide such explanations.

6. REFERENCES

1. S. Benvenga, H.J. Cahnmann, D. Rader, M. Kindt, A. Facchiano, J. Robbins: Thyroid hormone binding to isolated human apolipoproteins A-II, C-I, C-II, and C-III: homology in thyroxine binding sites. Thyroid 4, 261-267 (1994)
DOI: 10.1089/thy.1994.4.261

2. S. Benvenga: A thyroid hormone binding motif is evolutionarily conserved in apolipoproteins. Thyroid 7, 605-611 (1997)
DOI: 10.1089/thy.1997.7.605

3. S. Benvenga, F. Guarneri: Conservation in the phylum of the local homology of apolipoproteins with the thyroid hormone plasma carriers. Rev Endocr Metab Disord 17, 537-544 (2016)
DOI: 10.1007/s11154-016-9379-7

4. S. Benvenga, F. Guarneri: Deiodinases share an evolutionarily conserved thyroid hormone-binding motif. Front Biosci Landmark Ed 23, 2195-2204 (2018)

5. J. Bismuth, M. Castay, S. Lissitzky: Binding of 3,5-diiodotyrosine to serum proteins. Clin Chim Acta 69, 417-422 (1976)

6. N. Okabe, N. Manabe, R. Tokuoka, K. Tomita: Interaction of diiodo-L-tyrosine and triiodophenol with bovine serum albumin. Circular dichroism and fluorescence studies. J Biochem 80, 455-461 (1976)

7. K. Grygorian, H. Shilajyan: Physicochemical peculiarities of iodine-dimethylsulfoxide-H2O solutions and effect on ion binding to bovine serum albumin. Dataset Papers in Chemistry 2013, Article ID 534328 (2013)
DOI: 10.7167/2013/534328

8. N.M. Bourgeois, S.L. Van Herck, P. Vancamp, J. Delbaere, C. Zevenbergen, S. Kersseboom, V.M. Darras, T.J. Visser: Characterization of chicken thyroid hormone transporters. Endocrinology 157, 2560-2574 (2016)
DOI: 10.1210/en.2015-2025

9. B.B. Mughal, M. Leemans, E.C. Lima de Souza, S. le Mevel, P. Spirhanzlova, T. Visser, J.B. Fini, B.A. Demeneix: Functional characterisation of Xenopus thyroid hormone transporters McT8 and Oatp1c1. Endocrinology 158, 2694-2705 (2017)
DOI: 10.1210/en.2017-00108

10. B. Di Jeso, P. Arvan: Thyroglobulin from molecular and cellular biology to clinical endocrinology. Endocr Rev 37, 2-36 (2016)
DOI: 10.1210/er.2015-1090

11. A. Dedieu, J.C. Gaillard, T. Pourcher, E. Darrouzet, J. Armengaud: Revisiting iodination sites in thyroglobulin with an organ-oriented shotgun strategy. J Biol Chem 286, 259-269 (2011)
DOI: 10.1074/jbc.M110.159483

12. F. Guarneri, B. Guarneri: Bioinformatic analysis of HLA-linked genetic susceptibility to immunoallergic diseases: the MotiFinder software. Ann Ital Dermatol Allergol 64, 69-75 (2010)

13. S. Benvenga, F. Guarneri: Thyroid hormone-interacting cell and plasma proteins share a common motif. Front Biosci Schol Ed 10, 326-336 (2018)
DOI: 10.2741/S519

14. S. Benvenga, F. Guarneri: Homology of pendrin, sodium-iodide symporter and apical iodide transporter. Front Biosci Landmark Ed 23, 1864-1873 (2018).
DOI: 10.2741/4677

15. H.M. Targovnik, C.E. Citterio, C.M. Rivolta: Thyroglobulin gene mutations in congenital hypothyroidism. Horm Res Paediatr 75, 311-321 (2011)
DOI: 10.1159/000324882

Key Words: Thyroglobulin; Monoiodotyrosine; Diiodotyrosine; Iodination; Thyroid Hormones; Congenital Hypothyroidism

Send correspondence to: Fabrizio Guarneri, Department of Clinical and Experimental Medicine - Dermatology, via Consolare Valeria - Gazzi, 98125 Messina, Italy, Tel: +39 090 2212890, Fax: +39 090 2927691, E-mail: f.guarneri@tiscali.it