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Consensus sequences for early iodination and hormonogenesis in human thyroglobulin.
L Lamas1, P C Anderson, J W Fox
1Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville 22908.
The Journal of Biological Chemistry
|August 15, 1989
Summary
Thyroglobulin primary structure dictates thyroid hormone formation. Specific amino acid sequences guide the iodination process, influencing the creation of iodotyrosines and iodothyronines, crucial for thyroid hormone synthesis.
Area of Science:
- Biochemistry
- Endocrinology
- Molecular Biology
Background:
- Thyroglobulin (Tg) is a large glycoprotein essential for thyroid hormone synthesis.
- Iodination of thyroglobulin is a critical step in the production of thyroid hormones (T3 and T4).
- Understanding the specific sites and sequences involved in Tg iodination is key to elucidating thyroid hormone regulation.
Purpose of the Study:
- To investigate the role of thyroglobulin's primary structure in the in vitro iodination process.
- To identify specific iodination sites and consensus sequences within thyroglobulin.
- To correlate iodination patterns with the formation of iodotyrosines and iodothyronines.
Main Methods:
- In vitro iodination of human goiter thyroglobulin using Na 125I and KI.
- Fractionation of iodinated thyroglobulin using high-performance liquid chromatography (HPLC).
- Purification, sequencing, and characterization of iodinated tryptic peptides, including [125I]iodoamino acid distribution.
- Localization of iodinated sites within the thyroglobulin primary structure using published cDNA sequence data.
Main Results:
- Low-level iodination (2 atoms/molecule) resulted in iodotyrosyls at five principal sites without hormone formation.
- Higher-level iodination (7.8 atoms/molecule) increased iodination at existing sites, added 10 new iodotyrosyl sites, and formed iodothyronines at 5 sites.
- Specific tyrosyl residues (e.g., 24, 2572) showed differential iodination and hormone formation depending on iodine levels.
- Tyrosyls 149, 866, and 1466 were early iodination sites but did not form iodothyronines, suggesting roles in outer ring donation.
- Three consensus sequences (Glu/Asp-Tyr, Ser/Thr-Tyr-Ser, Glu-X-Tyr) were identified around iodotyrosyls, correlating with iodotyrosine and iodothyronine synthesis.
Conclusions:
- The primary structure of thyroglobulin significantly influences the location and extent of iodination.
- Consensus sequences within thyroglobulin play a major role in directing the formation of thyroid hormones and their iodinated precursors.
- Identified iodination sites and consensus sequences are conserved across different species' thyroglobulins.