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Minireview: structural and functional evolution of the thyrotropin receptor
Nadir R Farid1, Mariusz W Szkudlinski
1Osancor Biotech Inc, 31 Woodland Drive, Hertfordshire WD17 3BY, United Kingdom. farid@osancor96.fsnet.co.uk
Endocrinology
|July 3, 2004
Summary
Evolutionary analysis reveals TSH receptor (TSHR) variations across species, impacting hormone specificity and activity. Understanding these structural changes is key to developing targeted thyroid-stimulating hormone therapies.
Area of Science:
- Endocrinology
- Molecular Biology
- Evolutionary Biology
Background:
- The TSH receptor (TSHR) is a G protein-coupled receptor crucial for thyroid function.
- TSHR and its ligand TSH have evolved intricate specificity mechanisms to regulate thyrotropic activity.
Purpose of the Study:
- To analyze TSHR sequences from teleost and mammalian lineages to understand evolutionary adaptations.
- To identify structural determinants of TSHR specificity, activity, and trafficking.
Main Methods:
- Comparative sequence analysis of TSHR from teleost and mammalian species.
- Identification of critical residues and structural motifs involved in TSHR function.
Main Results:
- Teleost TSHRs exhibit diverse characteristics, including low affinity, tissue expression, gene duplication, and variable specificity/constitutive activity.
- Mammalian TSHR shows high constitutive activity, with declining TSH activity in hominoids possibly linked to metabolic adaptation.
- Specific residues in leucine-rich repeats and C-flanking regions, along with TM helices and intracellular structures, dictate TSHR specificity, activation, silencing, and trafficking.
Conclusions:
- Evolutionary analysis provides critical insights into TSHR structure-function relationships.
- Understanding TSHR evolution aids in designing novel therapeutics targeting thyroid hormone regulation.