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Biomedical subjects

Mariusz W Szkudlinski

Publications and source records attributed to Mariusz W Szkudlinski.

5 recordsLinked to original sources
PubMed2004

Minireview: structural and functional evolution of the thyrotropin receptor.

TSH receptor (TSHR) is a member of the leucine-rich repeat-containing G protein-coupled receptors. Both TSHR and its ligand TSH have evolved to acquire specificity, minimize cross-reaction to other glycoprotein hormone receptors, and modulate cognate interaction (and thereby thyrotropic activity). TSHR sequences available from two life orders, teleost and mammals, were analyzed. Teleost TSHRs with low affinity are expressed in many nonthyroidal tissues and show a tendency to gene duplication. In some teleosts, TSHR has limited specificity, and in others extremely high constitutive activity, suggesting the possibility of ligand-independent receptor function. Although mammalian TSHR, in contrast to other glycoprotein hormone receptors, maintains relatively high constitutive activity, the thyrotropic activity of TSH appears to decline in hominoids including humans, probably as part of metabolic adaptation to the changing environment. Critical TSHR residues that determine hormone specificity have been identified in the leucine-rich repeats, and others within the cysteine-rich C-flanking region that determines hormonal activation as well as receptor silencing. Transmembrane (TM) helices, particularly the TM5 and TM6, are likely involved in receptor homodimerization and a unique motif in TM7 appears essential to receptor silencing and internalization. Surprisingly, ternary structures in the intracellular domain as opposed to specific sequence motifs are critical for intracellular TSHR trafficking. It is evident that progress in understanding structure-function relationships of TSHR and its ligand can be further stimulated by inclusion of evolutionary analysis of their primary, secondary and tertiary structure. Such an integrated approach should also contribute to the rational design of highly efficacious therapeutics with either agonistic or antagonistic properties.

Amino Acid Sequence↗
PubMed2004

Human alpha-subunit analogs act as partial agonists to the thyroid-stimulating hormone receptor: differential effects of free and yoked subunits.

The alpha-subunit is common to the heterodimeric glycoprotein hormones and has been highly conserved throughout vertebrate evolution. In an effort to determine if wild-type and engineered human alpha analogs can serve as agonists or antagonists to the human thyroid-stimulating hormone (TSH) receptor (TSHR), a potent alpha mutant, obtained by replacing four amino acid residues with lysine (alpha4K), was assayed and compared with the wild-type alpha-subunit. When added to CHO cells expressing TSHR, alpha4K, and to a very limited extent the fused homodimer, alpha4K-alpha4K, but not alpha, exhibited agonist activity as judged by cAMP production. When yoked to TSHR to yield fusion proteins, neither alpha, alpha4K, alpha-alpha, nor alpha4K-alpha4K activated TSHR, although yoked alpha4K and alpha4K-alpha4K were weak inhibitors of TSH binding to TSHR. The yoked subunit-receptor complexes were, however, functional as evidenced by increased cAMP production in cells co-expressing human TSHbeta and alpha-TSHR, alpha4K-TSHR, alpha-alpha-TSHR, and alpha4K-alpha4K-TSHR. These results demonstrate that agonists to TSHR can be obtained with alpha-subunit analogs and suggest that rational protein engineering may lead to more potent alpha-based derivatives. The differences found between the experimental paradigms of adding free alpha analogs to TSHR and covalent attachment are attributed to con-formational constraints imposed by fusion of the alpha-subunit analog and receptor, and may suggest an important role for a free (C-terminal) alpha-carboxyl in the absence of the beta-subunit.

Animals↗
PubMed2004

Recombinant human thyrotropins of the twenty-first century.

In recent years, many new recombinant protein therapeutics have been developed and tested in clinical trials [1]. Current and future clinical uses of recombinant human thyroid-stimulating hormone (rhTSH; Thyrogen, Genzyme) in thyroid diseases are discussed in the review published in this issue of Expert Opinion on Pharmacotherapy [2]. As Thyrogen is a wild-type rhTSH produced in Chinese hamster ovary cells, it has relatively low affinity to the human TSH receptor. Such low affinity and weak intrinsic bioactivity of rhTSH, compared to the bovine or rodent TSH, may help to explain the results of several studies indicating limited clinical efficacy of Thyrogen. TSH analogues with largely increased receptor affinity, potency and efficacy, are expected to provide not only more effective than currently used diagnostic methods, but should also serve as indispensable second-generation thyrotropins for the diagnosis and treatment of thyroid carcinomas with a largely limited number of TSH receptors.

Drug Therapy↗
PubMed2002

Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships.

This review focuses on recent advances in the structure-function relationships of thyroid-stimulating hormone (TSH) and its receptor. TSH is a member of the glycoprotein hormone family constituting a subset of the cystine-knot growth factor superfamily. TSH is produced by the pituitary thyrotrophs and released to the circulation in a pulsatile manner. It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs). New insights into the structure-function relationships of TSH permitted better understanding of the role of specific protein and carbohydrate domains in the synthesis, bioactivity, and clearance of this hormone. Recent progress in studies on TSHR as well as studies on the other GPCRs provided new clues regarding the molecular mechanisms of receptor activation. Such advances are a result of extensive site-directed mutagenesis, peptide and antibody approaches, detailed sequence analyses, and molecular modeling as well as studies on naturally occurring gain- and loss-of-function mutations. This review integrates expanding information on TSH and TSHR structure-function relationships and summarizes current concepts on ligand-dependent and -independent TSHR activation. Special emphasis has been placed on TSH domains involved in receptor recognition, constitutive activity of TSHR, new insights into the evolution of TSH bioactivity, and the development of high-affinity TSH analogs. Such structural, physiological, pathophysiological, evolutionary, and therapeutic implications of TSH-TSHR structure-function studies are frequently discussed in relation to concomitant progress made in studies on gonadotropins and their receptors.

Amino Acid Sequence↗