FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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A new phenotype of nongoitrous and nonautoimmune hyperthyroidism caused by a heterozygous thyrotropin receptor mutation in transmembrane helix 6
Winkler(*), F., Kleinau, G., Tarnow(*), P., Rediger(*), A., Grohmann(*), L., Gaetjens(*), I., Krause, G., L'Allemand(*), D., Grüters(*), A., Krude(*), H.; Biebermann(*), H.
The Journal of clinical endocrinology and metabolism, 95:3605-3610
(2010)

Tags: Structural Bioinformatics and Protein Design (Krause, G.)

Abstract: CONTEXT: Activating mutations in the TSHR gene were found in patients suffering from nonautoimmune hyperthyroidism. In the past, it was assumed that thyroid hyperplasia is due to constitutive activation of the Gs/adenylyl cyclase signaling pathway; however, the physiological role of the Gq/11 pathway in this context remains unclear. OBJECTIVE: In this study, we investigated molecular details of the TSHR in a patient with nonautoimmune and nongoitrous hyperthyroidism. RESULTS: We detected a heterozygous mutation in exon 10 of the TSHR gene leading to an exchange of a cysteine residue for tryptophan at amino acid position 636 in transmembrane helix 6. Functional characterization of the mutant receptor revealed a slight reduction of the cell surface expression and TSH induced cAMP accumulation compared to the wild type. Additional observations included a constitutive activation of the Gs-mediated signaling pathway and a simultaneous nearly complete loss-of-function for the Gq/11 pathway after bovine TSH stimulation. Studies on TSHR models suggest significant changes of important amino acid interactions and the overall helix arrangement caused by mutation C636W. CONCLUSION: We report a patient in whom a TSHR mutation leads to nonautoimmune hyperthyroidism due to a mutation that constitutively activates the Gs signaling pathway but additionally completely inhibits the Gq/11 pathway. The absence of goiter in the patient suggests that the Gq/11 pathway is related to thyroid growth and that different signaling pathways are mediated and regulated by TSH. These functional data could be confirmed by reproducible findings of two siblings with a constitutive activation for both pathways.

Addressing protein-protein interactions with small molecules: a Pro-Pro dipeptide mimic with a PPII helix conformation as a module for the synthesis of PRD-binding ligands
Zaminer(*), J., Brockmann, C., Huy(*), P., Opitz, R., Reuter(*), C., Beyermann, M., Freund, C., Müller, M., Oschkinat, H., Kühne, R.; Schmalz(*), H. G.
Angew Chem Int Ed Engl, 49:7111-7115
(2010)

Tags: Computational Chemistry/Drug Design (Kühne), Protein Structure (Oschkinat), Peptide Synthesis (Beyermann)

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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