Untersuchung eines erweiterten Interaktionsspektrums des Thyrotropin Rezeptors

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The final goal of this DFG funded project (started in 2010) concerns a comprehensive understanding of the thyrotropin receptor (TSHR), with respect to related molecular biology, physiology and pathophysiology. Accordingly to this purpose important detailed insights into the TSHR were already identified by the applicants in recent years and published in Endocrine Reviews (2013). The relevance of these information is related to the versatile links of the TSHR to pathogenic situations like Graves disease, thyroid-carcinoma, Graves' orbitopathy, non-autoimmune and autoimmune thyroid hyperfunction. These frequently TSHR associated diseases are of world-wide and high prevalence, whereby a TSHR-directed medical intervention is not available. In this newly applied period of funding the applicants scheduled the extension, refinement and finalization of studies at the TSHR. For example: the monocarboxylate-transporter 8 was identified as an interacting protein with the TSHR. This finding induces the question how signal transduction at the receptor and substrate translocation at the transporter are mutually modified by this interaction. Such a co-incidence of both processes should provoke a fundamentally new perspective on signaling and substrate transport. Furthermore, the basal signaling activity of the TSHR (ligand independent) is of high importance, but is not comprehensively understood concerning their regulative impact. Why the TSHR exhibits a permanent basal activity and is it of pathophysiological significance? To answer these questions advanced approaches are planned during a funding-period III. Received new data together with already reported insights will be used for a bioinformatic-supported systems-biology analyses. Finally the determination of GPCR structures has become high attention and success-rate especially in the last seven years based on new methods developed for appropriate protein preparation, membrane protein crystallization and structure determination (e.g. Nobel-price chemistry, 2012, Brian Kobilka, Robert Lefkowitz). Therefore, this knowledge will be used in this project for unraveling the membrane protein crystal structure of the TSHR on the atomic level. Taken together, this application concerns an extended period of studies at the TSHR to continue the investigation of this receptor. The final purpose is to close the gap of knowledge concerning pharmacological properties and structural features on the atomic level. In consequence this will help to understand pathological mechanisms related to TSHR activation or inactivation, molecular causalities of regulation and to improve options of disease treatment.