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Implications for Molecular Mechanisms of Glycoprotein Hormone Receptors Using a New Sequence-Structure-Function Analysis Resource

Leibniz-Institut für Molekulare Pharmakologie (G.K., U.W., D.L., G.K.), 13125 Berlin, Germany; FH-Giessen (M.B.), 35390 Giessen, Germany; and Institute for Computer Science (U.L.), Humboldt-Universität Berlin, 10099 Berlin, Germany

Address all correspondence and requests for reprints to: Gerd Krause, Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, D-13125 Berlin, Germany. E-mail: GKrause{at}FMP-Berlin.de.

ABSTRACT

Comparison between wild-type and mutated glycoprotein hormone receptors (GPHRs), TSH receptor, FSH receptor, and LH-chorionic gonadotropin receptor is established to identify determinants involved in molecular activation mechanism. The basic aims of the current work are 1) the discrimination of receptor phenotypes according to the differences between activity states they represent, 2) the assignment of classified phenotypes to three-dimensional structural positions to reveal 3) functional-structural hot spots and 4) interrelations between determinants that are responsible for corresponding activity states. Because it is hard to survey the vast amount of pathogenic and site-directed mutations at GPHRs and to improve an almost isolated consideration of individual point mutations, we present a system for systematic and diversified sequence-structure-function analysis (http://www.fmp-berlin.de/ssfa). To combine all mutagenesis data into one set, we converted the functional data into unified scaled values. This at least enables their comparison in a rough classification manner. In this study we describe the compiled data set and a wide spectrum of functions for user-driven searches and classification of receptor functionalities such as cell surface expression, maximum of hormone binding capability, and basal as well as hormone-induced Gs/Gq mediated cAMP/inositol phosphate accumulation. Complementary to known databases, our data set and bioinformatics tools allow functional and biochemical specificities to be linked with spatial features to reveal concealed structure-function relationships by a semiquantitative analysis. A comprehensive discrimination of specificities of pathogenic mutations and in vitro mutant phenotypes and their relation to signaling mechanisms of GPHRs demonstrates the utility of sequence-structure-function analysis. Moreover, new interrelations of determinants important for selective G protein-mediated activation of GPHRs are resumed.

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