Endocrine Abstracts

Comparison between wild type and mutated glycoprotein hormone receptors (GPHRs) TSHR, FSHR and LHCGR is established to identify determinants involved in molecular activation mechanism. The basic aims of current work are the discrimination of receptor phenotypes according the differences between activity states they represent and hit-assignment of classified phenotypes to 3D-structural positions to reveal functional-structural hotspots and interrelations between determinants that are responsible for corresponding activity states. Since 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 (SSFA) (http://www.fmp-berlin.de/ssfa). In order 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 Gαs/Gαq mediated cAMP/IP accumulation. Complementary to known databases our data set and bioinformatics tools allow to link functional-, biochemical- specificities with spatial features to reveal concealed structure-function relationships by a semi-quantitative analysis. A comprehensive discrimination of specificities of pathogenic mutations and in vitro mutant phenotypes and their relation to signalling mechanisms of GPHRs demonstrates the utility of SSFA. Moreover, new interrelations of determinants important for selective G-protein mediated activation of GPHRs are resumed.