The pituitary/placental glycoprotein hormone receptor (GPHR) family includes follicle stimulating hormone receptor (FSHR), luteinizing hormone receptor, thyroid stimulating hormone receptor and chorionic gonadotropin receptor. Glycoprotein hormones control reproduction, sexual development and thyroid function. The overall goal of this research is to better understand FSHR structure, signaling and turnover. The field currently has no molecular structure for the GPHR. To understand the structure, significance, and mechanisms of GPHR regulation a tractable approach is to determine the structure of smaller biologically active domains of the GPHR. This laboratory has discovered a biologically active, receptor domain, which could provide the first structural test of the current receptor molecular models. The structure of this autologously-acting hFSHR peptide domain will be determined by NMR spectroscopy. This structure determination and mutagenesis of native receptor at this locus, will be used to guide synthesis of conformationally stable forms of the peptide to develop more potent antagonists of FSH action. The field has only recently substantiated a model that cytoplasmic mitogen activated protein kinase signaling pathways are activated by FSH. The complexity of these pathways, and their relationships to mechanisms through protein-protein interactions wit the receptor cytoplasmic domains. This laboratory has identified candidate genes, which are interacting partners with hFSHR, detected u sing a partial yeast genetic screen of mature human ovary mRNA. Since these proteins may coordinate the cell biology of FSHR signaling and trafficking they will be studied to determine their validity as interacting partners, and potential regulators of FSHR signal transduction. A full library screen will be executed enabling detection of rare messages. The field, currently accepts a one hormone-one receptor model of activation. Determination of the three dimensional structure of fully glycosylated fully active human FSH during the current grant period, revealed the hFSH belongs to the cystine knot growth factor family as does hCG. Based upon other members of this cystine knot growth factor family which activate cellular responses by inducing dimerization of their single pass membrane cognate receptors, an alternative model of activation can be proposed and is underpinned by recent studies showing dimerization of seven pass GPCRs. A goal then, is to elucidate the oligomerization state of human FSHR and how it relates to hFSHR activation and attenuation of hormonal response.
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