Structure-function relationships of the luteinizing hormone receptor.
Of the 800-900 genes in the human genome that appear to encode G-protein-coupled receptors (GPCRs), two are known to encode receptors that bind the three heterodimeric human gonadotropins, luteinizing hormone (LH), chorionic gonadotropin (CG), and follicle-stimulating hormone (FSH). LH and CG bind to a common receptor, LHR, and FSH binds to a paralogous receptor. These GPCRs contain a relatively large ectodomain (ECD), responsible for high-affinity ligand binding, and a transmembrane portion, as in the other GPCRs. The ECD contains nine leucine-rich repeats capped by N-terminal and C-terminal cysteine-rich regions. The overall goal of this research is to elucidate the molecular mechanisms by which CG and LH bind to and activate LHR and the latter, in turn, activates Gs alpha. A combination of molecular modeling and site-directed mutagenesis, coupled with binding and signaling studies in transiently transfected HEK 293 cells expressing wild-type and mutant forms of LHR, has been used to develop and test models for the LHR ECD, the CG-LHR ECD complex, and the structural changes in the transmembrane helices and intracellular loops, particularly loop 2, that accompany receptor activation. In addition, a single-chain CG-LHR complex was designed in which a fusion protein of the two subunits of human CG was linked to full-length LHR. This ligand-receptor complex was shown to be constitutively active in cellular models and in transgenic mice, the latter of which exhibit precocious puberty. From a combination of molecular modeling, site-directed mutagenesis, genetic/protein engineering, and receptor characterization in cellular and animal models, considerable insight is being developed on the mechanisms of normal and aberrant activation of LHR.
Department of Biochemistry & Molecular Biology, B129 Fred C. Davison Life Sciences Complex, University of Georgia, 120 Green St., Athens, GA 30602-7229, USA. puett@bmb.uga.edu
David
D
Puett
Yongsheng
Y
Li
Krassimira
K
Angelova
Geneva
G
Demars
Thomas P
TP
Meehan
Francesca
F
Fanelli
Prema
P
Narayan
D000818:Animals; D006063:Chorionic Gonadotropin / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D005640:Follicle Stimulating Hormone; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011974:Receptors, LH / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D006063:Chorionic Gonadotropin; D011974:Receptors, LH; D005640:Follicle Stimulating Hormone; D019204:GTP-Binding Proteins