Study On The Structure And Function Of Glycoprotein Hormones And Their Receptors

The endocrine system and nervous system control the internal homeostasis of the human body.Glycoprotein hormones include gonadotropins and thyroid-stimulating hormone(TSH);the former is comprised of luteinizing hormone(LH),folliclestimulating hormone(FSH),and chorionic gonadotropin(CG).Gonadotropins are pituitary hormones that connect the signaling cascade from the hypothalamus to the gonadal,termed the hypothalamic-pituitary-gonadal axis(HPG),which is critical for reproduction,body,and sex development.TSH connects the signaling cascade from the hypothalamus to the thyroid,designated as the hypothalamic-pituitary-thyroid axis(HPT),and is responsible for metabolism and growth.There are three glycoprotein hormone receptors,which belong to G protein-coupled receptors(GPCR),existing in the human body,including FSHR(FSH receptor),LHCGR(LH/CG receptor),and TSHR(TSH receptor).These receptors are activated by FSH,LH/CG,and TSH,respectively.Activated receptors couple to Gs and Gq proteins and trigger the signal cascade for function.Aberrant signal transduction of glycoprotein hormones and their receptors system is closely related to many diseases,such as infertility,ovarian dysfunction,gender dysplasia,hyperthyroidism,hypothyroidism,etc.Glycoprotein hormones have been widely applied as clinical therapeutic drugs.However,the molecular mechanisms for hormone recognition,hormone specificity,and hormone-induced receptor activation are still unknown.In addition,it is controversial for the functional form of the glycoprotein hormone receptors,whether in monomer,dimer or trimer.Also,there are many natural mutations on glycoprotein hormone receptors with unknown diseaseoccurring mechanisms.Moreover,the mechanism of antibody-induced TSHR activation,which results in GD and GO,and the difference between the mechanism of TSH and antibody-mediated TSHR activation still remain to be elucidated.In this paper,we systematically studied the structure and function of glycoprotein hormones and their receptors.By analyzing the nine structures of the full-length LHCGR,FSHR,and TSHR in various activated and inactivated states,and the functional assays of mutated receptors,we revealed the detailed hormone-receptor interactions and the molecular basis of hormone specificity between CG,LH,FSH,and TSH and their corresponding receptors.We identified that glycoprotein hormone receptors can be monomers in a physiological state.We further proposed a universal model of hormone-induced glycoprotein hormone receptor activation,termed the "Push and Pull" model.We also revealed that the activing antibody activate TSHR through a collision push to rotate the TSHR ECD away from the membrane layer into the upright ECD position in the active TSHR structure.We also clarified the structural basis of how inactivating antibody inhibits TSHR activation by TSH.Finally,we clarified the molecular basis of three small molecule agonists interacting with their receptor TMDs to directly activate the receptors.These findings provide a comprehensive and profound understanding of the glycoprotein hormone system.These high-resolution structures help us address the long-standing scientific issues on the mechanisms of hormone specificity,hormone and antibody-induced receptor activation,the disease-associated receptor mutations,and the small molecule agonists interacting with receptors.In summary,these structures provide important basis and insights for the design and development of drugs targeting glycoprotein hormone receptors.