title: Influence of subunit interactions on lutropin specificity. Implications for studies of glycoprotein hormone function.
abstract: Bovine lutropin (bLH) and human chorionic gonadotropin (hCG) are heterodimeric glycoprotein hormones required for reproduction. Both bind rat LH receptors (rLHRs), but hCG binds human LH receptors (hLHRs) 1000-10,000 fold better than bLH. We tested the premise that this difference in affinity could be used to identify lutropin receptor contacts. Heterodimers containing hCG/bLH alpha- or beta-subunit chimeras that bound hLHR like hCG (or bLH) were expected to have hCG (or bLH) residues at the receptor contact sites. Analogs containing one subunit derived from hCG bound hLHR much more like hCG than bLH, indicating that each bLH subunit contains all the residues sufficient for high affinity hLHR binding. Indeed, the presence of bovine alpha-subunit residues increased the activities of some hCG analogs. The low hLHR activity of bLH was due primarily to an interaction between its alpha-subunit and beta-subunit residue Leu95. Leu95 does not appear to contact the hLHR since it did not influence the hLHR activity of heterodimers containing human alpha-subunit. These observations show that interactions within and between the subunits can significantly influence the activities of lutropins, thereby confounding efforts to identify ligand residues that contact these receptors.
authors.affiliation: Department of Obstetrics and Gynecology, Robert Wood Johnson (Rutgers) Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cosowsky
authors.forename: W
authors.initials: W
authors.lastname: Lin
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.forename: M P
authors.initials: MP
authors.lastname: Bernard
authors.forename: R K
authors.initials: RK
authors.lastname: Campbell
authors.forename: W R
authors.initials: WR
authors.lastname: Moyle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002417:Cattle; D006063:Chorionic Gonadotropin / Q000737:chemistry; D006801:Humans; D007986:Luteinizing Hormone / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D006063:Chorionic Gonadotropin; D007986:Luteinizing Hormone