Bifunctional hCG analogs adopt different conformations in LH and FSH receptor complexes.
Human reproduction requires specific interactions between follitropin (hFSH) and its receptor (FSHR) and between lutropin (hLH) or choriogonadotropin (hCG) and the lutropin receptor (LHR). Substitution of hFSH residues between hCG beta-subunit cysteines 11-12 creates a bifunctional analog that binds both receptors. To understand the basis of this observation, we used antibody probes to compare the conformations of bifunctional analogs before and after they were complexed with each receptor. Introduction of hFSH residues between cysteines 11-12 changed a distant conformation-sensitive region created by the juxtaposition of the subunit aminotermini. This region, found not to contact either receptor, was altered further when bifunctional ligands bound FSHR. All other surfaces, detected in LHR complexes, were also recognized in FSHR complexes, an indication that bifunctional ligands bind both receptors in similar orientations. These observations suggest that unlike hCG or hFSH, bifunctional gonadotropins can acquire "lutropin" and "follitropin" conformations, a phenomenon accentuated by receptor contacts.
Wang
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Y
Department of Obstetrics and Gynecology, Robert Wood Johnson (Rutgers) Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Bernard
M P
MP
Moyle
W R
WR
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D001665:Binding Sites; D006063:Chorionic Gonadotropin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018604:Epitope Mapping; D005640:Follicle Stimulating Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011962:Receptors, FSH / Q000378:metabolism*; D011974:Receptors, LH / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
D000911:Antibodies, Monoclonal; D006063:Chorionic Gonadotropin; D011962:Receptors, FSH; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; D005640:Follicle Stimulating Hormone