hCG beta residues 94-96 alter LH activity without appearing to make key receptor contacts.
The ability of human chorionic gonadotropin (hCG) to distinguish lutropin (LHR) and follitropin (FSHR) receptors is controlled principally by beta-subunit residues 94-117. To learn how residues 94-96 (Arg-Arg-Ser) influence LHR binding, we studied the effects of replacing them on the LH and FSH activities of a bifunctional hCG analog in which residues 101-109 were derived from FSH. Analogs containing 1-3 arginines and no aspartates at residues 94-96 bound LHR with 25-400% the potency of hCG. When residues 94-96 were neutral or contained 1-3 aspartates, LHR binding was reduced 6-100 fold but remained at least ten-fold greater than the negative control analog containing residues 94-117 derived from FSH. Residues 94-96 had little influence on FSHR binding. These observations support a model [Moyle et al. (1995) J. Biol. Chem. 270:20,020] in which residues 94-96 influence LHR binding specificity primarily through an effect on hormone conformation rather than by direct participation in essential high affinity receptor contacts.
Han
Y
Y
Department of OBGYN, Robert Wood Johnson (Rutgers) Medical School, Piscataway, NJ 08854, USA.
Bernard
M P
MP
Moyle
W R
WR
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000031:analogs & derivatives / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D005640:Follicle Stimulating Hormone; D037201:Follicle Stimulating Hormone, beta Subunit; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011487:Protein Conformation; D051381:Rats; D011962:Receptors, FSH / Q000378:metabolism; D011974:Receptors, LH / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology
D018997:Chorionic Gonadotropin, beta Subunit, Human; D037201:Follicle Stimulating Hormone, beta Subunit; D011962:Receptors, FSH; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; D005640:Follicle Stimulating Hormone