Modulation of high affinity hormone binding. Human choriogonadotropin binding to the exodomain of the receptor is influenced by exoloop 2 of the receptor.
The lutropin/choriogonadotropin receptor is a seven-transmembrane receptor and consists of two major domains of similar size, an extracellular exodomain and a membrane-associated endodomain which includes 3 exoloops. The uniquely large exodomain is responsible for high affinity hormone binding whereas receptor activation occurs at the endodomain. However, little is known about the relationship between the exodomain and endodomain. It was reported that hormone binding to the exodomain was improved when the endodomain was truncated. This result suggests that hormone binding to the exodomain was influenced by the endodomain. To test this hypothesis, amino acids of exoloop 2 were examined by Ala substitutions. The binding affinity was enhanced by some Ala substitutions but attenuated by others. These results indicate that exoloop 2 influences the hormone binding to the exodomain. Particularly, the high affinity hormone binding at the exodomain is constrained by a group of amino acids, Ser484, Asn485, Lys488, Ser490, and Ser499. Computer modeling suggests these residues may be positioned on one side of exoloop 2. It also influences the affinity for cAMP induction and the maximal cAMP production in distinct ways, in addition to its influence on the hormone binding affinity. The distinct ways of influencing these functions are sometimes in conflict and compromised to attain the maximal affinity for cAMP induction. As a result, the exodomain attains the maximal affinity for hormone binding when the endodomain is truncated and cAMP induction is disengaged.
Ryu
K
K
Department of Molecular Biology, University of Wyoming, Laramie, Wyoming 82071-3944, USA.
Lee
H
H
Kim
S
S
Beauchamp
J
J
Tung
C S
CS
Isaacs
N W
NW
Ji
I
I
Ji
T H
TH
D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011974:Receptors, LH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
D006063:Chorionic Gonadotropin; D010446:Peptide Fragments; D011974:Receptors, LH; D011994:Recombinant Proteins; D000242:Cyclic AMP