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(Received for publication, April 17, 1995; and in revised form, May 12, 1995)
The goal of these studies was to devise a model that explains
how human chorionic gonadotropin (hCG) interacts with lutropin (LH)
receptors to elicit a hormone signal. Here we show that 
-subunit
residues near the N terminus, the exposed surface of the cysteine knot,
and portions of the first and third loops most distant from the
-subunit interface were recognized by antibodies that bound to
hCG-receptor complexes. These observations were combined with similar
data obtained for the -subunit (Cosowsky, L., Rao, S. N. V.,
Macdonald, G. J., Papkoff, H., Campbell, R. K., and Moyle, W. R.(1995) J. Biol. Chem. 270, 20011-20019), information on
residues of hCG that can be changed without disrupting hormone
function, the crystal structure of deglycosylated hCG, and the crystal
structure of a leucine-repeat protein to devise a model of hCG-receptor
interaction. This model suggests that the extracellular domain of the
LH receptor is ``U-'' or ``J''-shaped and makes
several contacts with the transmembrane domain. High affinity hormone
binding results from interactions between residues in the curved
portion of the extracellular domain of the receptor and the groove in
the hormone formed by the apposition of the second -subunit loop
and the first and third -subunit loops. Most of the remainder of
the hormone is found in the large space between the arms of the
extracellular domain and makes few, if any, additional specific
contacts with the receptor needed for high affinity binding. Signal
transduction is caused by steric or other influences of the hormone on
the distance between the arms of the extracellular domain, an effect
augmented by the oligosaccharides. Because the extracellular domain is
coupled at multiple sites to the transmembrane domain, the change in
conformation of the extracellular domain is relayed to the
transmembrane domain and subsequently to the cytoplasmic surface of the
plasma membrane. While the model does not require the hormone to
contact the transmembrane domain to initiate signal transduction, small
portions of both subunits may be near the transmembrane domain and
assist in initiating the hormonal signal. This is the first model that
is consistent with all known information on the activity of the
gonadotropins including the amounts of the hormone that are exposed in
the hormone-receptor complex, the apparent lack of specific contacts
between much of the hormone and the receptor, and the roles of the
oligosaccharides in signal transduction. This model differs from
existing models of hormone action in that the extracellular domain has
a much larger role in hormone action than serving as a high affinity
hormone trap.
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H. Zeng, T. Phang, Y. S. Song, I. Ji, and T. H. Ji The Role of the Hinge Region of the Luteinizing Hormone Receptor in Hormone Interaction and Signal Generation J. Biol. Chem., January 26, 2001; 276(5): 3451 - 3458. [Abstract] [Full Text] [PDF]
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A. Schmidt, R. MacColl, B. Lindau-Shepard, D. R. Buckler, and J. A. Dias Hormone-induced Conformational Change of the Purified Soluble Hormone Binding Domain of Follitropin Receptor Complexed with Single Chain Follitropin J. Biol. Chem., June 22, 2001; 276(26): 23373 - 23381. [Abstract] [Full Text] [PDF]
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S. D. Mahale, J. Cavanagh, A. Schmidt, R. MacColl, and J. A. Dias Autologous Biological Response Modification of the Gonadotropin Receptor J. Biol. Chem., April 6, 2001; 276(15): 12410 - 12419. [Abstract] [Full Text] [PDF]
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