The human lutropin (hLH)/choriogonadotropin (hCG) receptor (LHCGR) can be
activated by binding two slightly different gonadotropic glycoprotein
hormones, choriogonadotropin (CG) – secreted by the placenta, and lutropin
(LH) – produced by the pituitary. They induce different signaling profiles at
the LHCGR. This cannot be explained by binding to the receptor’s leucine-rich-
repeat domain (LRRD), as this binding is similar for the two hormones. We
therefore speculate that there are previously unknown differences in the
hormone/receptor interaction at the extracellular hinge region, which might
help to understand functional differences between the two hormones. We have
therefore performed a detailed study of the binding and action of LH and CG at
the LHCGR hinge region. We focused on a primate-specific additional exon in
the hinge region, which is located between LRRD and the serpentine domain. The
segment of the hinge region encoded by exon10 was previously reported to be
only relevant to hLH signaling, as the exon10-deletion receptor exhibits
decreased hLH signaling, but unchanged hCG signaling. We designed an advanced
homology model of the hormone/LHCGR complex, followed by experimental
characterization of relevant fragments in the hinge region. In addition, we
examined predictions of a helical exon10-encoded conformation by block-wise
polyalanine (helix supporting) mutations. These helix preserving modifications
showed no effect on hormone-induced signaling. However, introduction of a
structure-disturbing double-proline mutant LHCGR-Q303P/E305P within the
exon10-helix has, in contrast to exon10-deletion, no impact on hLH, but only
on hCG signaling. This opposite effect on signaling by hLH and hCG can be
explained by distinct sites of hormone interaction in the hinge region. In
conclusion, our analysis provides details of the differences between hLH- and
hCG-induced signaling that are mainly determined in the L2-beta loop of the
hormones and in the hinge region of the receptor