Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region
The human lutropin/choriogonadotropin 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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-09-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fendo.2015.00140/full |
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| author | Paul eGrzesik Annika eKreuchwig Claudia eRutz Jens eFurkert Burkhard eWiesner Ralf eSchülein Gunnar eKleinau Joerg eGromoll Gerd eKrause |
| author_facet | Paul eGrzesik Annika eKreuchwig Claudia eRutz Jens eFurkert Burkhard eWiesner Ralf eSchülein Gunnar eKleinau Joerg eGromoll Gerd eKrause |
| author_sort | Paul eGrzesik |
| collection | DOAJ |
| description | The human lutropin/choriogonadotropin 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 s. 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 |
| first_indexed | 2024-04-12T11:36:09Z |
| format | Article |
| id | doaj.art-3338222b162a4cf5b00dc7c50edb7ff0 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-12T11:36:09Z |
| publishDate | 2015-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-3338222b162a4cf5b00dc7c50edb7ff02022-12-22T03:34:49ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922015-09-01610.3389/fendo.2015.00140153392Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge regionPaul eGrzesik0Annika eKreuchwig1Claudia eRutz2Jens eFurkert3Burkhard eWiesner4Ralf eSchülein5Gunnar eKleinau6Joerg eGromoll7Gerd eKrause8Leibniz Institut fuer molekuare Pharmakologie (FMP) Berlin, GermanyLeibniz Institut fuer molekuare Pharmakologie (FMP) Berlin, GermanyLeibniz Institut fuer molekuare Pharmakologie (FMP) Berlin, GermanyLeibniz Institut fuer molekuare Pharmakologie (FMP) Berlin, GermanyLeibniz Institut fuer molekuare Pharmakologie (FMP) Berlin, GermanyLeibniz Institut fuer molekuare Pharmakologie (FMP) Berlin, GermanyCharite Universitätsmedizin, BerlinUniversity Hospital MuensterLeibniz Institut fuer molekuare Pharmakologie (FMP) Berlin, GermanyThe human lutropin/choriogonadotropin 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 s. 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 receptorhttp://journal.frontiersin.org/Journal/10.3389/fendo.2015.00140/fullGPCR ActivationchoriogonadotropinlutropinLutropin receptorGlycoprotein hormone receptors |
| spellingShingle | Paul eGrzesik Annika eKreuchwig Claudia eRutz Jens eFurkert Burkhard eWiesner Ralf eSchülein Gunnar eKleinau Joerg eGromoll Gerd eKrause Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region Frontiers in Endocrinology GPCR Activation choriogonadotropin lutropin Lutropin receptor Glycoprotein hormone receptors |
| title | Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region |
| title_full | Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region |
| title_fullStr | Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region |
| title_full_unstemmed | Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region |
| title_short | Differences in signal activation by LH and hCG are mediated by the LH/CG receptor`s extracellular hinge region |
| title_sort | differences in signal activation by lh and hcg are mediated by the lh cg receptor s extracellular hinge region |
| topic | GPCR Activation choriogonadotropin lutropin Lutropin receptor Glycoprotein hormone receptors |
| url | http://journal.frontiersin.org/Journal/10.3389/fendo.2015.00140/full |
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