The hinge region of the lutropin receptor mediates different activation mechanisms: CG induces trans- and LH only cis-initialization

Paul Grzesik; Annika Kreuchwig; Anke Teichmann; Jens Furkert; Claudia Rutz; Burghard Wiesner; Gunnar Kleinau; Ralf Schulein; Jorg Gromoll; Gerd Krause

doi:10.1530/endoabs.32.P577

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Endocrine Abstracts (2013) 32 P577 | DOI: 10.1530/endoabs.32.P577

ECE2013 Poster Presentations Female reproduction (47 abstracts)

The hinge region of the lutropin receptor mediates different activation mechanisms: CG induces trans- and LH only cis-initialization

Paul Grzesik ¹ , Annika Kreuchwig ¹ , Anke Teichmann ¹ , Jens Furkert ¹ , Claudia Rutz ¹ , Burghard Wiesner ¹ , Gunnar Kleinau ³ , Ralf Schülein ¹ , Jörg Gromoll ² & Gerd Krause ¹

Err

Author affiliations

¹Leibniz Institut für molekulare Pharmakologie (FMP), Berlin, Germany, ²Reproduktionsmedizin und Andrologie, Universität Münster, Münster, Germany, ³Charite-Berlin, Berlin, Germany.

The lutropin receptor (LHR) is associated with reproduction and becomes activated by choriogonadotropin (CG) or lutropin (LH) resulting in different physiological functions with regard to differing signaling cascades. The underlying mechanisms in receptor/hormone interaction are not yet understood. CG is known to induce trans-activation at LHR oligomers (activates a second receptor), but details of LH mechanisms were not clarified yet.

To study this issue, we here used the LHR variant lacking exon 10 (hLHR-delEx10) encoding 27 residues of the extracellular hinge region, because it was previously reported that in contrast to CG, LH-induced cAMP accumulation is decreased at hLHR-delEx10. We, therefore, hypothesised a potential relation between the hinge region and differentially initialized signal induction by the hormone subtypes.

Since coexpression of binding- and signaling-deficient LHR mutants can restore CG-induced function, we assumed that CG maintains full signaling capacity at hLHR-delEx10 by trans-activation, while the lack of exon 10 might disturb trans-activation of hLH. Thus, we coexpressed the hLHR-delEx10 and the hLHR Lys605Glu mutant – in which signaling is abolished – with the binding-deficient mutant hLHR-C131R. In contrast to CG, LH only activates LHR via cis- (bound protomer), but not via trans-activation.

Structure predictions and advanced structural models suggest that exon 10 encoded and consecutive residues likely form two helical elements. In accordance to this, block-wise poly-alanine (structure preserving) mutations within this region showed no effect on signaling. Surprisingly, the structure disturbing double-proline mutant LHR-303P/305P within exon 10 has – in contrast to hLHR-delExon10 – no impact on hLH, but on hCG signaling, while a single proline mutation after exon 10 showed wild type-like functions.

In conclusion, our complementary structural and functional insights support that the structure of exon 10 encoded and proximate residues of LHR function as spacer elements interacting differently with LH and CG by mediating distinct cis- and trans- initialization of hLHR signaling dependent on the hormone subtype.