Glycoprotein hormone receptors( This press release is also available ...)

In this thesis of the University of the Basque Country we have aspired at understanding and further dissecting the molecular mechanism of activation of the Glycoprotein hormone receptors (GpHr), members of the G protein coupled receptor (GPCR) superfamily.

First, we have focused on a network of polar interactions among highly conserved residues within the transmembrane (TM) region. Combination of site-directed mutagenesis and molecular dynamics simulations applied to the thyrotropin receptor (TSHr) have allowed identification of the residue N7.49, belonging to the canonical NPxxY motif of TM 7, as a molecular control in the mechanism of TSHr activation. N7.49 appears to adopt two different conformations in the inactive and active states. The inactive conformation is maintained by interactions with residues T6.43 and D6.44 (GpHr specific residues, located at the bottom of TM 6). Mutations that disrupt these interactions result in constitutive receptor activation. Our data suggest that upon receptor activation N7.49 undergoes a conformational change and that it might interact with D2.50 and a charged residue not identified yet. Moreover, the conserved L2.46 of the (N/S)LxxxD motif also seems to play a significant role in restraining the receptor in the inactive state.

On the other hand, growing body of evidence indicates that the GPCRs function as oligo(di)mers. Therefore we have used the GpHr family as a model to study the possible functional consequences of this oligomerization process. We first demonstrated in recombinant living cells, with a combination of biophysical methodologies (BRET and HTRF/FRET), that the TSH and lutropin (LH/CG) receptors form homo- and heterodimers, via interactions involving, primarily, their heptahelical domains. The large hormone-binding ectodomains were not essential for dimerization but ad
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Contact: Garazi Andonegi
garazi@elhuyar.com
34-943-363-040
Elhuyar Fundazioa
16-Jan-2006