Trends in Biochemical Sciences
A molecular dissection of the glycoprotein hormone receptors
Section snippets
The recognition step
Three-dimensional structures are available for hCG and FSH 9, 10, 11, whereas for the ectodomains of the receptors, we are left with structural models covering only part of their structure (Figure 2a,b). These are based on the known 3D structure of proteins containing leucine-rich repeats (LRRs) 12, 13, 14. LRRs are 20–25-residue protein motifs consisting of a β strand and an α helix that are connected by a turn (Figure 2c). When assembled sequentially in a protein, the LRRs determine a
Activation of the serpentine region of GpHRs
As they belong to the rhodopsin-like GPCR family and display many of the cognate signatures in primary structure, the serpentine regions of GpHRs are likely to share common mechanisms of activation with rhodopsin [26]. Crystallographic data are only available for the inactive conformation of rhodopsin [26]. Nevertheless, molecular scenarios that are based on a panel of experimental approaches involving site-directed mutagenesis, cross-linking and molecular modeling have been proposed for the
Interaction between the ectodomain and the serpentine domain
The hypothesis that the ectodomain would exert an inhibitory effect on an inherently noisy rhodopsin-like serpentine domain is supported by early data showing that mild treatment of TSHr-expressing cells with trypsin causes partial activation of the receptor [46]. Definite demonstration of such an effect was made by Zhang et al. [47], who showed that activation of the TSHr is secondary to ‘beheading’ in N-terminal truncated mutants. However, careful comparison of the activity of truncated
Unexpected complications
According to an appealing evolutionary scenario, and fitting with the functional data analyzed, GpHRs would have evolved from two distinct genes: the first encoding a typical rhodopsin-like serpentine receptor, the second encoding multiple LRR domains involved in protein–protein interactions [50]. The ancestral gene encoding GpHR must be extremely old because a similar genomic organization is found in LGRs, members of which are already present in sea anemones [51]. All this points to a neat
Concluding remarks and future perspectives
It is remarkable that the study of spontaneous gain-of-function mutations has played a major part in our understanding of the structure–function relationships of the GpHRs, while simultaneously providing novel insight into the pathophysiology of a series of endocrine diseases. We believe, however, that we are close of having reached the limits of this approach and of its extension, site-directed mutagenesis. The challenge is now to acquire direct structural data and develop new strategies to
Acknowledgements
We thank our colleagues in the C6.136 laboratory who participated in the study. Supported by the Belgian State, Prime Minister's Office, Service for Sciences, Technology and Culture, and by grants from the Fonds de la Recherche en Sciences et Médecine, the Fonds National de la Recherche Scientifique, Association Recherche Biomédicale et Diagnostic, and BRAHMS Diagnostica. S.C. is a Research Associate at the Belgian Fonds National de la Recherche Scientifique.
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