The molecular landscape of G protein signaling through the human luteinizing hormone receptor
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The molecular mechanism employed by the human luteinizing hormone receptor (hLHR), a G protein coupled receptor (GPCR) necessary for fertility and reproduction, to couple to its cognate signaling partner, the stimulatory G protein (Gs), remains undefined. GPCRs constitute the largest gene family in the human genome (~800-900 genes) yet signal through only a few isoforms of heterotrimeric G proteins. Thus, in general, the translation of activation from GPCR to G protein may exhibit conserved elements that include common points of contact for receptors that activate the same G protein, but unique determinants of the coupling mechanism must define the signaling specificity for each GPCR/G protein pair. This concept challenges the entrenched paradigm of GPCR signaling that was established after experiments with only a few receptor systems. To probe the molecular landscape of hLHR/Gs signaling, the impact of engineered mutations within the extreme C-terminus (CT) of Gs, an area hypothesized as necessary for GPCR/G protein coupling, was tested in a newly-created hLHR+/Gs- model cell system. For comparative purposes, parallel studies were also conducted with the naturally expressed β2-adrenergic receptor (β2-AR), a well characterized GPCR. This work initiated the exploration of the Gs contribution to the hLHR and β2-AR signaling interfaces, exposed amino acid residues within the CT of Gs that are critical for signal transduction, and characterized these findings within a preliminary mechanism of hLHR/Gs coupling. In addition, these results support the hypothesis that the network of interactions that define GPCR/G protein coupling is distinctive for each singular relationship. The physiochemical nature of hLHR limited attempts to further characterize its signaling properties, additionally suggesting that although this homologous family of proteins evolved within a structural constraint to maintain signaling integrity, traits of the individual GPCR may have diverged significantly from those of its cohort. The pharmacological relevance of this work thus extends beyond the potential design of drugs that more precisely treat abnormalities of hLHR signaling to prompt the pharmaceutical industry to target the GPCR/G protein interface as a viable, and perhaps preferred, candidate for drug development to improve the specificity of engineered therapeutics.