Molecular basis for the evolved instability of a human G-protein coupled receptor

Membrane proteins are prone to misfolding and degradation. This is
particularly true for mammalian forms of the gonadotropin-releasing
hormone receptor (GnRHR). Although they function at the plasma membrane,
mammalian GnRHRs accumulate within the secretory pathway. Their apparent
instability is believed to have evolved through selection for attenuated
GnRHR activity. Nevertheless, the molecular basis of this adaptation
remains unclear. We show that adaptation coincides with a C-terminal
truncation that compromises the translocon-mediated membrane integration
of its seventh transmembrane domain (TM7). We also identify a series of
polar residues in mammalian GnRHRs that compromise the membrane
integration of TM2 and TM6. Reverting a lipid-exposed polar residue in TM6
to an ancestral hydrophobic residue restores expression with no impact on
function. Evolutionary trends suggest variations in the polarity of this
residue track with reproductive phenotypes. Our findings suggest that the
marginal energetics of cotranslational folding can be exploited to tune
membrane protein fitness.