ABSTRACT
Eukaryotic membrane proteins are prone to misfolding and degradation within the endoplasmic reticulum (ER). This is particularly true for the mammalian forms of the gonadotropin-releasing hormone receptor (GnRHR). Though they function at the plasma membrane, mammalian GnRHRs tend to accumulate within the secretory pathway. Their apparent instability is believed to have evolved in response to a selection for GnRHRs with attenuated activity. Nevertheless, the structural basis of this adaptation remains unclear. An experimental characterization of natural GnRHRs reveals this adaptation coincides with a C-terminal truncation and an increase in the polarity of its transmembrane (TM) domains. We show that this enhanced polarity compromises the translocon-mediated cotranslational folding of two nascent TM domains. Moreover, replacing a conserved polar residue in TM6 with an ancestral hydrophobic residue partially restores GnRHR expression with minimal impact on function. Our findings suggest the marginal energetics of cotranslational folding can be exploited to tune membrane protein fitness.
