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Significance Odor detection in mammals depends on the largest family of G protein-coupled receptors, the odorant receptors, which represent ∼2% of our protein-coding genes. The vast majority of odorant receptors are trapped within the cell when expressed in nonolfactory cells. The underlying causes of why odorant receptors cannot be functionally expressed in nonolfactory cells have remained enigmatic for over 20 years. Our study points to divergence from a consensus sequence as a key factor in a receptor’s inability to function in nonolfactory cells, which, in turn, helps explain odorant receptors’ exceptional functional diversity and rapid evolution. We also show the success of protein engineering strategies for promoting odorant receptor cell surface expression.

Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors