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Protein Folding as Posttranslational Regulation: Evolution of a Mechanism for Controlled Plasma Membrane Expression of a G Protein-Coupled Receptor

Divisions of Neuroscience and Reproductive Biology (P.M.C., P.E.K., S.P.B., J.A.J.), Oregon National Primate Research Center and Departments of Physiology and Pharmacology (P.M.C., S.P.B.) and Cell and Developmental Biology (P.M.C.), Oregon Health and Science University, Beaverton, Oregon 97006

Address all correspondence and requests for reprints to: P. Michael Conn, Oregon National Primate Research Center/Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon, 97006. E-mail: connm{at}ohsu.edu.

Recent studies reveal that a number of G protein-coupled receptors (GPCRs) and other proteins are expressed inefficiently at the site normally associated with their biological action. In the case of some GPCRs, large amounts of receptor (perhaps more than half) may be destroyed without ever binding ligand or even arriving at the plasma membrane. For the human GnRH receptor (GnRHR), this apparent inefficiency has evolved under strong and convergent evolutionary pressure. The result is a human GnRHR molecule that is delicately balanced between either expression at the plasma membrane (PM) or retention/degradation in the endoplasmic reticulum, an effect mediated by engagement with the cellular quality control system. This balance appears to be the reason that the human receptor, but not the rat or mouse counterpart (which are more robustly routed to the PM), is highly susceptible to single-point mutations that result in disease. A single change in net charge is sufficient to tip the balance in favor of the endoplasmic reticulum and diminish GnRHR available at the PM. The apparent paradox that results from observing convergent pressure for evolution of a receptor that is both inefficiently produced and highly susceptible to mutational disease suggests that this approach must offer a strong advantage. This review focuses on the evolved mechanisms and considers that this is an underappreciated mechanism by which the cell controls functional levels of receptors and other proteins at the posttranslational level.

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