Specific ligands as pharmacological chaperones: The transport of misfolded G-protein coupled receptors to the cell surface.
In the endoplasmic reticulum (ER), quality control mechanisms distinguish between correctly and incorrectly folded structures to ensure that aberrant proteins are not processed along the secretory pathway. Numerous studies have demonstrated the functional rescue of ER-retained, aberrant proteins by small membrane permeable molecules called pharmacological chaperones. Pharmacological chaperones can bind to misfolded proteins, including G-protein coupled receptors (GPCRs), and promote their correct folding and export from the ER. Recently, common structural features of GPCRs have been uncovered, including the eighth helical domain in the C-terminal tail and conserved residues in the transmembrane domains. However, little is known about the importance of these features in signaling and intracellular trafficking, because receptors deficient in these domains are likely retained in the ER due to misfolding. In this review, we summarize the current knowledge about the requirement of these consensus domains and amino acid residues for the passing through the quality control of the ER. Furthermore, we propose the utilization of membrane permeable ligands for the transport of their cognate, ER-retained GPCRs to the cell surface. The chaperone activity of these ligands allows us to perform functional analyses of the structure-deficient receptors after their trafficking to the cell surface.
Nakamura
Motonao
M
Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Tokyo, Japan. moto-nakamura@umin.net
Yasuda
Daisuke
D
Hirota
Nobuaki
N
Shimizu
Takao
T
D000595:Amino Acid Sequence; D000818:Animals; D002626:Chemistry, Pharmaceutical; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D018832:Molecular Chaperones; D043562:Receptors, G-Protein-Coupled