title: ER-bound steps in the biosynthesis of G protein-coupled receptors.
abstract: The polypeptide of a G protein-coupled receptor is inserted into the membrane of the endoplasmic reticulum while being translated and this process by itself may be sufficient to establish the proper receptor fold. X-ray structures reveal a common polypeptide topology with little variation in the alignment and orientation of the seven transmembrane segments, the proximal carboxyl terminus (C-tail) and parts of the extracellular loops. These define a structural core the stability of which probably represents a major criterion for the receptor to pass endoplasmic reticulum (ER) quality control; point mutations affecting the structure of the core have an extraordinary chance of causing receptor retention. In contrast, cytoplasmic loops 2 and 3 and the distal C-tail are poorly ordered at least in the absence of an interaction partner. Similarly, the amino terminal tail of rhodopsin-related receptors (but not of receptor subtypes where ligand binding requires a stable fold of the N-tail) is unlikely to establish a stable fold. These segments can cause ER retention when mutated to inappropriately expose hydrophobic peptide patches; to prevent protein aggregation chaperone molecules attach to them thus initiating selection for ER-associated degradation. It is less clear however if there are additional mechanisms to specifically survey the transmembrane core at the level of the lipid bilayer or if insufficient packing is detected due to misalignment of the cytoplasmic or extracellular face of the receptor.
authors.affiliation: Institute of Pharmacology, Centre for Physiology and Pharmacology, Medizinische Universität Wien, Vienna, Austria, christian.nanoff@meduniwien.ac.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Nanoff
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D043562:Receptors, G-Protein-Coupled