The sequence after the signal peptide of the g protein-coupled endothelin B receptor is required for efficient translocon gating at the endoplasmic reticulum membrane

Item Type:	Article
Title:	The sequence after the signal peptide of the g protein-coupled endothelin B receptor is required for efficient translocon gating at the endoplasmic reticulum membrane
Creators Name:	Alken, M. and Schmidt, A. and Rutz, C. and Furkert, J. and Kleinau, G. and Rosenthal, W. and Schuelein, R.
Abstract:	The heptahelical G protein-coupled receptors (GPCRs) must reach their correct subcellular location to exert their function. Receptor domains relevant for receptor trafficking include signal sequences mediating receptor integration into the membrane of the endoplasmic reticulum (ER) and anterograde or retrograde transport signals promoting receptor sorting into the vesicles of the secretory pathway. In addition, receptors must be correctly folded to pass the quality control system of the early secretory pathway. Taking the endothelin B receptor as a model, we describe a new type of a transport-relevant GPCR domain. Deletion of this domain (residues Glu(28) to Trp(54)) leads to a fully functional receptor protein that is expressed at a lower level than the wild-type receptor. Subcellular localization experiments and glycosylation state analyses demonstrate that the mutant receptor is neither misfolded, retained intracellularly, nor misrouted. Fluorescence recovery after photobleaching analyses demonstrate that constitutive internalization is also not affected. By using an in vitro prion protein targeting assay, we show that this domain is necessary for efficient translocon gating at the ER membrane during early receptor biogenesis. Taken together, we identified a novel transport-relevant domain in the GPCR protein family. Our data may also be relevant for other GPCRs and unrelated integral membrane proteins.
Keywords:	Amino Acid Sequence, Calcium-Binding Proteins, Cell Line, Endoplasmic Reticulum, Ion Channel Gating, Membrane Glycoproteins, Membrane Proteins, Molecular Sequence Data, Peptide Fragments, Protein Binding, Protein Sorting Signals, Endothelin B Receptor, Cytoplasmic and Nuclear Receptors, Peptide Receptors
Source:	Molecular Pharmacology
ISSN:	0026-895X
Publisher:	American Society for Pharmacology and Experimental Therapeutics
Volume:	75
Number:	4
Page Range:	801-811
Date:	April 2009
Official Publication:	https://doi.org/10.1124/mol.108.051581
PubMed:	View item in PubMed

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