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ORIGINAL ARTICLE

Subtype-Specific Sorting of the ET_A Endothelin Receptor by a Novel Endocytic Recycling Signal for G Protein-Coupled Receptors

MSD Cardiovascular Research Center and Institute for Surgical Research, Rikshospitalet University Hospital, University of Oslo, Norway (J.D.P., T.A., H.K.J., H.A.); Institute of Pathology, Rikshospitalet University Hospital, University of Oslo, Norway (M.P.O., H.S.H.); and Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Norway (K.K., S.G.D.)

Abstract

We have previously reported that endocytic sorting of ET_A endothelin receptors to the recycling pathway is dependent on a signal residing in the cytoplasmic carboxyl-terminal region. The aim of the present work was to characterize the carboxyl-terminal recycling motif of the ET_A receptor. Assay of truncation mutants of the ET_A receptor with increasing deletions of the carboxyl-terminal tail revealed that amino acids 390 to 406 contained information critical for the ability of the receptor to recycle. This peptide sequence displayed significant sequence similarity to several protein segments confirmed by X-ray crystallography to adopt antiparallel -strand structures (-finger). One of these segments was the -finger motif of neuronal nitric-oxide synthase reported to function as an internal PDZ (postsynaptic density-95/disc-large/zona occludens) domain-binding ligand. Based on these findings, the three-dimensional structure of the recycling motif of ET_A receptor was predicted to attain a -finger conformation acting as an internal PDZ ligand. Site-directed mutagenesis at residues that would be crucial to the structural integrity of the putative -finger conformation or PDZ ligand function prevented recycling of the ET_A receptor. Analysis of more than 300 G protein-coupled receptors (GPCRs) identified 35 different human GPCRs with carboxylterminal sequence patterns that fulfilled the structural criteria of an internal PDZ ligand. Among these are several receptors reported to follow a recycling pathway. In conclusion, recycling of ET_A receptor is mediated by a motif with the structural characteristics of an internal PDZ ligand. This structural motif may represent a more general principle of endocytic sorting of GPCRs.

Address correspondence to: Dr. Håvard Attramadal, Institute for Surgical Research, A3.1013, Rikshospitalet University Hospital, Sognsvannsveien 20, N-0027 Oslo, Norway. E-mail: havard.attramadal{at}medisin.uio.no

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