title: A systematic evaluation of sorting motifs in the sodium-iodide symporter (NIS).
abstract: The sodium-iodide symporter (NIS) is an integral membrane protein that plays a crucial role in iodide accumulation, especially in the thyroid. As for many other membrane proteins, its intracellular sorting and distribution have a tremendous effect on its function, and constitute an important aspect of its regulation. Many short sequences have been shown to contribute to protein trafficking along the sorting or endocytic pathways. Using bioinformatics tools, we identified such potential sites on human NIS [tyrosine-based motifs, SH2-(Src homology 2), SH3- and PDZ (post-synaptic density-95/discs large tumour suppressor/zonula occludens-1)-binding motifs, and diacidic, dibasic and dileucine motifs] and analysed their roles using mutagenesis. We found that several of these sites play a role in protein stability and/or targeting to the membrane. Aside from the mutation at position 178 (SH2 plus tyrosine-based motif) that affects iodide uptake, the most drastic effect is associated with the mutation of an internal PDZ-binding motif at position 121 that completely abolishes NIS expression at the plasma membrane. Mutating the sites located on the C-terminal domain of the protein has no effect except for the creation of a diacidic motif that decreases the total NIS protein level without affecting its expression at the plasma membrane.
authors.affiliation: Laboratoire TIRO, CEA, iBEB, SBTN, centre de Marcoule, 30207 Bagnols sur Cèze, France elisabeth.darrouzet@cea.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Darrouzet
authors.affiliation: Laboratoire TIRO, CEA, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France Laboratoire TIRO, Université de Nice Sophia Antipolis, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06100 Nice, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Graslin
authors.affiliation: Laboratoire TIRO, CEA, iBEB, SBTN, centre de Marcoule, 30207 Bagnols sur Cèze, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Marcellin
authors.affiliation: Laboratoire TIRO, CEA, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France Laboratoire TIRO, Université de Nice Sophia Antipolis, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France.
authors.forename: Iulia
authors.initials: I
authors.lastname: Tcheremisinova
authors.affiliation: Laboratoire LI2D, CEA, iBiTECS, SPI, centre de Marcoule, 30207 Bagnols sur Cèze, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Marchetti
authors.affiliation: Laboratoire TIRO, CEA, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France Laboratoire TIRO, Université de Nice Sophia Antipolis, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France.
authors.forename: Lisa
authors.initials: L
authors.lastname: Salleron
authors.affiliation: Laboratoire TIRO, CEA, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France Laboratoire TIRO, Université de Nice Sophia Antipolis, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France CNRS, Délégation Côte d'Azur, 250 rue Albert Einstein, 06905 Sophia Antipolis, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pognonec
authors.affiliation: Laboratoire TIRO, CEA, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France Laboratoire TIRO, Université de Nice Sophia Antipolis, Faculté de médecine, 28 Avenue de Valombrose, 06107 Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pourcher
mesh_terms: D020816:Amino Acid Motifs; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D054731:PDZ Domains; D021381:Protein Transport / Q000502:physiology; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains; D000099209:Sodium-Iodide Symporters
chemical_list: D027981:Symporters; D000099209:Sodium-Iodide Symporters
keywords: NIS; PDZ-binding motif; SLC5A5; protein trafficking; sodium–iodide symporter; thyroid