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J. Biol. Chem., Vol. 282, Issue 35, 25290-25298, August 31, 2007

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Amino Acid Residues in Transmembrane Segment IX of the Na⁺/I^– Symporter Play a Role in Its Na⁺ Dependence and Are Critical for Transport Activity^*

From the Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

The Na⁺/I^– symporter (NIS) is a key plasma membrane glycoprotein that mediates Na⁺-dependent active I^– transport in the thyroid, lactating breast, and other tissues. The OH group of the side chain at position 354 in transmembrane segment (TMS) IX of NIS has been demonstrated to be essential for NIS function, as revealed by the study of the congenital I^– transport defect-causing T354P NIS mutation. TMS IX has the most -OH group-containing amino acids (Ser and Thr) of any TMS in NIS. We have thoroughly characterized the functional significance of all Ser and Thr in TMS IX in NIS, as well as of other residues in TMS IX that are highly conserved in other transporters of the SLC5A protein family. Here we show that five -OH group-containing residues (Thr-351, Ser-353, Thr-354, Ser-356, and Thr-357) and Asn-360, all of which putatively face the same side of the helix in TMS IX, plus Asp-369, located in the membrane/cytosol interface, play key roles in NIS function and seem to be involved in Na⁺ binding/translocation.

Received for publication, January 5, 2007 , and in revised form, June 25, 2007.

^* This work was supported in part by National Institutes of Health Grants DK41544 and CA098390 (to N. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by Ministry of Education and Culture (Ministerio de Educación y Cultura) of Spain Grant PF 97 52094152. Present address: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC), C/Arturo Duperier, 4. 28029 Madrid, Spain 28029.

² Supported by National Institutes of Health Grant 5T32 GM 07491 and a supplement of Grant CA098390.

³ Present address: Dept. of Physiology and Biophysics, Cornell Weill Medical College, New York, NY 10021.

⁴ To whom correspondence should be addressed: Albert Einstein College of Medicine, Dept. of Molecular Pharmacology, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-3523; Fax: 718-430-8922; E-mail: carrasco{at}aecom.yu.edu.

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