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First published online 20 January 2004
doi: 10.1242/jcs.00898
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Research Article |
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
* Author for correspondence (e-mail: carrasco{at}aecom.yu.edu)
Accepted 19 September 2003
The Na+/I- symporter (NIS) is a key plasma membrane glycoprotein that mediates active iodide (I-) transport in the thyroid and other tissues. Since isolation of the cDNA encoding NIS (G. Dai, O. Levy, and N. Carrasco (1996) Nature 379, 458-460), ten mutations in NIS have been identified as causes of congenital iodide transport defect (ITD). Two of these mutations (T354P and G395R) have been thoroughly characterized at the molecular level. Both mutant NIS proteins are inactive but normally expressed and correctly targeted to the plasma membrane. The hydroxyl group at the ß-carbon of residue 354 is essential for NIS function, whereas the presence of a charged or large side-chain at position 395 interferes with NIS function. We report the extensive molecular analysis of the Q267E mutation in COS-7 cells transfected with rat or human Q267E NIS cDNA constructs. We used site-directed mutagenesis to engineer various residue substitutions into position 267. In contrast to previous suggestions that Q267E NIS was inactive, possibly because of a trafficking defect, we conclusively show that Q267E NIS is modestly active and properly targeted to the plasma membrane. Q267E NIS exhibited lower Vmax values for I- than wild-type NIS, suggesting that the decreased level of activity of Q267E NIS is due to a lower catalytic rate. That Q267E NIS retains even partial activity sets this ITD-causing mutant apart from T354P and G395R NIS. The presence of charged residues (of any polarity) other than Glu at position 267 rendered NIS inactive without affecting its expression or targeting, but substitution with neutral residues at this position was compatible with partial activity.
Key words: NIS (sodium/iodide symporter), ITD (iodide transport defect), Thyroid, Membrane proteins
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