Asn441 plays a key role in folding and function of the Na +/I- symporter (NIS)

Wenjing Li, Juan Pablo Nicola, L. Mario Amzel, Nancy Carrasco

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


The Na+/I-symporter (NIS) is a plasma membrane glycoprotein that mediates active I-transport in the thyroid, the first step in the biosynthesis of the iodine-containing thyroid hormones T3 and T4. Several NIS mutants have been identified as a cause of congenital I-transport defect (ITD), and their investigation has yielded valuable mechanistic information on NIS. Here we report a thorough characterization of the ITD-causing NIS mutation in which the sixth intracellular loop residues 439-443 are missing. This mutant protein was intracellularly retained, incompletely glycosylated, and intrinsically inactive. Engineering 5 Ala at positions 439-443 partially recovered cell surface targeting and activity (15%). Strikingly, NIS with the sequence 439-AANAA-443, in which Asn was restored at position 441, was targeted to the plasma membrane and exhibited 95% the transport activity of WT NIS. Based on our NIS homology model, we propose that the side chain of N441, a residue conserved throughout most of the SLC5 family, interacts with the main chain amino group of G444, capping the α-helix of transmembrane segment XII and thus stabilizing the structure of the molecule. Our data provide insight into a critical interhelical interaction required for NIS folding and activity.

Original languageEnglish (US)
Pages (from-to)3229-3238
Number of pages10
JournalFASEB Journal
Issue number8
StatePublished - Aug 2013
Externally publishedYes


  • Congenital hypothyroidism
  • Helix capping
  • Interhelical interaction
  • Plasma membrane targeting
  • Protein folding

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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