Na+ coordination at the Na2 site of the Na+/I- symporter

Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5379-88. doi: 10.1073/pnas.1607231113. Epub 2016 Aug 25.


The sodium/iodide symporter (NIS) mediates active I(-) transport in the thyroid-the first step in thyroid hormone biosynthesis-with a 2 Na(+): 1 I(-) stoichiometry. The two Na(+) binding sites (Na1 and Na2) and the I(-) binding site interact allosterically: when Na(+) binds to a Na(+) site, the affinity of NIS for the other Na(+) and for I(-) increases significantly. In all Na(+)-dependent transporters with the same fold as NIS, the side chains of two residues, S353 and T354 (NIS numbering), were identified as the Na(+) ligands at Na2. To understand the cooperativity between the substrates, we investigated the coordination at the Na2 site. We determined that four other residues-S66, D191, Q194, and Q263-are also involved in Na(+) coordination at this site. Experiments in whole cells demonstrated that these four residues participate in transport by NIS: mutations at these positions result in proteins that, although expressed at the plasma membrane, transport little or no I(-) These residues are conserved throughout the entire SLC5 family, to which NIS belongs, suggesting that they serve a similar function in the other transporters. Our findings also suggest that the increase in affinity that each site displays when an ion binds to another site may result from changes in the dynamics of the transporter. These mechanistic insights deepen our understanding not only of NIS but also of other transporters, including many that, like NIS, are of great medical relevance.

Keywords: NIS; Na+ binding site; Na+-driven cotransporters; Na+/I− symporter; protein dynamics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acids / chemistry
  • Amino Acids / genetics
  • Binding Sites
  • Humans
  • Iodine / chemistry
  • Iodine / metabolism*
  • Ion Transport / genetics
  • Ions / chemistry
  • Ligands
  • Models, Molecular
  • Sodium / metabolism*
  • Symporters / genetics
  • Symporters / metabolism*
  • Thyroid Gland / chemistry
  • Thyroid Gland / metabolism*
  • Thyroid Hormones / biosynthesis
  • Thyroid Hormones / metabolism


  • Amino Acids
  • Ions
  • Ligands
  • Symporters
  • Thyroid Hormones
  • sodium-iodide symporter
  • Iodine
  • Sodium