ESPE Yearbook of Paediatric Endocrinology

Brief summary: The sodium/iodide symporter (NIS) is the first and limiting step for thyroid hormone synthesis (1). NIS is located at the basolateral membrane of the thyroid follicular cells. NIS translocates iodide against its electrochemical gradient from the blood into the cytosol of the thyroid follicular cell by a co-transport with sodium. Besides iodide, the sodium/iodide symporter has also further substrates such as the environmental endocrine disruptor perchlorate, or substrates used for scintigraphy or single-photon emission computed tomography, such as pertechnetate, and perrhenate, respectively. This extensive study gives a detailed insight into the mechanism of the sodium/iodide symport by NIS.

Ravera et al. combined structural analyses by single-particle cryo-electron microscopy of the rat NIS protein in three different conditions: NIS without iodide binding (apo-NIS), NIS with iodide binding (NIS-I⁻), and NIS with binding of perrhenate (NIS-ReO⁻). They determined the binding sites of iodide and sodium within the substrate-binding pocket of the NIS-protein and investigated the functional effect of known NIS gene mutations in the binding residues. Then, they compared structural changes of the binding sites induced by iodide or perrhenate, revealing important structural dynamics between NIS-I⁻ and NIS-ReO⁻. Finally, they describe the NIS-I⁻ binding mechanism in detail: binding of a first sodium, binding of a second sodium inducing an important conformational change of structure, and increasing the affinity of NIS to iodide by a factor of ten, iodine binding, occluded conformation, and finally release of the two sodium and the iodide into the cytosol of the thyroid follicular cell.

Twenty-six years after cloning and characterization of the NIS gene, this fundamental, elegant and extensive study by Ravera et al. describes the structural changes during sodium/iodide symport by NIS conserved in many species (2). The work represents a milestone in thyroid physiology providing the full picture of NIS function integrating and completing previous results of the last decades.

References: 1. Szinnai G, Lacroix L, Carré A, Guimiot F, Talbot M, Martinovic J, Delezoide AL, Vekemans M, Michiels S, Caillou B, Schlumberger M, Bidart JM, Polak M. Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus. J Clin Endocrinol Metab. 2007 Jan;92(1):70–6. doi: 10.1210/jc.2006-1450. Epub 2006 Oct 31. PMID: 17077129. 2. Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature. 1996 Feb 1;379(6564):458–60. doi: 10.1038/379458a0. PMID: 8559252.