Structural insights into the mechanism of the sodium/iodide symporter (NIS)

RAVERA, S; NICOLA, JP; SALAZAR DE SIMONE, G; SIGWORTH, FJ; KARAKAS, E; AMZEL, LM; BIANCHET, MA; CARRASCO, N

NATURE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2022

0028-0836

The sodium/iodide symporter (NIS) is the essential plasma membraneprotein that mediates active iodide (I-) transport into the thyroid gland, the first stepin the biosynthesis of the thyroid hormones—the master regulators of intermediarymetabolism. NIS couples the inward translocation of I- against its electrochemicalgradient to the inward transport of Na+ down its electrochemical gradient. For nearly50 years before its molecular identification, NIS was already the molecule at the centerof the single most effective internal radiation cancer therapy ever devised:radioiodide (131I-) treatment for thyroid cancer. Mutations in NIS cause congenitalhypothyroidism, which must be treated immediately after birth to prevent stuntedgrowth and cognitive deficiency. To date, the structure of NIS has been unknown.Here, we report three structures of rat NIS, determined by single-particle cryoelectronmicroscopy (cryo-EM): one with no substrates bound, one with 2 Na+ and 1 Ibound,and one with 1 Na+ and the oxyanion perrhenate bound. Structural analyses,functional characterization, and computational studies reveal the substrate bindingsites and residues key for transport activity. Our results yield insights into how NISselects, couples, and translocates anions—thereby establishing a framework forunderstanding NIS function—and into how it transports different substrates withdifferent stoichiometries and releases substrates from its substrate-binding cavityinto the cytosol.