Structural insights into the mechanism of the sodium/iodide symporter.
Structural insights into the mechanism of the sodium/iodide symporter.
复制标题
DOI：
10.1038/s41586-022-05530-2
复制
发表时间：
2022-12
期刊：
影响因子：
64.8
通讯作者：
Carrasco, Nancy
中科院分区：
文献类型：
--
作者：
Ravera, Silvia;Nicola, Juan Pablo;Salazar-De Simone, Glicella;Sigworth, Fred J.;Karakas, Erkan;Amzel, L. Mario;Bianchet, Mario A.;Carrasco, Nancy
钠/碘同向转运体（NIS）是介导活性碘（I-）转运进入甲状腺的必需质膜蛋白，这是甲状腺生物合成的第一步-中间代谢的主要调节剂。NIS将I−逆着其电化学梯度的向内移位耦合到Na+沿其电化学梯度的向内转运。在其分子鉴定之前的近50年里，NIS已经是有史以来最有效的内部放射癌症治疗的中心分子：放射性碘（131 I-）治疗甲状腺癌。NIS突变会导致先天性甲状腺功能减退症，出生后必须立即治疗，以防止发育迟缓和认知缺陷。迄今为止，国家创新系统的结构尚不清楚。在这里，我们报告了三种结构的大鼠NIS，确定由单粒子冷冻电子显微镜（cryo-EM）：一个没有底物结合，一个与2 Na+和1 I−结合，一个与1 Na+和氧阴离子过氧化氢结合。结构分析、功能表征和计算研究揭示了底物结合位点和转运活性的关键残基。我们的研究结果产生的见解如何NIS选择，夫妇，和易位阴离子，从而建立一个框架，了解NIS功能，并进入它如何运输不同的基板与不同的化学计量和释放基板从其基板结合腔到胞质溶胶。
The sodium/iodide symporter (NIS) is the essential plasma membrane protein that mediates active iodide (I−) transport into the thyroid gland, the first step in the biosynthesis of the thyroid hormones—the master regulators of intermediary metabolism. NIS couples the inward translocation of I− against its electrochemical gradient to the inward transport of Na+ down its electrochemical gradient. For nearly 50 years before its molecular identification, NIS was already the molecule at the center of the single most effective internal radiation cancer therapy ever devised: radioiodide (131I−) treatment for thyroid cancer. Mutations in NIS cause congenital hypothyroidism, which must be treated immediately after birth to prevent stunted growth and cognitive deficiency. To date, the structure of NIS has been unknown. Here, we report three structures of rat NIS, determined by single-particle cryo-electron microscopy (cryo-EM): one with no substrates bound, one with 2 Na+ and 1 I− bound, and one with 1 Na+ and the oxyanion perrhenate bound. Structural analyses, functional characterization, and computational studies reveal the substrate binding sites and residues key for transport activity. Our results yield insights into how NIS selects, couples, and translocates anions—thereby establishing a framework for understanding NIS function—and into how it transports different substrates with different stoichiometries and releases substrates from its substrate-binding cavity into the cytosol.
登录
查看更多内容
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.0707207104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Dohan, Orsolya;Portulano, Carla;Carrasco, Nancy
通讯作者：
Carrasco, Nancy
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1073/pnas.1607231113
发表时间：
2016-09-13
影响因子：
11.1
作者：
Ferrandino, Giuseppe;Nicola, Juan Pablo;Carrasco, Nancy
通讯作者：
Carrasco, Nancy
影响因子：
4.8
作者：
Li, Wenjing;Nicola, Juan Pablo;Carrasco, Nancy
通讯作者：
Carrasco, Nancy