{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T02:57:44Z","timestamp":1791082664231,"version":"4.1.0"},"reference-count":54,"publisher":"The Company of Biologists","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Na+\/I\u2212 symporter (NIS)-mediated active accumulation of I\u2212 in thyrocytes is a key 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\u2212 transport defect (ITD), and their investigation has yielded valuable mechanistic information on NIS. Here we report novel findings derived from the thorough characterization of the ITD-causing mutation R124H, located in the second intracellular loop (IL-2). R124H NIS is incompletely glycosylated and colocalizes with ER-resident protein markers. As a result, R124H NIS is not targeted to the plasma membrane and therefore does not mediate any I\u2212 transport in transfected COS-7 cells. Strikingly, however, the mutant is intrinsically active, as revealed by its ability to mediate I\u2212 transport in membrane vesicles. Of all the amino acid substitutions we carried out at position 124 (K, D, E, A, W, N and Q), only Gln restored targeting of NIS to the plasma membrane and NIS activity, suggesting a key structural role for the \u03b4-amino of R124 in the transporter's maturation and cell surface targeting. Using our NIS homology model based on the structure of the Vibrio parahaemolyticus Na+\/galactose symporter, we propose an interaction between the \u03b4-amino group of either R or Q124 and the thiol group of C440, located in IL-6. We conclude that the interaction between IL-2 and IL-6 is critical for the local folding required for NIS maturation and plasma membrane trafficking.<\/jats:p>","DOI":"10.1242\/jcs.120246","type":"journal-article","created":{"date-parts":[[2013,5,21]],"date-time":"2013-05-21T02:01:54Z","timestamp":1369101714000},"source":"Crossref","is-referenced-by-count":25,"title":["The iodide transport defect-causing mutation R124H: a \u03b4-amino group at position 124 is critical for maturation and trafficking of the Na+\/I\u2212 symporter (NIS)"],"prefix":"10.1242","author":[{"given":"Viktoriya","family":"Paroder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan P.","family":"Nicola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S.","family":"Ginter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Carrasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2013,1,1]]},"reference":[{"key":"2021042612595065700_b1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1471-2407-7-5","article-title":"Expression of the Na+\/I- symporter (NIS) is markedly decreased or absent in gastric cancer and intestinal metaplastic mucosa of Barrett esophagus.","volume":"7","author":"Altorjay","year":"2007","journal-title":"BMC Cancer"},{"key":"2021042612595065700_b2","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1002\/pro.5560030402","article-title":"A structural role for arginine in proteins: multiple hydrogen bonds to backbone carbonyl oxygens.","volume":"3","author":"Borders","year":"1994","journal-title":"Protein Sci."},{"key":"2021042612595065700_b3","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1038\/sj.ki.5000194","article-title":"Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting.","volume":"69","author":"Calado","year":"2006","journal-title":"Kidney Int."},{"key":"2021042612595065700_b4","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/379458a0","article-title":"Cloning and characterization of the thyroid iodide transporter.","volume":"379","author":"Dai","year":"1996","journal-title":"Nature"},{"key":"2021042612595065700_b5","doi-asserted-by":"publisher","first-page":"e10438","DOI":"10.1371\/journal.pone.0010438","article-title":"Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking to the cell surface resulting in selective denaturation of the C-domain.","volume":"5","author":"Danilov","year":"2010","journal-title":"PLoS ONE"},{"key":"2021042612595065700_b6","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1242\/jcs.00898","article-title":"The Q267E mutation in the sodium\/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number.","volume":"117","author":"De la Vieja","year":"2004","journal-title":"J. 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