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2.A.21.5.1
Sodium iodide symporter, NIS (I-:Na+ = 1:2). It also transports other monovalent anions including: ClO3-, SCN-, SeCN-, NO3-, Br-, BF4-, IO4- and BrO3-. It mediates electroneutral active transport of the environmental pollutant perchlorate (Dohan et al., 2007) and inhibits I- uptake. The stoichometry of ClO4-:Na+ uptake is 1 to 1 as perchlorate binds both to the anion and one of the two cation binding sites (Llorente-Esteban et al. 2020). Five beta-OH group-containing residues (Thr-351, Ser-353, Thr-354, Ser-356, and Thr-357) and Asn-360, all of which putatively face the same side of the helix in TMS IX, plus Asp-369, located in the membrane/cytosol interface, play key roles in NIS function and seem to be involved in Na+ binding/translocation (De la Vieja et al. 2007). Thr-354 is essential for iodide uptake (Tatsumi et al., 2010). The G39R mutant (congenital) is inactive. G93 is a pivot for the inwardly to outwardly conformational change (Paroder-Belenitsky et al., 2011).  The protein is present as a dimer (Huc-Brandt et al. 2011).  Functionally equivalent systems have been reviewed (Darrouzet et al. 2014). Mutations cause congenital I- transport defects (ITD; Li et al. 2013).  The physiological, medical and mechanistic features of NIS have been reviewed (Portulano et al. 2014). Mutations in TMS IX can give rise to hypothyroidism (Watanabe et al. 2018). NIS may also have a pump-independent, protumorigenic role in thyroid cancer via its cross-talk with PTEN signaling (Feng et al. 2018). Mutations in its gene gives rise to fetal goitrous hypothyroidism (Stoupa et al. 2020). Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral NIS and the apical anion exchanger pendrin (PDS; SLC26A4; TC# 2.A.53.2.17) (Eleftheriadou et al. 2020). Autoimmunity against NIS for thyroid disease has been documented (Eleftheriadou et al. 2020). The iodide transport defect-causing Y348D mutation in the Na+/I- symporter (NIS) renders the protein intrinsically inactive and impairs its targeting to the plasma membrane (Reyna-Neyra et al. 2021).

Accession Number:Q92911
Protein Name:SL55 aka SLC5A5 aka NIS
Length:643
Molecular Weight:68666.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:13
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Sodium iodide, Chlorate, Thiocyanate, Selenium cyanide, nitrate, Br-, Tetrafluoroborate, Periodate, Bromate

Cross database links:

Genevestigator: Q92911 Q92911
eggNOG: prNOG04668 COG0591
HEGENOM: HBG446891 HOG000261662
RefSeq: NP_000444.1   
Entrez Gene ID: 6528   
Pfam: PF00474   
OMIM: 274400  phenotype
601843  gene
KEGG: hsa:6528    hsa:6528   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0015111 F:iodide transmembrane transporter activity
GO:0006814 P:sodium ion transport
GO:0055085 P:transmembrane transport
GO:0005634 C:nucleus
GO:0008507 F:sodium:iodide symporter activity
GO:0071320 P:cellular response to cAMP
GO:0071371 P:cellular response to gonadotropin stimulus
GO:0006590 P:thyroid hormone generation

References (16)

[1] “Cloning of the human sodium iodide symporter.”  Smanik P.A.et.al.   8806637
[2] “Increased expression of the Na+/I- symporter in cultured human thyroid cells exposed to thyrotropin and in Graves' thyroid tissue.”  Saito T.et.al.   9329364
[3] “The DNA sequence and biology of human chromosome 19.”  Grimwood J.et.al.   15057824
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[5] “Congenital hypothyroidism caused by a mutation in the Na(+)/I(-) symporter.”  Fujiwara H.et.al.   9171822
[6] “Novel, missense and loss-of-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients.”  Kosugi S.et.al.   9745458
[7] “Congenital hypothyroidism due to mutations in the sodium/iodide symporter: identification of a nonsense mutation producing a downstream cryptic 3' splice site.”  Pohlenz J.et.al.   9486973
[8] “A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect.”  Kosugi S.et.al.   10487695
[9] “Cloning of the human sodium iodide symporter.”  Smanik P.A.et.al.   8806637
[10] “Increased expression of the Na+/I- symporter in cultured human thyroid cells exposed to thyrotropin and in Graves' thyroid tissue.”  Saito T.et.al.   9329364
[11] “The DNA sequence and biology of human chromosome 19.”  Grimwood J.et.al.   15057824
[12] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[13] “Congenital hypothyroidism caused by a mutation in the Na(+)/I(-) symporter.”  Fujiwara H.et.al.   9171822
[14] “Novel, missense and loss-of-function mutations in the sodium/iodide symporter gene causing iodide transport defect in three Japanese patients.”  Kosugi S.et.al.   9745458
[15] “Congenital hypothyroidism due to mutations in the sodium/iodide symporter: identification of a nonsense mutation producing a downstream cryptic 3' splice site.”  Pohlenz J.et.al.   9486973
[16] “A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect.”  Kosugi S.et.al.   10487695

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FASTA formatted sequence
1:	MEAVETGERP TFGAWDYGVF ALMLLVSTGI GLWVGLARGG QRSAEDFFTG GRRLAALPVG 
61:	LSLSASFMSA VQVLGVPSEA YRYGLKFLWM CLGQLLNSVL TALLFMPVFY RLGLTSTYEY 
121:	LEMRFSRAVR LCGTLQYIVA TMLYTGIVIY APALILNQVT GLDIWASLLS TGIICTFYTA 
181:	VGGMKAVVWT DVFQVVVMLS GFWVVLARGV MLVGGPRQVL TLAQNHSRIN LMDFNPDPRS 
241:	RYTFWTFVVG GTLVWLSMYG VNQAQVQRYV ACRTEKQAKL ALLINQVGLF LIVSSAACCG 
301:	IVMFVFYTDC DPLLLGRISA PDQYMPLLVL DIFEDLPGVP GLFLACAYSG TLSTASTSIN 
361:	AMAAVTVEDL IKPRLRSLAP RKLVIISKGL SLIYGSACLT VAALSSLLGG GVLQGSFTVM 
421:	GVISGPLLGA FILGMFLPAC NTPGVLAGLG AGLALSLWVA LGATLYPPSE QTMRVLPSSA 
481:	ARCVALSVNA SGLLDPALLP ANDSSRAPSS GMDASRPALA DSFYAISYLY YGALGTLTTV 
541:	LCGALISCLT GPTKRSTLAP GLLWWDLARQ TASVAPKEEV AILDDNLVKG PEELPTGNKK 
601:	PPGFLPTNED RLFFLGQKEL EGAGSWTPCV GHDGGRDQQE TNL