ID ZNT8_HUMAN Reviewed; 369 AA. AC Q8IWU4; A0AVP9; A5YM39; B4DPE0; Q8TCL3; DT 20-MAR-2007, integrated into UniProtKB/Swiss-Prot. DT 10-JUN-2008, sequence version 2. DT 24-JAN-2024, entry version 164. DE RecName: Full=Proton-coupled zinc antiporter SLC30A8 {ECO:0000305|PubMed:32723473}; DE AltName: Full=Solute carrier family 30 member 8 {ECO:0000312|HGNC:HGNC:20303}; DE AltName: Full=Zinc transporter 8 {ECO:0000303|PubMed:15331542}; DE Short=ZnT-8 {ECO:0000303|PubMed:15331542}; GN Name=SLC30A8 {ECO:0000312|HGNC:HGNC:20303}; GN Synonyms=ZNT8 {ECO:0000303|PubMed:16984975}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, AND RP TISSUE SPECIFICITY. RC TISSUE=Pancreas; RX PubMed=15331542; DOI=10.2337/diabetes.53.9.2330; RA Chimienti F., Devergnas S., Favier A., Seve M.; RT "Identification and cloning of a beta-cell-specific zinc transporter, ZnT- RT 8, localized into insulin secretory granules."; RL Diabetes 53:2330-2337(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Kidney; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Amygdala, and Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP TISSUE SPECIFICITY. RX PubMed=16158222; DOI=10.1007/s10534-005-3687-9; RA Chimienti F., Favier A., Seve M.; RT "ZnT-8, a pancreatic beta-cell-specific zinc transporter."; RL BioMetals 18:313-317(2005). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND TOPOLOGY. RX PubMed=16984975; DOI=10.1242/jcs.03164; RA Chimienti F., Devergnas S., Pattou F., Schuit F., Garcia-Cuenca R., RA Vandewalle B., Kerr-Conte J., Van Lommel L., Grunwald D., Favier A., RA Seve M.; RT "In vivo expression and functional characterization of the zinc transporter RT ZnT8 in glucose-induced insulin secretion."; RL J. Cell Sci. 119:4199-4206(2006). RN [9] RP TISSUE SPECIFICITY. RX PubMed=17118530; DOI=10.1016/j.mce.2006.10.010; RA Smidt K., Pedersen S.B., Brock B., Schmitz O., Fisker S., Bendix J., RA Wogensen L., Rungby J.; RT "Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean RT versus obese."; RL Mol. Cell. Endocrinol. 264:68-73(2007). RN [10] RP TISSUE SPECIFICITY. RX PubMed=17971500; DOI=10.1189/jlb.0307148; RA Overbeck S., Uciechowski P., Ackland M.L., Ford D., Rink L.; RT "Intracellular zinc homeostasis in leukocyte subsets is regulated by RT different expression of zinc exporters ZnT-1 to ZnT-9."; RL J. Leukoc. Biol. 83:368-380(2008). RN [11] RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND CHARACTERIZATION OF RP VARIANT TRP-325. RX PubMed=27875315; DOI=10.1074/jbc.m116.764605; RA Merriman C., Huang Q., Rutter G.A., Fu D.; RT "Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with RT Risk for Type-2 Diabetes."; RL J. Biol. Chem. 291:26950-26957(2016). RN [12] {ECO:0007744|PDB:6XPD, ECO:0007744|PDB:6XPE, ECO:0007744|PDB:6XPF} RP STRUCTURE BY ELECTRON MICROSCOPY (3.80 ANGSTROMS) OF 50-369 OF WILD-TYPE RP AND DOUBLE MUTANT ASN-110/ASN-224 IN COMPLEXES WITH ZINC IONS, FUNCTION, RP CATALYTIC ACTIVITY, SUBUNIT, MUTAGENESIS OF 52-HIS--HIS-54; HIS-106; RP ASP-110; HIS-137; HIS-220; ASP-224 AND HIS-345, MOTIF, AND REACTION RP MECHANISM. RX PubMed=32723473; DOI=10.7554/elife.58823; RA Xue J., Xie T., Zeng W., Jiang Y., Bai X.C.; RT "Cryo-EM structures of human ZnT8 in both outward- and inward-facing RT conformations."; RL Elife 9:0-0(2020). RN [13] RP VARIANT TRP-325, AND INVOLVEMENT IN T2D. RX PubMed=17293876; DOI=10.1038/nature05616; RA Sladek R., Rocheleau G., Rung J., Dina C., Shen L., Serre D., Boutin P., RA Vincent D., Belisle A., Hadjadj S., Balkau B., Heude B., Charpentier G., RA Hudson T.J., Montpetit A., Pshezhetsky A.V., Prentki M., Posner B.I., RA Balding D.J., Meyre D., Polychronakos C., Froguel P.; RT "A genome-wide association study identifies novel risk loci for type 2 RT diabetes."; RL Nature 445:881-885(2007). CC -!- FUNCTION: Proton-coupled zinc ion antiporter mediating the entry of CC zinc into the lumen of pancreatic beta cell secretory granules, thereby CC regulating insulin secretion. {ECO:0000269|PubMed:15331542, CC ECO:0000269|PubMed:16984975, ECO:0000269|PubMed:27875315, CC ECO:0000269|PubMed:32723473}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2 H(+)(out) + Zn(2+)(in) = 2 H(+)(in) + Zn(2+)(out); CC Xref=Rhea:RHEA:72627, ChEBI:CHEBI:15378, ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:32723473}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=71.42 uM for Zn(2+) (in reconstituted proteoliposomes composed of CC phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, CC phosphatidylserine and cholesterol) {ECO:0000269|PubMed:27875315}; CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:27875315, CC ECO:0000269|PubMed:32723473}. CC -!- INTERACTION: CC Q8IWU4; P16157-17: ANK1; NbExp=3; IntAct=EBI-10262251, EBI-941819; CC Q8IWU4; Q13520: AQP6; NbExp=3; IntAct=EBI-10262251, EBI-13059134; CC Q8IWU4; Q9NVJ2: ARL8B; NbExp=3; IntAct=EBI-10262251, EBI-718376; CC Q8IWU4; Q9HD20-3: ATP13A1; NbExp=3; IntAct=EBI-10262251, EBI-12069500; CC Q8IWU4; Q9BXK5: BCL2L13; NbExp=3; IntAct=EBI-10262251, EBI-747430; CC Q8IWU4; Q13323: BIK; NbExp=3; IntAct=EBI-10262251, EBI-700794; CC Q8IWU4; Q8WZ55: BSND; NbExp=3; IntAct=EBI-10262251, EBI-7996695; CC Q8IWU4; P13236: CCL4; NbExp=3; IntAct=EBI-10262251, EBI-2873970; CC Q8IWU4; Q8TCZ2: CD99L2; NbExp=3; IntAct=EBI-10262251, EBI-2824782; CC Q8IWU4; Q99675: CGRRF1; NbExp=3; IntAct=EBI-10262251, EBI-2130213; CC Q8IWU4; P56747: CLDN6; NbExp=3; IntAct=EBI-10262251, EBI-12955011; CC Q8IWU4; Q96FZ5: CMTM7; NbExp=3; IntAct=EBI-10262251, EBI-2807956; CC Q8IWU4; Q7Z7G2: CPLX4; NbExp=3; IntAct=EBI-10262251, EBI-18013275; CC Q8IWU4; Q96BA8: CREB3L1; NbExp=9; IntAct=EBI-10262251, EBI-6942903; CC Q8IWU4; Q9BUN8: DERL1; NbExp=3; IntAct=EBI-10262251, EBI-398977; CC Q8IWU4; Q15125: EBP; NbExp=3; IntAct=EBI-10262251, EBI-3915253; CC Q8IWU4; Q9GZR5: ELOVL4; NbExp=3; IntAct=EBI-10262251, EBI-18535450; CC Q8IWU4; Q9Y282: ERGIC3; NbExp=3; IntAct=EBI-10262251, EBI-781551; CC Q8IWU4; P60508: ERVFRD-1; NbExp=3; IntAct=EBI-10262251, EBI-17973325; CC Q8IWU4; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-10262251, EBI-18304435; CC Q8IWU4; Q96KR6: FAM210B; NbExp=3; IntAct=EBI-10262251, EBI-18938272; CC Q8IWU4; Q96IV6: FAXDC2; NbExp=3; IntAct=EBI-10262251, EBI-12142299; CC Q8IWU4; Q8TBE3: FNDC9; NbExp=3; IntAct=EBI-10262251, EBI-12142257; CC Q8IWU4; O60883: GPR37L1; NbExp=3; IntAct=EBI-10262251, EBI-2927498; CC Q8IWU4; O15529: GPR42; NbExp=3; IntAct=EBI-10262251, EBI-18076404; CC Q8IWU4; Q14416: GRM2; NbExp=3; IntAct=EBI-10262251, EBI-10232876; CC Q8IWU4; Q9NP66: HMG20A; NbExp=3; IntAct=EBI-10262251, EBI-740641; CC Q8IWU4; P30519: HMOX2; NbExp=3; IntAct=EBI-10262251, EBI-712096; CC Q8IWU4; Q8NBQ5: HSD17B11; NbExp=3; IntAct=EBI-10262251, EBI-1052304; CC Q8IWU4; Q96MG2: JSRP1; NbExp=3; IntAct=EBI-10262251, EBI-11305455; CC Q8IWU4; A8MZ59: LEUTX; NbExp=3; IntAct=EBI-10262251, EBI-17490413; CC Q8IWU4; P15941-11: MUC1; NbExp=3; IntAct=EBI-10262251, EBI-17263240; CC Q8IWU4; Q16617: NKG7; NbExp=3; IntAct=EBI-10262251, EBI-3919611; CC Q8IWU4; Q9P0S3: ORMDL1; NbExp=3; IntAct=EBI-10262251, EBI-1054848; CC Q8IWU4; Q9NUU6: OTULINL; NbExp=3; IntAct=EBI-10262251, EBI-6916492; CC Q8IWU4; P12004: PCNA; NbExp=3; IntAct=EBI-10262251, EBI-358311; CC Q8IWU4; O15173: PGRMC2; NbExp=3; IntAct=EBI-10262251, EBI-1050125; CC Q8IWU4; Q99640-2: PKMYT1; NbExp=3; IntAct=EBI-10262251, EBI-12257782; CC Q8IWU4; P26678: PLN; NbExp=3; IntAct=EBI-10262251, EBI-692836; CC Q8IWU4; P43378: PTPN9; NbExp=3; IntAct=EBI-10262251, EBI-742898; CC Q8IWU4; Q9H6H4: REEP4; NbExp=3; IntAct=EBI-10262251, EBI-7545592; CC Q8IWU4; Q96HR9-2: REEP6; NbExp=3; IntAct=EBI-10262251, EBI-14065960; CC Q8IWU4; Q8NC24: RELL2; NbExp=3; IntAct=EBI-10262251, EBI-10269209; CC Q8IWU4; Q96TC7: RMDN3; NbExp=3; IntAct=EBI-10262251, EBI-1056589; CC Q8IWU4; O95197-3: RTN3; NbExp=3; IntAct=EBI-10262251, EBI-11525735; CC Q8IWU4; Q96GQ5: RUSF1; NbExp=3; IntAct=EBI-10262251, EBI-8636004; CC Q8IWU4; Q9NR31: SAR1A; NbExp=3; IntAct=EBI-10262251, EBI-3920694; CC Q8IWU4; Q9NY72: SCN3B; NbExp=3; IntAct=EBI-10262251, EBI-17247926; CC Q8IWU4; Q9Y6D0: SELENOK; NbExp=3; IntAct=EBI-10262251, EBI-9679163; CC Q8IWU4; Q8WV19: SFT2D1; NbExp=3; IntAct=EBI-10262251, EBI-2854842; CC Q8IWU4; O95562: SFT2D2; NbExp=3; IntAct=EBI-10262251, EBI-4402330; CC Q8IWU4; P54219-3: SLC18A1; NbExp=3; IntAct=EBI-10262251, EBI-17595455; CC Q8IWU4; Q99726: SLC30A3; NbExp=3; IntAct=EBI-10262251, EBI-10294651; CC Q8IWU4; Q9NP94: SLC39A2; NbExp=3; IntAct=EBI-10262251, EBI-12898013; CC Q8IWU4; Q9NPE6: SPAG4; NbExp=3; IntAct=EBI-10262251, EBI-10819434; CC Q8IWU4; Q8WWF3: SSMEM1; NbExp=3; IntAct=EBI-10262251, EBI-17280858; CC Q8IWU4; Q8N2H4: SYS1; NbExp=3; IntAct=EBI-10262251, EBI-13075176; CC Q8IWU4; Q8N9I0: SYT2; NbExp=3; IntAct=EBI-10262251, EBI-8032987; CC Q8IWU4; Q8WY91: THAP4; NbExp=3; IntAct=EBI-10262251, EBI-726691; CC Q8IWU4; Q9C0I4: THSD7B; NbExp=3; IntAct=EBI-10262251, EBI-311394; CC Q8IWU4; P17152: TMEM11; NbExp=3; IntAct=EBI-10262251, EBI-723946; CC Q8IWU4; Q8IV31: TMEM139; NbExp=3; IntAct=EBI-10262251, EBI-7238458; CC Q8IWU4; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-10262251, EBI-8638294; CC Q8IWU4; Q9BTX3: TMEM208; NbExp=3; IntAct=EBI-10262251, EBI-12876824; CC Q8IWU4; Q96Q45-2: TMEM237; NbExp=3; IntAct=EBI-10262251, EBI-10982110; CC Q8IWU4; O95807: TMEM50A; NbExp=3; IntAct=EBI-10262251, EBI-12903814; CC Q8IWU4; Q4KMG9: TMEM52B; NbExp=3; IntAct=EBI-10262251, EBI-18178701; CC Q8IWU4; Q96HE8: TMEM80; NbExp=3; IntAct=EBI-10262251, EBI-11742770; CC Q8IWU4; Q9P0T7: TMEM9; NbExp=3; IntAct=EBI-10262251, EBI-723976; CC Q8IWU4; O60636: TSPAN2; NbExp=3; IntAct=EBI-10262251, EBI-3914288; CC Q8IWU4; P23763-3: VAMP1; NbExp=3; IntAct=EBI-10262251, EBI-12097582; CC Q8IWU4; P63027: VAMP2; NbExp=3; IntAct=EBI-10262251, EBI-520113; CC Q8IWU4; Q9BSR8: YIPF4; NbExp=3; IntAct=EBI-10262251, EBI-751253; CC Q8IWU4; Q96EC8: YIPF6; NbExp=3; IntAct=EBI-10262251, EBI-751210; CC Q8IWU4; Q5T4F4: ZFYVE27; NbExp=3; IntAct=EBI-10262251, EBI-3892947; CC Q8IWU4; PRO_0000041304 [P08563]; Xeno; NbExp=2; IntAct=EBI-10262251, EBI-11477759; CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle membrane CC {ECO:0000269|PubMed:15331542, ECO:0000269|PubMed:16984975}; Multi-pass CC membrane protein {ECO:0000255}. Cell membrane CC {ECO:0000269|PubMed:15331542, ECO:0000269|PubMed:16984975}; Multi-pass CC membrane protein {ECO:0000255}. Note=Associated with insulin and CC glucagon secretory granules. {ECO:0000269|PubMed:15331542}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8IWU4-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8IWU4-2; Sequence=VSP_024025; CC -!- TISSUE SPECIFICITY: In the endocrine pancreas, expressed in insulin- CC producing beta cells. Expressed at relatively high levels in CC subcutaneous fat tissue from lean persons; much lower levels in CC visceral fat, whether from lean or obese individuals, and in CC subcutaneous fat tissue from obese individuals. Expressed in peripheral CC blood mononuclear cells, including T-cells and B-cells, with great CC variation among individuals ranging from negative to strongly positive. CC {ECO:0000269|PubMed:15331542, ECO:0000269|PubMed:16158222, CC ECO:0000269|PubMed:16984975, ECO:0000269|PubMed:17118530, CC ECO:0000269|PubMed:17971500}. CC -!- POLYMORPHISM: Variant Trp-325 is a risk factor that confers CC susceptibility to type 2 diabetes mellitus (T2D) [MIM:125853]. CC {ECO:0000269|PubMed:17293876}. CC -!- MISCELLANEOUS: Each subunit of the homodimer independently transports CC zinc ions in a pH-dependent manner. The cytosolic pH promotes binding CC of zinc ions to the transporter binding site. Upon change into the CC organelle-facing conformation, the two histidines of the zinc-binding CC site get protonated at lumenal lower pH, triggering zinc release into CC the organelle. The transporter then moves back to the cytosolic-facing CC conformation where the two histidines get deprotonated at higher pH, CC resulting in a net antiport of 2 protons. CC {ECO:0000303|PubMed:32723473}. CC -!- SIMILARITY: Belongs to the cation diffusion facilitator (CDF) CC transporter (TC 2.A.4) family. SLC30A subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY117411; AAM80562.1; -; mRNA. DR EMBL; AK298294; BAG60552.1; -; mRNA. DR EMBL; AL713790; CAD28545.1; -; mRNA. DR EMBL; EF560713; ABQ59023.1; -; mRNA. DR EMBL; AC027419; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC084114; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471060; EAW91968.1; -; Genomic_DNA. DR EMBL; BC126446; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS55272.1; -. [Q8IWU4-2] DR CCDS; CCDS6322.1; -. [Q8IWU4-1] DR RefSeq; NP_001166282.1; NM_001172811.1. [Q8IWU4-2] DR RefSeq; NP_001166284.1; NM_001172813.1. [Q8IWU4-2] DR RefSeq; NP_001166285.1; NM_001172814.1. [Q8IWU4-2] DR RefSeq; NP_001166286.1; NM_001172815.2. [Q8IWU4-2] DR RefSeq; NP_776250.2; NM_173851.2. [Q8IWU4-1] DR PDB; 6XPD; EM; 3.80 A; A/B=50-369. DR PDB; 6XPE; EM; 4.10 A; A/B=50-369. DR PDB; 6XPF; EM; 5.90 A; A/B=50-369. DR PDBsum; 6XPD; -. DR PDBsum; 6XPE; -. DR PDBsum; 6XPF; -. DR AlphaFoldDB; Q8IWU4; -. DR EMDB; EMD-22285; -. DR EMDB; EMD-22286; -. DR EMDB; EMD-22287; -. DR SMR; Q8IWU4; -. DR BioGRID; 127975; 70. DR IntAct; Q8IWU4; 76. DR MINT; Q8IWU4; -. DR STRING; 9606.ENSP00000415011; -. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.4.3.5; the cation diffusion facilitator (cdf) family. DR iPTMnet; Q8IWU4; -. DR PhosphoSitePlus; Q8IWU4; -. DR BioMuta; SLC30A8; -. DR DMDM; 190358866; -. DR jPOST; Q8IWU4; -. DR MassIVE; Q8IWU4; -. DR PaxDb; 9606-ENSP00000415011; -. DR PeptideAtlas; Q8IWU4; -. DR ProteomicsDB; 70895; -. [Q8IWU4-1] DR ProteomicsDB; 70896; -. [Q8IWU4-2] DR Antibodypedia; 42965; 267 antibodies from 33 providers. DR DNASU; 169026; -. DR Ensembl; ENST00000427715.2; ENSP00000407505.2; ENSG00000164756.13. [Q8IWU4-2] DR Ensembl; ENST00000456015.7; ENSP00000415011.2; ENSG00000164756.13. [Q8IWU4-1] DR Ensembl; ENST00000519688.5; ENSP00000431069.1; ENSG00000164756.13. [Q8IWU4-2] DR Ensembl; ENST00000521243.5; ENSP00000428545.1; ENSG00000164756.13. [Q8IWU4-2] DR GeneID; 169026; -. DR KEGG; hsa:169026; -. DR MANE-Select; ENST00000456015.7; ENSP00000415011.2; NM_173851.3; NP_776250.2. DR UCSC; uc003yog.3; human. [Q8IWU4-1] DR AGR; HGNC:20303; -. DR CTD; 169026; -. DR DisGeNET; 169026; -. DR GeneCards; SLC30A8; -. DR HGNC; HGNC:20303; SLC30A8. DR HPA; ENSG00000164756; Tissue enriched (pancreas). DR MalaCards; SLC30A8; -. DR MIM; 125853; phenotype. DR MIM; 611145; gene. DR neXtProt; NX_Q8IWU4; -. DR OpenTargets; ENSG00000164756; -. DR PharmGKB; PA134915546; -. DR VEuPathDB; HostDB:ENSG00000164756; -. DR eggNOG; KOG1482; Eukaryota. DR GeneTree; ENSGT00940000160706; -. DR HOGENOM; CLU_013430_0_1_1; -. DR InParanoid; Q8IWU4; -. DR OMA; RATKMYA; -. DR OrthoDB; 1331349at2759; -. DR PhylomeDB; Q8IWU4; -. DR TreeFam; TF313382; -. DR PathwayCommons; Q8IWU4; -. DR Reactome; R-HSA-264876; Insulin processing. DR Reactome; R-HSA-435368; Zinc efflux and compartmentalization by the SLC30 family. DR SignaLink; Q8IWU4; -. DR BioGRID-ORCS; 169026; 12 hits in 1148 CRISPR screens. DR ChiTaRS; SLC30A8; human. DR GeneWiki; SLC30A8; -. DR GenomeRNAi; 169026; -. DR Pharos; Q8IWU4; Tbio. DR PRO; PR:Q8IWU4; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q8IWU4; Protein. DR Bgee; ENSG00000164756; Expressed in islet of Langerhans and 93 other cell types or tissues. DR ExpressionAtlas; Q8IWU4; baseline and differential. DR GO; GO:0031410; C:cytoplasmic vesicle; ISS:BHF-UCL. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL. DR GO; GO:0030141; C:secretory granule; IDA:BHF-UCL. DR GO; GO:0030667; C:secretory granule membrane; IDA:UniProtKB. DR GO; GO:0030658; C:transport vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0042803; F:protein homodimerization activity; ISS:BHF-UCL. DR GO; GO:0008270; F:zinc ion binding; IC:BHF-UCL. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:BHF-UCL. DR GO; GO:0140826; F:zinc:proton antiporter activity; IDA:UniProtKB. DR GO; GO:0030070; P:insulin processing; TAS:Reactome. DR GO; GO:0030073; P:insulin secretion; IMP:BHF-UCL. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; ISS:BHF-UCL. DR GO; GO:0032024; P:positive regulation of insulin secretion; ISS:BHF-UCL. DR GO; GO:0060627; P:regulation of vesicle-mediated transport; ISS:BHF-UCL. DR GO; GO:0009749; P:response to glucose; IMP:BHF-UCL. DR GO; GO:0070555; P:response to interleukin-1; IEA:Ensembl. DR GO; GO:0034341; P:response to type II interferon; IEA:Ensembl. DR GO; GO:0010043; P:response to zinc ion; IBA:GO_Central. DR GO; GO:0071578; P:zinc ion import across plasma membrane; ISS:BHF-UCL. DR GO; GO:0062111; P:zinc ion import into organelle; IMP:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IBA:GO_Central. DR GO; GO:0006829; P:zinc ion transport; IDA:BHF-UCL. DR Gene3D; 1.20.1510.10; Cation efflux protein transmembrane domain; 1. DR InterPro; IPR002524; Cation_efflux. DR InterPro; IPR036837; Cation_efflux_CTD_sf. DR InterPro; IPR027469; Cation_efflux_TMD_sf. DR NCBIfam; TIGR01297; CDF; 1. DR PANTHER; PTHR11562; CATION EFFLUX PROTEIN/ ZINC TRANSPORTER; 1. DR PANTHER; PTHR11562:SF37; ZINC TRANSPORTER 8; 1. DR Pfam; PF01545; Cation_efflux; 1. DR SUPFAM; SSF160240; Cation efflux protein cytoplasmic domain-like; 1. DR SUPFAM; SSF161111; Cation efflux protein transmembrane domain-like; 1. DR Genevisible; Q8IWU4; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Antiport; Cell membrane; KW Cytoplasmic vesicle; Diabetes mellitus; Ion transport; Membrane; KW Metal-binding; Reference proteome; Transmembrane; Transmembrane helix; KW Transport; Zinc; Zinc transport. FT CHAIN 1..369 FT /note="Proton-coupled zinc antiporter SLC30A8" FT /id="PRO_0000281740" FT TOPO_DOM 1..79 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:16984975" FT TRANSMEM 80..100 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 101..103 FT /note="Lumenal, vesicle" FT /evidence="ECO:0000269|PubMed:16984975" FT TRANSMEM 104..124 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 125..140 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:16984975" FT TRANSMEM 141..161 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 162..175 FT /note="Lumenal, vesicle" FT /evidence="ECO:0000269|PubMed:16984975" FT TRANSMEM 176..196 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 197..217 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:16984975" FT TRANSMEM 218..238 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 239..245 FT /note="Lumenal, vesicle" FT /evidence="ECO:0000269|PubMed:16984975" FT TRANSMEM 246..266 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 267..369 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:16984975" FT REGION 31..52 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 52..54 FT /note="HCH Motif; seals regulatory zinc-binding pocket" FT /evidence="ECO:0000269|PubMed:32723473" FT COMPBIAS 33..48 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 52 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain A" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 53 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain A" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 54 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain A" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 106 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="transported zinc" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 110 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="transported zinc" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 137 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /ligand_note="low affinity" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 220 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="transported zinc" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 224 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="transported zinc" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 301 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain B" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 318 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain B" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 345 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="4" FT /ligand_note="low affinity" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 352 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain B" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 361 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain B" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT BINDING 364 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /ligand_note="regulatory; ligand shared between homodimeric FT partners" FT /note="in chain B" FT /evidence="ECO:0000269|PubMed:32723473, FT ECO:0000312|PDB:6XPE" FT VAR_SEQ 1..49 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:17974005" FT /id="VSP_024025" FT VARIANT 325 FT /note="R -> Q (in dbSNP:rs16889462)" FT /id="VAR_031258" FT VARIANT 325 FT /note="R -> W (decreased transport reaction kinetics; FT decreased affinity for zinc ions; decreased zinc ion import FT into organelle; no effect on protein abundance; FT dbSNP:rs13266634)" FT /evidence="ECO:0000269|PubMed:17293876, FT ECO:0000269|PubMed:27875315" FT /id="VAR_031259" FT MUTAGEN 52..54 FT /note="Missing: Decreased zinc ion transmembrane FT transport." FT /evidence="ECO:0000269|PubMed:32723473" FT MUTAGEN 106 FT /note="H->A: Decreased zinc ion transmembrane transport; FT when associated with A-220." FT /evidence="ECO:0000269|PubMed:32723473" FT MUTAGEN 110 FT /note="D->N: Loss of transported zinc binding and decreased FT zinc ion transmembrane transport; when associated with FT N-224." FT /evidence="ECO:0000269|PubMed:32723473" FT MUTAGEN 137 FT /note="H->A: Decreased zinc ion transmembrane transport; FT when associated with A-345." FT /evidence="ECO:0000269|PubMed:32723473" FT MUTAGEN 220 FT /note="H->A: Decreased zinc ion transmembrane transport; FT when associated with A-106." FT /evidence="ECO:0000269|PubMed:32723473" FT MUTAGEN 224 FT /note="D->N: Loss of transported zinc binding and decreased FT zinc ion transmembrane transport; when associated with FT N-110." FT /evidence="ECO:0000269|PubMed:32723473" FT MUTAGEN 345 FT /note="H->A: Decreased zinc ion transmembrane transport; FT when associated with A-137." FT /evidence="ECO:0000269|PubMed:32723473" FT CONFLICT 18 FT /note="Y -> H (in Ref. 1; AAM80562)" FT /evidence="ECO:0000305" FT CONFLICT 123 FT /note="L -> S (in Ref. 3; ABQ59023)" FT /evidence="ECO:0000305" FT CONFLICT 222 FT /note="L -> P (in Ref. 3; CAD28545)" FT /evidence="ECO:0000305" FT CONFLICT 302 FT /note="S -> C (in Ref. 3; CAD28545)" FT /evidence="ECO:0000305" SQ SEQUENCE 369 AA; 40755 MW; 45926FADCEE18FF3 CRC64; MEFLERTYLV NDKAAKMYAF TLESVELQQK PVNKDQCPRE RPEELESGGM YHCHSGSKPT EKGANEYAYA KWKLCSASAI CFIFMIAEVV GGHIAGSLAV VTDAAHLLID LTSFLLSLFS LWLSSKPPSK RLTFGWHRAE ILGALLSILC IWVVTGVLVY LACERLLYPD YQIQATVMII VSSCAVAANI VLTVVLHQRC LGHNHKEVQA NASVRAAFVH ALGDLFQSIS VLISALIIYF KPEYKIADPI CTFIFSILVL ASTITILKDF SILLMEGVPK SLNYSGVKEL ILAVDGVLSV HSLHIWSLTM NQVILSAHVA TAASRDSQVV RREIAKALSK SFTMHSLTIQ MESPVDQDPD CLFCEDPCD //