NRAM2_HUMAN
ID NRAM2_HUMAN Reviewed; 568 AA.
AC P49281; B3KT08; B4DK84; F5H741; O43288; O60932; O94801; Q498Z5; Q8IUD7;
AC Q96J35;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, sequence version 2.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Natural resistance-associated macrophage protein 2;
DE Short=NRAMP 2;
DE AltName: Full=Divalent cation transporter 1;
DE AltName: Full=Divalent metal transporter 1;
DE Short=DMT-1;
DE AltName: Full=Solute carrier family 11 member 2;
GN Name=SLC11A2; Synonyms=DCT1, DMT1, NRAMP2; ORFNames=OK/SW-cl.20;
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).
RC TISSUE=Brain;
RX PubMed=9464519; DOI=10.1016/s0161-5890(97)00110-7;
RA Kishi F., Tabuchi M.;
RT "Complete nucleotide sequence of human NRAMP2 cDNA.";
RL Mol. Immunol. 34:839-842(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=9790986; DOI=10.1006/bbrc.1998.9415;
RA Kishi F., Tabuchi M.;
RT "Human natural resistance-associated macrophage protein 2: gene cloning and
RT protein identification.";
RL Biochem. Biophys. Res. Commun. 251:775-783(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), TISSUE
RP SPECIFICITY, AND VARIANT ILE-435.
RX PubMed=9642100; DOI=10.1006/bcmd.1998.0186;
RA Lee P.L., Gelbart T., West C., Halloran C., Beutler E.;
RT "The human Nramp2 gene: characterization of the gene structure, alternative
RT splicing, promoter region and polymorphisms.";
RL Blood Cells Mol. Dis. 24:199-215(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [MRNA] OF 1-583
RP (ISOFORM 3), ALTERNATIVE SPLICING (ISOFORMS 2 AND 4), AND TISSUE
RP SPECIFICITY.
RX PubMed=12209011; DOI=10.1073/pnas.192423399;
RA Hubert N., Hentze M.W.;
RT "Previously uncharacterized isoforms of divalent metal transporter (DMT)-1:
RT implications for regulation and cellular function.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:12345-12350(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE (ISOFORM 1).
RA Worthington M.T., Battle E., Luo R.Q.;
RT "Cloning and functional expression of the full length human NRAMP2 iron
RT transporter.";
RL Submitted (FEB-1998) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5).
RC TISSUE=Brain, Thalamus, and Trachea;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Colon adenocarcinoma;
RA Shichijo S., Itoh K.;
RT "Identification of immuno-peptidmics that are recognized by tumor-reactive
RT CTL generated from TIL of colon cancer patients.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Hypothalamus, and Neuroblastoma;
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 [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 58-568 (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=7613023; DOI=10.1007/bf00352405;
RA Vidal S., Belouchi A.-M., Cellier M., Beatty B., Gros P.;
RT "Cloning and characterization of a second human NRAMP gene on chromosome
RT 12q13.";
RL Mamm. Genome 6:224-230(1995).
RN [12]
RP SUBCELLULAR LOCATION, ALTERNATIVE SPLICING, AND MUTAGENESIS OF TYR-555.
RX PubMed=12475959; DOI=10.1091/mbc.e02-03-0165;
RA Tabuchi M., Tanaka N., Nishida-Kitayama J., Ohno H., Kishi F.;
RT "Alternative splicing regulates the subcellular localization of divalent
RT metal transporter 1 isoforms.";
RL Mol. Biol. Cell 13:4371-4387(2002).
RN [13]
RP FUNCTION.
RX PubMed=17109629; DOI=10.1042/bj20061290;
RA Mackenzie B., Takanaga H., Hubert N., Rolfs A., Hediger M.A.;
RT "Functional properties of multiple isoforms of human divalent metal-ion
RT transporter 1 (DMT1).";
RL Biochem. J. 403:59-69(2007).
RN [14]
RP BIOPHYSICOCHEMICAL PROPERTIES, AND NIFEDIPINE TREATMENT.
RX PubMed=17293870; DOI=10.1038/nm1542;
RA Ludwiczek S., Theurl I., Muckenthaler M.U., Jakab M., Mair S.M., Theurl M.,
RA Kiss J., Paulmichl M., Hentze M.W., Ritter M., Weiss G.;
RT "Ca2+ channel blockers reverse iron overload by a new mechanism via
RT divalent metal transporter-1.";
RL Nat. Med. 13:448-454(2007).
RN [15]
RP INTERACTION WITH NDFIP1; NDFIP2 AND WWP2, AND SUBCELLULAR LOCATION.
RX PubMed=18776082; DOI=10.1182/blood-2008-04-150953;
RA Foot N.J., Dalton H.E., Shearwin-Whyatt L.M., Dorstyn L., Tan S.S.,
RA Yang B., Kumar S.;
RT "Regulation of the divalent metal ion transporter DMT1 and iron homeostasis
RT by a ubiquitin-dependent mechanism involving Ndfips and WWP2.";
RL Blood 112:4268-4275(2008).
RN [16]
RP INTERACTION WITH NDFIP1 AND NEDD4L.
RX PubMed=19706893; DOI=10.1073/pnas.0904880106;
RA Howitt J., Putz U., Lackovic J., Doan A., Dorstyn L., Cheng H., Yang B.,
RA Chan-Ling T., Silke J., Kumar S., Tan S.S.;
RT "Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal
RT toxicity in human neurons.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:15489-15494(2009).
RN [17]
RP ALTERNATIVE SPLICING, SUBCELLULAR LOCATION, FUNCTION, AND GLYCOSYLATION.
RX PubMed=25491917; DOI=10.1002/cbin.10403;
RA Yanatori I., Yasui Y., Noguchi Y., Kishi F.;
RT "Inhibition of iron uptake by ferristatin II is exerted through
RT internalization of DMT1 at the plasma membrane.";
RL Cell Biol. Int. 39:427-434(2015).
RN [18]
RP SUBCELLULAR LOCATION, FUNCTION, AND INTERACTION WITH COX2 AND TOM6.
RX PubMed=24448823; DOI=10.1096/fj.13-240564;
RA Wolff N.A., Ghio A.J., Garrick L.M., Garrick M.D., Zhao L., Fenton R.A.,
RA Thevenod F.;
RT "Evidence for mitochondrial localization of divalent metal transporter 1
RT (DMT1).";
RL FASEB J. 28:2134-2145(2014).
RN [19]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-86; ASN-89 AND
RP MET-265.
RX PubMed=25326704; DOI=10.1038/nsmb.2904;
RA Ehrnstorfer I.A., Geertsma E.R., Pardon E., Steyaert J., Dutzler R.;
RT "Crystal structure of a SLC11 (NRAMP) transporter reveals the basis for
RT transition-metal ion transport.";
RL Nat. Struct. Mol. Biol. 21:990-996(2014).
RN [20]
RP INTERACTION WITH ARRDC1, AND SUBCELLULAR LOCATION.
RX PubMed=27462458; DOI=10.1038/celldisc.2016.11;
RA Mackenzie K., Foot N.J., Anand S., Dalton H.E., Chaudhary N., Collins B.M.,
RA Mathivanan S., Kumar S.;
RT "Regulation of the divalent metal ion transporter via membrane budding.";
RL Cell Discov. 2:16011-16011(2016).
RN [21]
RP VARIANT AHMIO1 ASP-399.
RX PubMed=15459009; DOI=10.1182/blood-2004-07-2966;
RA Mims M.P., Guan Y., Pospisilova D., Priwitzerova M., Indrak K., Ponka P.,
RA Divoky V., Prchal J.T.;
RT "Identification of a human mutation of DMT1 in a patient with microcytic
RT anemia and iron overload.";
RL Blood 105:1337-1342(2005).
RN [22]
RP VARIANT AHMIO1 CYS-416.
RX PubMed=16160008; DOI=10.1182/blood-2005-06-2477;
RA Iolascon A., d'Apolito M., Servedio V., Cimmino F., Piga A.,
RA Camaschella C.;
RT "Microcytic anemia and hepatic iron overload in a child with compound
RT heterozygous mutations in DMT1 (SCL11A2).";
RL Blood 107:349-354(2006).
RN [23]
RP VARIANTS AHMIO1 VAL-114 DEL AND VAL-212.
RX PubMed=16439678; DOI=10.1182/blood-2005-10-4269;
RA Beaumont C., Delaunay J., Hetet G., Grandchamp B., de Montalembert M.,
RA Tchernia G.;
RT "Two new human DMT1 gene mutations in a patient with microcytic anemia, low
RT ferritinemia, and liver iron overload.";
RL Blood 107:4168-4170(2006).
RN [24]
RP VARIANT [LARGE SCALE ANALYSIS] THR-48.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Important in metal transport, in particular iron. Can also
CC transport manganese, cobalt, cadmium, nickel, vanadium and lead.
CC Involved in apical iron uptake into duodenal enterocytes. Involved in
CC iron transport from acidified endosomes into the cytoplasm of erythroid
CC precursor cells. May play an important role in hepatic iron
CC accumulation and tissue iron distribution. May serve to import iron
CC into the mitochondria. {ECO:0000269|PubMed:17109629,
CC ECO:0000269|PubMed:24448823, ECO:0000269|PubMed:25326704,
CC ECO:0000269|PubMed:25491917}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 5.5-6.5 for Fe(2+) uptake.
CC {ECO:0000269|PubMed:17293870};
CC -!- SUBUNIT: Forms a complex with NDFIP1 and NEDD4L, in cortical neurons,
CC in response to iron and colbalt exposure; this interaction leads to
CC ubiquitination by NEDD4L and proteasome-dependent degradation.
CC Interacts with NDFIP2. Interacts with COX2 and TOM6 at the outer
CC mitochondrion membrane. Interacts with ARRDC1; controls the
CC incorporation of SLC11A2 into extracellular vesicles through an
CC ubiquitination-dependent mechanism (PubMed:27462458). Interacts with
CC ARRDC4; controls the incorporation of SLC11A2 into extracellular
CC vesicles through an ubiquitination-dependent mechanism (By similarity).
CC {ECO:0000250|UniProtKB:P49282, ECO:0000269|PubMed:18776082,
CC ECO:0000269|PubMed:19706893, ECO:0000269|PubMed:24448823,
CC ECO:0000269|PubMed:27462458}.
CC -!- INTERACTION:
CC P49281; Q9BT67: NDFIP1; NbExp=2; IntAct=EBI-4319335, EBI-11732799;
CC P49281; Q96PU5: NEDD4L; NbExp=2; IntAct=EBI-4319335, EBI-717962;
CC P49281-3; P00403: MT-CO2; NbExp=2; IntAct=EBI-10828817, EBI-2105756;
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cell membrane
CC {ECO:0000269|PubMed:12475959, ECO:0000269|PubMed:25491917}; Multi-pass
CC membrane protein {ECO:0000305}. Early endosome
CC {ECO:0000269|PubMed:12475959}.
CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:12475959,
CC ECO:0000269|PubMed:18776082, ECO:0000269|PubMed:25491917}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:18776082}. Mitochondrion outer
CC membrane {ECO:0000269|PubMed:24448823}; Multi-pass membrane protein.
CC Cell membrane {ECO:0000269|PubMed:12475959,
CC ECO:0000269|PubMed:25326704, ECO:0000269|PubMed:25491917}; Multi-pass
CC membrane protein {ECO:0000305}. Note=Also found in extracellular
CC vesicles different from exosomes. {ECO:0000269|PubMed:27462458}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=2; Synonyms=Non-IRE, DMT1B;
CC IsoId=P49281-1; Sequence=Displayed;
CC Name=1; Synonyms=IRE;
CC IsoId=P49281-2; Sequence=VSP_003595;
CC Name=3; Synonyms=1A-IRE;
CC IsoId=P49281-3; Sequence=VSP_038144, VSP_003595;
CC Name=4; Synonyms=1A-Non-IRE;
CC IsoId=P49281-4; Sequence=VSP_038144;
CC Name=5;
CC IsoId=P49281-5; Sequence=VSP_046058, VSP_003595;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Isoform 1 is highly
CC expressed in brain. Isoform 2 is highly expressed in spleen, thymus and
CC pancreas. Isoform 3 and isoform 4 are abundantly expressed in duodenum
CC and kidney. {ECO:0000269|PubMed:12209011, ECO:0000269|PubMed:9642100}.
CC -!- PTM: Ubiquitinated by WWP2. {ECO:0000250}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:25491917}.
CC -!- DISEASE: Anemia, hypochromic microcytic, with iron overload 1 (AHMIO1)
CC [MIM:206100]: A hematologic disease characterized by abnormal
CC hemoglobin content in the erythrocytes which are reduced in size. The
CC disorder is due to an error of iron metabolism that results in high
CC serum iron, massive hepatic iron deposition, and absence of
CC sideroblasts and stainable bone marrow iron store. Despite adequate
CC transferrin-iron complex, delivery of iron to the erythroid bone marrow
CC is apparently insufficient for the demands of hemoglobin synthesis.
CC {ECO:0000269|PubMed:15459009, ECO:0000269|PubMed:16160008,
CC ECO:0000269|PubMed:16439678}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: NRAMP2-mediated iron uptake is markedly stimulated by
CC nifedipine in a concentration-dependent manner.
CC -!- SIMILARITY: Belongs to the NRAMP family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH02592.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAA34374.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AB004857; BAA24933.1; -; mRNA.
DR EMBL; AB015355; BAA34374.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AF064482; AAC21460.1; -; Genomic_DNA.
DR EMBL; AF064476; AAC21460.1; JOINED; Genomic_DNA.
DR EMBL; AF064477; AAC21460.1; JOINED; Genomic_DNA.
DR EMBL; AF064478; AAC21460.1; JOINED; Genomic_DNA.
DR EMBL; AF064479; AAC21460.1; JOINED; Genomic_DNA.
DR EMBL; AF064480; AAC21460.1; JOINED; Genomic_DNA.
DR EMBL; AF064481; AAC21460.1; JOINED; Genomic_DNA.
DR EMBL; AF064483; AAC21461.1; -; Genomic_DNA.
DR EMBL; AF064476; AAC21461.1; JOINED; Genomic_DNA.
DR EMBL; AF064477; AAC21461.1; JOINED; Genomic_DNA.
DR EMBL; AF064478; AAC21461.1; JOINED; Genomic_DNA.
DR EMBL; AF064479; AAC21461.1; JOINED; Genomic_DNA.
DR EMBL; AF064480; AAC21461.1; JOINED; Genomic_DNA.
DR EMBL; AF064481; AAC21461.1; JOINED; Genomic_DNA.
DR EMBL; AF064482; AAC21461.1; JOINED; Genomic_DNA.
DR EMBL; AF064484; AAC21459.1; -; mRNA.
DR EMBL; AJ493662; CAD38517.1; -; mRNA.
DR EMBL; AF046997; AAC18078.1; -; mRNA.
DR EMBL; AK094735; BAG52920.1; -; mRNA.
DR EMBL; AK296445; BAG59096.1; -; mRNA.
DR EMBL; AK316507; BAH14878.1; -; mRNA.
DR EMBL; AB062284; BAB93467.1; -; mRNA.
DR EMBL; AC087884; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471111; EAW58159.1; -; Genomic_DNA.
DR EMBL; BC002592; AAH02592.1; ALT_INIT; mRNA.
DR EMBL; BC100014; AAI00015.1; -; mRNA.
DR EMBL; L37347; AAA79219.1; -; mRNA.
DR CCDS; CCDS53791.1; -. [P49281-5]
DR CCDS; CCDS53792.1; -. [P49281-1]
DR CCDS; CCDS53793.1; -. [P49281-3]
DR CCDS; CCDS8805.1; -. [P49281-2]
DR PIR; I57022; I57022.
DR RefSeq; NP_000608.1; NM_000617.2. [P49281-2]
DR RefSeq; NP_001167596.1; NM_001174125.1. [P49281-3]
DR RefSeq; NP_001167597.1; NM_001174126.1. [P49281-1]
DR RefSeq; NP_001167598.1; NM_001174127.1. [P49281-1]
DR RefSeq; NP_001167599.1; NM_001174128.1. [P49281-2]
DR RefSeq; NP_001167600.1; NM_001174129.1. [P49281-2]
DR RefSeq; NP_001167601.1; NM_001174130.1. [P49281-5]
DR RefSeq; XP_005268968.1; XM_005268911.3.
DR RefSeq; XP_011536706.1; XM_011538404.2. [P49281-1]
DR RefSeq; XP_011536707.1; XM_011538405.2. [P49281-1]
DR RefSeq; XP_016874844.1; XM_017019355.1.
DR PDB; 5F0L; X-ray; 3.20 A; D=545-568.
DR PDB; 5F0M; X-ray; 3.10 A; D=549-560.
DR PDB; 5F0P; X-ray; 2.78 A; D=549-560.
DR PDB; 7BLO; EM; 9.50 A; H/N=551-560.
DR PDB; 7BLQ; EM; 9.20 A; U/V=551-560.
DR PDBsum; 5F0L; -.
DR PDBsum; 5F0M; -.
DR PDBsum; 5F0P; -.
DR PDBsum; 7BLO; -.
DR PDBsum; 7BLQ; -.
DR AlphaFoldDB; P49281; -.
DR SMR; P49281; -.
DR BioGRID; 110950; 48.
DR CORUM; P49281; -.
DR DIP; DIP-48957N; -.
DR IntAct; P49281; 6.
DR STRING; 9606.ENSP00000378364; -.
DR BindingDB; P49281; -.
DR ChEMBL; CHEMBL1932895; -.
DR DrugBank; DB09130; Copper.
DR DrugBank; DB15598; Ferric maltol.
DR DrugBank; DB13257; Ferrous sulfate anhydrous.
DR DrugBank; DB06796; Mangafodipir.
DR DrugBank; DB14520; Tetraferric tricitrate decahydrate.
DR GuidetoPHARMACOLOGY; 967; -.
DR TCDB; 2.A.55.2.1; the metal ion (mn(2+)-iron) transporter (nramp) family.
DR GlyGen; P49281; 2 sites.
DR iPTMnet; P49281; -.
DR PhosphoSitePlus; P49281; -.
DR SwissPalm; P49281; -.
DR BioMuta; SLC11A2; -.
DR DMDM; 8247934; -.
DR EPD; P49281; -.
DR jPOST; P49281; -.
DR MassIVE; P49281; -.
DR MaxQB; P49281; -.
DR PaxDb; P49281; -.
DR PeptideAtlas; P49281; -.
DR PRIDE; P49281; -.
DR ProteomicsDB; 27377; -.
DR ProteomicsDB; 55979; -. [P49281-1]
DR ProteomicsDB; 55980; -. [P49281-2]
DR ProteomicsDB; 55981; -. [P49281-3]
DR ProteomicsDB; 55982; -. [P49281-4]
DR Antibodypedia; 26282; 377 antibodies from 31 providers.
DR DNASU; 4891; -.
DR Ensembl; ENST00000262052.9; ENSP00000262052.5; ENSG00000110911.17. [P49281-2]
DR Ensembl; ENST00000394904.9; ENSP00000378364.3; ENSG00000110911.17. [P49281-3]
DR Ensembl; ENST00000541174.6; ENSP00000444542.2; ENSG00000110911.17. [P49281-2]
DR Ensembl; ENST00000545993.7; ENSP00000442810.2; ENSG00000110911.17. [P49281-5]
DR Ensembl; ENST00000546636.5; ENSP00000449008.1; ENSG00000110911.17. [P49281-1]
DR Ensembl; ENST00000547198.5; ENSP00000446769.1; ENSG00000110911.17. [P49281-1]
DR Ensembl; ENST00000547688.7; ENSP00000449200.2; ENSG00000110911.17. [P49281-4]
DR Ensembl; ENST00000644495.1; ENSP00000494107.1; ENSG00000110911.17. [P49281-1]
DR GeneID; 4891; -.
DR KEGG; hsa:4891; -.
DR MANE-Select; ENST00000262052.9; ENSP00000262052.5; NM_000617.3; NP_000608.1. [P49281-2]
DR UCSC; uc001rxc.5; human. [P49281-1]
DR CTD; 4891; -.
DR DisGeNET; 4891; -.
DR GeneCards; SLC11A2; -.
DR HGNC; HGNC:10908; SLC11A2.
DR HPA; ENSG00000110911; Low tissue specificity.
DR MalaCards; SLC11A2; -.
DR MIM; 206100; phenotype.
DR MIM; 600523; gene.
DR neXtProt; NX_P49281; -.
DR OpenTargets; ENSG00000110911; -.
DR Orphanet; 83642; Microcytic anemia with liver iron overload.
DR PharmGKB; PA259; -.
DR VEuPathDB; HostDB:ENSG00000110911; -.
DR eggNOG; KOG1291; Eukaryota.
DR GeneTree; ENSGT00940000155330; -.
DR InParanoid; P49281; -.
DR OMA; PHTIYLG; -.
DR OrthoDB; 666470at2759; -.
DR PhylomeDB; P49281; -.
DR TreeFam; TF315185; -.
DR PathwayCommons; P49281; -.
DR Reactome; R-HSA-425410; Metal ion SLC transporters.
DR Reactome; R-HSA-5619048; Defective SLC11A2 causes hypochromic microcytic anemia, with iron overload 1 (AHMIO1).
DR Reactome; R-HSA-917937; Iron uptake and transport.
DR SignaLink; P49281; -.
DR SIGNOR; P49281; -.
DR BioGRID-ORCS; 4891; 15 hits in 1089 CRISPR screens.
DR ChiTaRS; SLC11A2; human.
DR GeneWiki; DMT1; -.
DR GenomeRNAi; 4891; -.
DR Pharos; P49281; Tchem.
DR PRO; PR:P49281; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; P49281; protein.
DR Bgee; ENSG00000110911; Expressed in inferior vagus X ganglion and 207 other tissues.
DR ExpressionAtlas; P49281; baseline and differential.
DR Genevisible; P49281; HS.
DR GO; GO:0045177; C:apical part of cell; IDA:UniProtKB.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0045178; C:basal part of cell; IDA:UniProtKB.
DR GO; GO:0031526; C:brush border membrane; ISS:BHF-UCL.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:1903561; C:extracellular vesicle; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IDA:BHF-UCL.
DR GO; GO:0005765; C:lysosomal membrane; IDA:BHF-UCL.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0070826; C:paraferritin complex; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0005773; C:vacuole; IMP:BHF-UCL.
DR GO; GO:0046870; F:cadmium ion binding; IDA:UniProtKB.
DR GO; GO:0015086; F:cadmium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0015087; F:cobalt ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005375; F:copper ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0015093; F:ferrous iron transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0022890; F:inorganic cation transmembrane transporter activity; IGI:UniProtKB.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0015094; F:lead ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0015099; F:nickel cation transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:1905394; F:retromer complex binding; IDA:UniProtKB.
DR GO; GO:0015295; F:solute:proton symporter activity; IDA:UniProtKB.
DR GO; GO:0046915; F:transition metal ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015100; F:vanadium ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0070574; P:cadmium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:UniProtKB.
DR GO; GO:0006824; P:cobalt ion transport; IDA:UniProtKB.
DR GO; GO:0006825; P:copper ion transport; IDA:BHF-UCL.
DR GO; GO:0048813; P:dendrite morphogenesis; IEA:Ensembl.
DR GO; GO:0003032; P:detection of oxygen; IEP:UniProtKB.
DR GO; GO:0048821; P:erythrocyte development; IEA:Ensembl.
DR GO; GO:0006783; P:heme biosynthetic process; IEA:Ensembl.
DR GO; GO:0033212; P:iron import into cell; IDA:UniProtKB.
DR GO; GO:0034755; P:iron ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:0006826; P:iron ion transport; IDA:BHF-UCL.
DR GO; GO:0015692; P:lead ion transport; IDA:BHF-UCL.
DR GO; GO:0007611; P:learning or memory; IEA:Ensembl.
DR GO; GO:0006828; P:manganese ion transport; IDA:BHF-UCL.
DR GO; GO:0060586; P:multicellular organismal iron ion homeostasis; IMP:BHF-UCL.
DR GO; GO:0015675; P:nickel cation transport; IDA:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; IEP:UniProtKB.
DR GO; GO:0010039; P:response to iron ion; IEP:UniProtKB.
DR GO; GO:0015676; P:vanadium ion transport; IDA:UniProtKB.
DR HAMAP; MF_00221; NRAMP; 1.
DR InterPro; IPR001046; NRAMP_fam.
DR PANTHER; PTHR11706; PTHR11706; 1.
DR Pfam; PF01566; Nramp; 1.
DR PRINTS; PR00447; NATRESASSCMP.
DR TIGRFAMs; TIGR01197; nramp; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Disease variant;
KW Endosome; Glycoprotein; Ion transport; Iron; Iron transport; Membrane;
KW Mitochondrion; Mitochondrion outer membrane; Phosphoprotein;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport;
KW Ubl conjugation.
FT CHAIN 1..568
FT /note="Natural resistance-associated macrophage protein 2"
FT /id="PRO_0000212594"
FT TOPO_DOM 1..69
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 70..90
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 91..96
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 97..117
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 118..154
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 155..175
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 176..179
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 180..200
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 201..208
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 209..229
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 230..255
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 256..276
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 277..301
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 302..322
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 323..360
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 361..381
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 382..408
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 409..429
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 430..440
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 441..461
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 462..482
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 483..503
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 504..506
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 507..527
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 528..568
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..40
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 16..40
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 564
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49282"
FT MOD_RES 567
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49282"
FT CARBOHYD 336
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 349
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..12
FT /note="MVLGPEQKMSDD -> MSTVDYLN (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046058"
FT VAR_SEQ 1
FT /note="M -> MRKKQLKTEAAPHCELKSYSKNSATQVSTM (in isoform 3
FT and isoform 4)"
FT /evidence="ECO:0000303|PubMed:12209011,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_038144"
FT VAR_SEQ 544..568
FT /note="CHLGLTAQPELYLLNTMDADSLVSR -> VSISKGLLTEEATRGYVK (in
FT isoform 1, isoform 3 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:12209011,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:7613023, ECO:0000303|PubMed:9464519,
FT ECO:0000303|PubMed:9642100"
FT /id="VSP_003595"
FT VARIANT 48
FT /note="A -> T (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs760028045)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036434"
FT VARIANT 114
FT /note="Missing (in AHMIO1)"
FT /evidence="ECO:0000269|PubMed:16439678"
FT /id="VAR_033011"
FT VARIANT 212
FT /note="G -> V (in AHMIO1; dbSNP:rs121918367)"
FT /evidence="ECO:0000269|PubMed:16439678"
FT /id="VAR_033012"
FT VARIANT 399
FT /note="E -> D (in AHMIO1; increased skipping of exon 12;
FT dbSNP:rs121918365)"
FT /evidence="ECO:0000269|PubMed:15459009"
FT /id="VAR_033013"
FT VARIANT 416
FT /note="R -> C (in AHMIO1; dbSNP:rs121918366)"
FT /evidence="ECO:0000269|PubMed:16160008"
FT /id="VAR_033014"
FT VARIANT 435
FT /note="L -> I (in dbSNP:rs144863268)"
FT /evidence="ECO:0000269|PubMed:9642100"
FT /id="VAR_008882"
FT MUTAGEN 86
FT /note="D->A: Abolishes ion transport across the cell
FT membrane."
FT /evidence="ECO:0000269|PubMed:25326704"
FT MUTAGEN 89
FT /note="N->A: Decreases affinity for divalent metal cations.
FT Impairs ion transport across the cell membrane."
FT /evidence="ECO:0000269|PubMed:25326704"
FT MUTAGEN 265
FT /note="M->A: Abolishes ion transport across the cell
FT membrane."
FT /evidence="ECO:0000269|PubMed:25326704"
FT MUTAGEN 555
FT /note="Y->A: Abolishes localization at early endosomes and
FT leads to localization at late endosomes and lysosomes."
FT /evidence="ECO:0000269|PubMed:12475959"
FT MUTAGEN 557
FT /note="L->A: Abolishes localization at early endosomes and
FT leads to localization at late endosomes and lysosomes."
FT /evidence="ECO:0000269|PubMed:12475959"
FT CONFLICT 58..59
FT /note="PE -> GM (in Ref. 11; AAA79219)"
FT /evidence="ECO:0000305"
FT CONFLICT 81
FT /note="S -> T (in Ref. 11; AAA79219)"
FT /evidence="ECO:0000305"
FT CONFLICT 119
FT /note="Q -> K (in Ref. 10; AAI00015)"
FT /evidence="ECO:0000305"
FT CONFLICT 124
FT /note="R -> K (in Ref. 11; AAA79219)"
FT /evidence="ECO:0000305"
FT CONFLICT 462..463
FT /note="SL -> YV (in Ref. 11; AAA79219)"
FT /evidence="ECO:0000305"
FT CONFLICT 476
FT /note="W -> C (in Ref. 11; AAA79219)"
FT /evidence="ECO:0000305"
FT STRAND 554..556
FT /evidence="ECO:0007829|PDB:5F0P"
FT CONFLICT P49281-5:6
FT /note="Y -> S (in Ref. 6; BAG59096/BAH14878)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 568 AA; 62266 MW; 4E45D6A448A23263 CRC64;
MVLGPEQKMS DDSVSGDHGE SASLGNINPA YSNPSLSQSP GDSEEYFATY FNEKISIPEE
EYSCFSFRKL WAFTGPGFLM SIAYLDPGNI ESDLQSGAVA GFKLLWILLL ATLVGLLLQR
LAARLGVVTG LHLAEVCHRQ YPKVPRVILW LMVELAIIGS DMQEVIGSAI AINLLSVGRI
PLWGGVLITI ADTFVFLFLD KYGLRKLEAF FGFLITIMAL TFGYEYVTVK PSQSQVLKGM
FVPSCSGCRT PQIEQAVGIV GAVIMPHNMY LHSALVKSRQ VNRNNKQEVR EANKYFFIES
CIALFVSFII NVFVVSVFAE AFFGKTNEQV VEVCTNTSSP HAGLFPKDNS TLAVDIYKGG
VVLGCYFGPA ALYIWAVGIL AAGQSSTMTG TYSGQFVMEG FLNLKWSRFA RVVLTRSIAI
IPTLLVAVFQ DVEHLTGMND FLNVLQSLQL PFALIPILTF TSLRPVMSDF ANGLGWRIAG
GILVLIICSI NMYFVVVYVR DLGHVALYVV AAVVSVAYLG FVFYLGWQCL IALGMSFLDC
GHTCHLGLTA QPELYLLNTM DADSLVSR
