Natural resistance-associated macrophage protein 2

Details

Name
Natural resistance-associated macrophage protein 2
Kind
protein
Synonyms
  • DCT1
  • Divalent cation transporter 1
  • Divalent metal transporter 1
  • DMT-1
  • DMT1
  • NRAMP 2
  • NRAMP2
  • Solute carrier family 11 member 2
Gene Name
SLC11A2
UniProtKB Entry
P49281Swiss-Prot
Organism
Humans
NCBI Taxonomy ID
9606
Amino acid sequence
>lcl|BSEQ0049446|Natural resistance-associated macrophage protein 2
MVLGPEQKMSDDSVSGDHGESASLGNINPAYSNPSLSQSPGDSEEYFATYFNEKISIPEE
EYSCFSFRKLWAFTGPGFLMSIAYLDPGNIESDLQSGAVAGFKLLWILLLATLVGLLLQR
LAARLGVVTGLHLAEVCHRQYPKVPRVILWLMVELAIIGSDMQEVIGSAIAINLLSVGRI
PLWGGVLITIADTFVFLFLDKYGLRKLEAFFGFLITIMALTFGYEYVTVKPSQSQVLKGM
FVPSCSGCRTPQIEQAVGIVGAVIMPHNMYLHSALVKSRQVNRNNKQEVREANKYFFIES
CIALFVSFIINVFVVSVFAEAFFGKTNEQVVEVCTNTSSPHAGLFPKDNSTLAVDIYKGG
VVLGCYFGPAALYIWAVGILAAGQSSTMTGTYSGQFVMEGFLNLKWSRFARVVLTRSIAI
IPTLLVAVFQDVEHLTGMNDFLNVLQSLQLPFALIPILTFTSLRPVMSDFANGLGWRIAG
GILVLIICSINMYFVVVYVRDLGHVALYVVAAVVSVAYLGFVFYLGWQCLIALGMSFLDC
GHTCHLGLTAQPELYLLNTMDADSLVSR
Number of residues
568
Molecular Weight
62265.195
Theoretical pI
Not Available
GO Classification
Functions
retromer complex binding
Processes
intracellular iron ion homeostasis / iron import into cell / iron ion transmembrane transport / iron ion transport / multicellular organismal-level iron ion homeostasis
Components
early endosome membrane / endosome membrane / extracellular vesicle / Golgi apparatus / recycling endosome membrane
General Function
Proton-coupled metal ion symporter operating with a proton to metal ion stoichiometry of 1:1 (PubMed:17109629, PubMed:17293870, PubMed:22736759, PubMed:25326704, PubMed:25491917). Selectively transports various divalent metal cations, in decreasing affinity: Cd(2+) > Fe(2+) > Co(2+), Mn(2+) >> Zn(2+), Ni(2+), VO(2+) (PubMed:17109629, PubMed:17293870, PubMed:22736759, PubMed:25326704, PubMed:25491917). Essential for maintenance of iron homeostasis by modulating intestinal absorption of dietary Fe(2+) and TF-associated endosomal Fe(2+) transport in erythroid precursors and other cells (By similarity). Enables Fe(2+) and Mn(2+) ion entry into mitochondria, and is thus expected to promote mitochondrial heme synthesis, iron-sulfur cluster biogenesis and antioxidant defense (By similarity) (PubMed:24448823). Can mediate uncoupled fluxes of either protons or metal ions
Specific Function
Cadmium ion binding
Pfam Domain Function
Signal Regions
Not Available
Transmembrane Regions
70-90 97-117 155-175 180-200 209-229 256-276 302-322 361-381 409-429 441-461 483-503 507-527
Cellular Location
Early endosome membrane
Gene sequence
>lcl|BSEQ0049447|Natural resistance-associated macrophage protein 2 (SLC11A2)
ATGGTGCTGGGTCCTGAACAGAAGATGTCAGATGACAGTGTTTCTGGAGATCATGGGGAG
TCTGCCAGTCTTGGTAACATCAACCCTGCCTATAGTAATCCCTCTCTTTCACAGTCCCCT
GGGGACTCAGAGGAGTACTTCGCCACTTACTTTAATGAGAAGATCTCCATTCCTGAGGAG
GAGTACTCTTGTTTTAGCTTTCGTAAACTCTGGGCTTTCACCGGACCAGGTTTTCTTATG
AGCATTGCCTACCTGGATCCAGGAAATATTGAATCCGATTTGCAGTCTGGAGCAGTGGCT
GGATTTAAGTTGCTCTGGATCCTTCTGTTGGCCACCCTTGTGGGGCTGCTGCTCCAGCGG
CTTGCAGCTAGACTGGGAGTGGTTACTGGGCTGCATCTTGCTGAAGTATGTCACCGTCAG
TATCCCAAGGTCCCACGAGTCATCCTGTGGCTGATGGTGGAGTTGGCTATCATCGGCTCA
GACATGCAAGAAGTCATTGGCTCAGCCATTGCTATCAATCTTCTGTCTGTAGGAAGAATT
CCTCTGTGGGGTGGCGTTCTCATCACCATTGCAGATACTTTTGTATTTCTCTTCTTGGAC
AAATATGGCTTGCGGAAGCTAGAAGCATTTTTTGGCTTTCTCATCACTATTATGGCCCTC
ACATTTGGATATGAGTATGTTACAGTGAAACCCAGCCAGAGCCAGGTACTCAAGGGCATG
TTCGTACCATCCTGTTCAGGCTGTCGCACTCCACAGATTGAACAGGCTGTGGGCATCGTG
GGAGCTGTCATCATGCCACACAACATGTACCTGCATTCTGCCTTAGTCAAGTCTAGACAG
GTAAACCGGAACAATAAGCAGGAAGTTCGAGAAGCCAATAAGTACTTTTTCATTGAATCC
TGCATTGCACTCTTTGTTTCCTTCATCATCAATGTCTTTGTTGTCTCAGTCTTTGCTGAA
GCATTTTTTGGGAAAACCAACGAGCAGGTGGTTGAAGTCTGTACAAATACCAGCAGTCCT
CATGCTGGCCTCTTTCCTAAAGATAACTCGACACTGGCTGTGGACATCTACAAAGGGGGT
GTTGTGCTGGGATGTTACTTTGGGCCTGCTGCACTCTACATTTGGGCAGTGGGGATCCTG
GCTGCAGGACAGAGCTCCACCATGACAGGAACCTATTCTGGCCAGTTTGTCATGGAGGGA
TTCCTGAACCTAAAGTGGTCACGCTTTGCCCGAGTGGTTCTGACTCGCTCTATTGCCATC
ATCCCCACTCTGCTTGTTGCTGTCTTCCAAGATGTAGAGCATCTAACAGGGATGAATGAC
TTTCTGAATGTTCTACAGAGCTTACAGCTTCCCTTTGCTCTCATACCCATCCTCACATTT
ACGAGCTTGCGGCCAGTAATGAGTGACTTTGCCAATGGACTAGGCTGGCGGATTGCAGGA
GGAATCTTGGTCCTTATCATCTGTTCCATCAATATGTACTTTGTAGTGGTTTATGTCCGG
GACCTAGGGCATGTGGCATTATATGTGGTGGCTGCTGTGGTCAGCGTGGCTTATCTGGGC
TTTGTGTTCTACTTGGGTTGGCAATGTTTGATTGCACTGGGCATGTCCTTCCTGGACTGT
GGGCATACGTGCCATCTGGGATTGACAGCTCAGCCTGAACTCTATCTTCTGAACACCATG
GACGCTGACTCACTTGTGTCTAGATGA
Chromosome Location
12
Locus
12q13.12
External Identifiers
ResourceLink
UniProtKB IDP49281
UniProtKB Entry NameNRAM2_HUMAN
GeneCard IDSLC11A2
HGNC IDHGNC:10908
PDB ID(s)5F0L, 5F0M, 5F0P, 7BLO, 7BLQ
KEGG IDhsa:4891
IUPHAR/Guide To Pharmacology ID967
NCBI Gene ID4891
General References
  1. Kishi F, Tabuchi M: Complete nucleotide sequence of human NRAMP2 cDNA. Mol Immunol. 1997 Aug-Sep;34(12-13):839-42. [Article]
  2. Kishi F, Tabuchi M: Human natural resistance-associated macrophage protein 2: gene cloning and protein identification. Biochem Biophys Res Commun. 1998 Oct 29;251(3):775-83. [Article]
  3. Lee PL, Gelbart T, West C, Halloran C, Beutler E: The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis. 1998 Jun;24(2):199-215. [Article]
  4. Hubert N, Hentze MW: Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12345-50. Epub 2002 Sep 3. [Article]
  5. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
  6. Scherer SE, Muzny DM, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Montgomery KT, Morgan MB, Nazareth LV, Scott G, Sodergren E, Song XZ, Steffen D, Lovering RC, Wheeler DA, Worley KC, Yuan Y, Zhang Z, Adams CQ, Ansari-Lari MA, Ayele M, Brown MJ, Chen G, Chen Z, Clerc-Blankenburg KP, Davis C, Delgado O, Dinh HH, Draper H, Gonzalez-Garay ML, Havlak P, Jackson LR, Jacob LS, Kelly SH, Li L, Li Z, Liu J, Liu W, Lu J, Maheshwari M, Nguyen BV, Okwuonu GO, Pasternak S, Perez LM, Plopper FJ, Santibanez J, Shen H, Tabor PE, Verduzco D, Waldron L, Wang Q, Williams GA, Zhang J, Zhou J, Allen CC, Amin AG, Anyalebechi V, Bailey M, Barbaria JA, Bimage KE, Bryant NP, Burch PE, Burkett CE, Burrell KL, Calderon E, Cardenas V, Carter K, Casias K, Cavazos I, Cavazos SR, Ceasar H, Chacko J, Chan SN, Chavez D, Christopoulos C, Chu J, Cockrell R, Cox CD, Dang M, Dathorne SR, David R, Davis CM, Davy-Carroll L, Deshazo DR, Donlin JE, D'Souza L, Eaves KA, Egan A, Emery-Cohen AJ, Escotto M, Flagg N, Forbes LD, Gabisi AM, Garza M, Hamilton C, Henderson N, Hernandez O, Hines S, Hogues ME, Huang M, Idlebird DG, Johnson R, Jolivet A, Jones S, Kagan R, King LM, Leal B, Lebow H, Lee S, LeVan JM, Lewis LC, London P, Lorensuhewa LM, Loulseged H, Lovett DA, Lucier A, Lucier RL, Ma J, Madu RC, Mapua P, Martindale AD, Martinez E, Massey E, Mawhiney S, Meador MG, Mendez S, Mercado C, Mercado IC, Merritt CE, Miner ZL, Minja E, Mitchell T, Mohabbat F, Mohabbat K, Montgomery B, Moore N, Morris S, Munidasa M, Ngo RN, Nguyen NB, Nickerson E, Nwaokelemeh OO, Nwokenkwo S, Obregon M, Oguh M, Oragunye N, Oviedo RJ, Parish BJ, Parker DN, Parrish J, Parks KL, Paul HA, Payton BA, Perez A, Perrin W, Pickens A, Primus EL, Pu LL, Puazo M, Quiles MM, Quiroz JB, Rabata D, Reeves K, Ruiz SJ, Shao H, Sisson I, Sonaike T, Sorelle RP, Sutton AE, Svatek AF, Svetz LA, Tamerisa KS, Taylor TR, Teague B, Thomas N, Thorn RD, Trejos ZY, Trevino BK, Ukegbu ON, Urban JB, Vasquez LI, Vera VA, Villasana DM, Wang L, Ward-Moore S, Warren JT, Wei X, White F, Williamson AL, Wleczyk R, Wooden HS, Wooden SH, Yen J, Yoon L, Yoon V, Zorrilla SE, Nelson D, Kucherlapati R, Weinstock G, Gibbs RA: The finished DNA sequence of human chromosome 12. Nature. 2006 Mar 16;440(7082):346-51. [Article]
  7. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  8. Vidal S, Belouchi AM, Cellier M, Beatty B, Gros P: Cloning and characterization of a second human NRAMP gene on chromosome 12q13. Mamm Genome. 1995 Apr;6(4):224-30. [Article]
  9. Tabuchi M, Tanaka N, Nishida-Kitayama J, Ohno H, Kishi F: Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms. Mol Biol Cell. 2002 Dec;13(12):4371-87. [Article]
  10. Mackenzie B, Takanaga H, Hubert N, Rolfs A, Hediger MA: Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem J. 2007 Apr 1;403(1):59-69. [Article]
  11. Ludwiczek S, Theurl I, Muckenthaler MU, Jakab M, Mair SM, Theurl M, Kiss J, Paulmichl M, Hentze MW, Ritter M, Weiss G: Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med. 2007 Apr;13(4):448-54. Epub 2007 Feb 11. [Article]
  12. Foot NJ, Dalton HE, Shearwin-Whyatt LM, Dorstyn L, Tan SS, Yang B, Kumar S: Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood. 2008 Nov 15;112(10):4268-75. doi: 10.1182/blood-2008-04-150953. Epub 2008 Sep 5. [Article]
  13. Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan SS: Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15489-94. doi: 10.1073/pnas.0904880106. Epub 2009 Aug 25. [Article]
  14. Yanatori I, Yasui Y, Noguchi Y, Kishi F: Inhibition of iron uptake by ferristatin II is exerted through internalization of DMT1 at the plasma membrane. Cell Biol Int. 2015 Apr;39(4):427-34. doi: 10.1002/cbin.10403. Epub 2015 Jan 5. [Article]
  15. Wolff NA, Ghio AJ, Garrick LM, Garrick MD, Zhao L, Fenton RA, Thevenod F: Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1). FASEB J. 2014 May;28(5):2134-45. doi: 10.1096/fj.13-240564. Epub 2014 Jan 21. [Article]
  16. Ehrnstorfer IA, Geertsma ER, Pardon E, Steyaert J, Dutzler R: Crystal structure of a SLC11 (NRAMP) transporter reveals the basis for transition-metal ion transport. Nat Struct Mol Biol. 2014 Nov;21(11):990-6. doi: 10.1038/nsmb.2904. Epub 2014 Oct 19. [Article]
  17. Mims MP, Guan Y, Pospisilova D, Priwitzerova M, Indrak K, Ponka P, Divoky V, Prchal JT: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005 Feb 1;105(3):1337-42. Epub 2004 Sep 30. [Article]
  18. Iolascon A, d'Apolito M, Servedio V, Cimmino F, Piga A, Camaschella C: Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood. 2006 Jan 1;107(1):349-54. Epub 2005 Sep 13. [Article]
  19. Beaumont C, Delaunay J, Hetet G, Grandchamp B, de Montalembert M, Tchernia G: Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood. 2006 May 15;107(10):4168-70. Epub 2006 Jan 26. [Article]
  20. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE: The consensus coding sequences of human breast and colorectal cancers. Science. 2006 Oct 13;314(5797):268-74. Epub 2006 Sep 7. [Article]

Associated Data

Drug Relations
DrugDrug groupPharmacological action?TypeActionsDetails
Copperapproved, investigationalnotransportersubstrateDetails
Mangafodipirapproved, investigational, withdrawnunknowntransportersubstrateDetails
Ferrous sulfate anhydrousapprovedunknowntransportersubstrateDetails
Ferric maltolapprovedunknowntargetsubstrateDetails
Ferric maltolapprovedunknowntransportersubstrateDetails
Tetraferric tricitrate decahydrateapprovedunknowntransportersubstrateDetails
Manganese cationapproved, nutraceuticalunknowntransportersubstrateDetails