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2.A.55.2.1
Heavy metal (Fe2+, Zn2+, Mn2+, Cu2+, Cd2+, Co2+, Ni2+ and Pb2+) ion:H+ symporter, Nramp2 or divalent metal transporter, DMT1 (Garrick et al. 2003). A 12 TMS topology with intracellular N- and C- termini is established. Two-fold structural symmetry in the arrangement of membrane helices for TM1-5 and TM6-10 (conserved Slc11 hydrophobic core) is suggested (Czachorowski et al., 2009).  A conserved motif in a central flexible region of TMS1 (DPGN) binds the metal ion (Wang et al. 2011).  Upregulated by iron deficiency and downregulated by iron loading (Nam et al. 2013).  NRAMP2 also serves as the Sindbis alpha virus receptor (Rose et al. 2011).  DMT1 interacts with the iron chaparone protein, PCBP2 (Q15366), in an iron-dependent fashion, and may be essential for iron uptake (Lane and Richardson 2014). Mutations cause a syndrome of congenital microcytic hypochromic anemia, poorly responsive to oral iron treatment, with liver iron overload associated paradoxically with normal to moderately elevated serum ferritin levels (Beaumont et al. 2006). Nigral iron accumulation and activation of NMDA receptors (NRs) contribute to the neurodegeneration of dopamine (DA) neurons in Parkinson's disease (PD), and activation of NRs participates in iron metabolism in the hippocampus (Xu et al. 2018). NR inhibitors MK-801 and AP5 protect nigrostriatal projection systems and reduce nigral iron levels. NMDA treatment increased the expression of DMT1 and decreased the expression of the iron exporter ferroportin 1 (Fpn1) (TC# 2.A.100.1.4) (Xu et al. 2018).

Accession Number:P49281
Protein Name:NRM2 aka Nramp2 aka SLC11A2
Length:568
Molecular Weight:62266.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:11
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Fe2+, Zn2+, Mn2+, Cu2+, Cd2+, Ni2+, Pb2+

Cross database links:

DIP-48957N
Genevestigator: P49281 P49281
eggNOG: prNOG17896 COG1914
RefSeq: NP_000608.1   
Entrez Gene ID: 4891   
Pfam: PF01566   
OMIM: 206100  phenotype
600523  gene
KEGG: hsa:4891    hsa:4891   

Gene Ontology

GO:0016324 C:apical plasma membrane
GO:0045178 C:basal part of cell
GO:0009986 C:cell surface
GO:0031410 C:cytoplasmic vesicle
GO:0005769 C:early endosome
GO:0016021 C:integral to membrane
GO:0005770 C:late endosome
GO:0031902 C:late endosome membrane
GO:0005765 C:lysosomal membrane
GO:0005764 C:lysosome
GO:0005634 C:nucleus
GO:0070826 C:paraferritin complex
GO:0048471 C:perinuclear region of cytoplasm
GO:0005886 C:plasma membrane
GO:0055037 C:recycling endosome
GO:0005802 C:trans-Golgi network
GO:0015086 F:cadmium ion transmembrane transporter activity
GO:0015087 F:cobalt ion transmembrane transporter activity
GO:0005375 F:copper ion transmembrane transporter activity
GO:0015093 F:ferrous iron transmembrane transporter acti...
GO:0015094 F:lead ion transmembrane transporter activity
GO:0005384 F:manganese ion transmembrane transporter act...
GO:0015099 F:nickel ion transmembrane transporter activity
GO:0005515 F:protein binding
GO:0015295 F:solute:hydrogen symporter activity
GO:0015100 F:vanadium ion transmembrane transporter acti...
GO:0005385 F:zinc ion transmembrane transporter activity
GO:0006919 P:activation of caspase activity
GO:0070574 P:cadmium ion transmembrane transport
GO:0034599 P:cellular response to oxidative stress
GO:0006824 P:cobalt ion transport
GO:0006825 P:copper ion transport
GO:0003032 P:detection of oxygen
GO:0070627 P:ferrous iron import
GO:0015684 P:ferrous iron transport
GO:0015692 P:lead ion transport
GO:0006828 P:manganese ion transport
GO:0060586 P:multicellular organismal iron ion homeostasis
GO:0015675 P:nickel ion transport
GO:0001666 P:response to hypoxia
GO:0010039 P:response to iron ion
GO:0015676 P:vanadium ion transport
GO:0005903 C:brush border
GO:0012505 C:endomembrane system
GO:0005887 C:integral to plasma membrane
GO:0046870 F:cadmium ion binding
GO:0050897 F:cobalt ion binding
GO:0005507 F:copper ion binding
GO:0015093 F:ferrous iron transmembrane transporter activity
GO:0015078 F:hydrogen ion transmembrane transporter activity
GO:0005506 F:iron ion binding
GO:0030145 F:manganese ion binding
GO:0005384 F:manganese ion transmembrane transporter activity
GO:0016151 F:nickel cation binding
GO:0015099 F:nickel cation transmembrane transporter activity
GO:0015100 F:vanadium ion transmembrane transporter activity
GO:0008270 F:zinc ion binding
GO:0006919 P:activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0006879 P:cellular iron ion homeostasis
GO:0048813 P:dendrite morphogenesis
GO:0048821 P:erythrocyte development
GO:0006783 P:heme biosynthetic process
GO:0007611 P:learning or memory
GO:0046686 P:response to cadmium ion
GO:0010288 P:response to lead ion
GO:0010042 P:response to manganese ion

References (28)

[1] “Complete nucleotide sequence of human NRAMP2 cDNA.”  Kishi F.et.al.   9464519
[2] “Human natural resistance-associated macrophage protein 2: gene cloning and protein identification.”  Kishi F.et.al.   9790986
[3] “The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms.”  Lee P.L.et.al.   9642100
[4] “Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function.”  Hubert N.et.al.   12209011
[5] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[6] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[7] “Cloning and characterization of a second human NRAMP gene on chromosome 12q13.”  Vidal S.et.al.   7613023
[8] “Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1).”  Mackenzie B.et.al.   17109629
[9] “Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1.”  Ludwiczek S.et.al.   17293870
[10] “Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.”  Mims M.P.et.al.   15459009
[11] “Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).”  Iolascon A.et.al.   16160008
[12] “Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload.”  Beaumont C.et.al.   16439678
[13] “The consensus coding sequences of human breast and colorectal cancers.”  Sjoeblom T.et.al.   16959974
[14] “Complete nucleotide sequence of human NRAMP2 cDNA.”  Kishi F.et.al.   9464519
[15] “Human natural resistance-associated macrophage protein 2: gene cloning and protein identification.”  Kishi F.et.al.   9790986
[16] “The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms.”  Lee P.L.et.al.   9642100
[17] “Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function.”  Hubert N.et.al.   12209011
[18] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[19] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[20] “Cloning and characterization of a second human NRAMP gene on chromosome 12q13.”  Vidal S.et.al.   7613023
[21] “Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1).”  Mackenzie B.et.al.   17109629
[22] “Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1.”  Ludwiczek S.et.al.   17293870
[23] “Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2.”  Foot N.J.et.al.   18776082
[24] “Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons.”  Howitt J.et.al.   19706893
[25] “Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.”  Mims M.P.et.al.   15459009
[26] “Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).”  Iolascon A.et.al.   16160008
[27] “Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload.”  Beaumont C.et.al.   16439678
[28] “The consensus coding sequences of human breast and colorectal cancers.”  Sjoeblom T.et.al.   16959974

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FASTA formatted sequence
1:	MVLGPEQKMS DDSVSGDHGE SASLGNINPA YSNPSLSQSP GDSEEYFATY FNEKISIPEE 
61:	EYSCFSFRKL WAFTGPGFLM SIAYLDPGNI ESDLQSGAVA GFKLLWILLL ATLVGLLLQR 
121:	LAARLGVVTG LHLAEVCHRQ YPKVPRVILW LMVELAIIGS DMQEVIGSAI AINLLSVGRI 
181:	PLWGGVLITI ADTFVFLFLD KYGLRKLEAF FGFLITIMAL TFGYEYVTVK PSQSQVLKGM 
241:	FVPSCSGCRT PQIEQAVGIV GAVIMPHNMY LHSALVKSRQ VNRNNKQEVR EANKYFFIES 
301:	CIALFVSFII NVFVVSVFAE AFFGKTNEQV VEVCTNTSSP HAGLFPKDNS TLAVDIYKGG 
361:	VVLGCYFGPA ALYIWAVGIL AAGQSSTMTG TYSGQFVMEG FLNLKWSRFA RVVLTRSIAI 
421:	IPTLLVAVFQ DVEHLTGMND FLNVLQSLQL PFALIPILTF TSLRPVMSDF ANGLGWRIAG 
481:	GILVLIICSI NMYFVVVYVR DLGHVALYVV AAVVSVAYLG FVFYLGWQCL IALGMSFLDC 
541:	GHTCHLGLTA QPELYLLNTM DADSLVSR