Natural resistance-associated macrophage protein
Natural resistance-associated macrophage proteins (NRAMPs) are members of the metal ion (Mn2+-iron) transporter family (TC# 2.A.55). The NRAMP family is a member of the large APC Superfamily of secondary carriers. Homologues of this family are found in various yeasts, plants, animals, archaea, and Gram-negative and Gram-positive bacteria termed "natural resistance-associated" macrophage proteins because one of the animal homologues plays a role in resistance to intracellular bacterial pathogens such as Salmonella enterica serovar Typhimurium, Leishmania donovani and Mycobacterium bovis. The natural history of SLC11 genes in vertebrates has been discussed by Neves et al. (2011). Proposed to be a distant member of the APC Superfamily, several human pathologies may result from defects in NRAMP-dependent Fe2+ or Mn2+ transport, including iron overload, neurodegenerative diseases and innate susceptibility to infectious diseases.
Humans and rodents possess two distinct NRAMPs. The broad specificity NRAMP2 (DMT1), which transports a range of divalent metal cations, transports Fe2+ and H+ with a 1:1 stoichiometry and apparent affinities of 6 μm and about 1 μm, respectively. Variable H+:Fe2+ stoichiometry has also been reported. The order of substrate preference for NRAMP2 is:
Fe2+> Zn2+> Mn2+> Co2+> Ca2+> Cu2+> Ni2+> Pb2+
Many of these ions can inhibit iron absorption. Mutation of NRAMP2 in rodents leads to defective endosomal iron export within the ferritin cycle, impaired intestinal iron absorption and microcytic anemia. Symptoms of Mn2+ deficiency are also seen. It is found in apical membranes of intestinal epithelial cells but also in late endosomes and lysosomes.
In contrast to the widely expressed NRAMP2, NRAMP1 is expressed primarily in macrophages and monocytes and appears to have a preference for Mn2+ rather than Fe2+. NRAMP1 (TC# 2.A.55.2.3) has been reported to function by metal:H+ antiport. It is hypothesized that a deficiency for Mn2+ or some other metal prevents the generation of reactive oxygenic and nitrogenic compounds that are used by macrophage to combat pathogens. This hypothesis is supported by studies on the bacterial NRAMP homologues which exhibit extremely high selectivity for Mn2+ over Fe2+, Zn2+ and other divalent cations. Regulation of these transporters in bacteria can occur through Fur, OxyR, and most commonly a DtxR homolog, MntR.
Smf and other homologues
The Smf1 protein of Saccharomyces cerevisiae appears to catalyze high-affinity (KM = 0.3 μm) Mn2+ uptake while the closely related Smf2 protein may catalyze low affinity (KM = 60 μm) Mn2+ uptake in the same organism. Both proteins also mediate H+-dependent Fe2+ uptake. These proteins are of 575 and 549 amino acyl residues in length and are predicted to have 8-12 transmembrane α-helical spanners. The E. coli homologue of 412 aas exhibits 11 putative and confirmed TMSs with the N-terminus in and the C-terminus out. The yeast proteins may be localized to the vacuole and/or the plasma membrane of the yeast cell. Indirect and some direct experiments suggest that they may be able to transport several heavy metals including Mn2+, Cu2+, Cd2+ and Co2+. A third yeast protein, Smf3p, appears to be exclusively intracellular, possibly in the Golgi. NRAMP2 (Slc11A2) of Homo sapiens (TC# 2.A.55.2.1) has a 12 TMS topology with intracellular N- and C-termini. Two-fold structural symmetry in the arrangement of membrane helices for TM1-5 and TM6-10 (conserved Slc2 hydrophobic core) is suggested.
The generalized transport reaction catalyzed by NRAMP family proteins is:
Me2+ (out) + H+ (out) ⇌ Me2+ (in) + H+ (in).
- Vastermark A, Wollwage S, Houle ME, Rio R, Saier MH (October 2014). "Expansion of the APC superfamily of secondary carriers". Proteins. 82 (10): 2797–811. doi:10.1002/prot.24643. PMC 4177346. PMID 25043943.
- Neves JV, Wilson JM, Kuhl H, Reinhardt R, Castro LF, Rodrigues PN (April 2011). "Natural history of SLC11 genes in vertebrates: tales from the fish world". BMC Evolutionary Biology. 11: 106. doi:10.1186/1471-2148-11-106. PMC 3103463. PMID 21501491.
- Cellier MF (2012-01-01). "Nramp: from sequence to structure and mechanism of divalent metal import". Current Topics in Membranes. 69: 249–93. doi:10.1016/B978-0-12-394390-3.00010-0. PMID 23046654.
- Techau ME, Valdez-Taubas J, Popoff JF, Francis R, Seaman M, Blackwell JM (December 2007). "Evolution of differences in transport function in Slc11a family members". The Journal of Biological Chemistry. 282 (49): 35646–56. doi:10.1074/jbc.M707057200. PMID 17932044.
- Wei W, Chai T, Zhang Y, Han L, Xu J, Guan Z (January 2009). "The Thlaspi caerulescens NRAMP homologue TcNRAMP3 is capable of divalent cation transport". Molecular Biotechnology. 41 (1): 15–21. doi:10.1007/s12033-008-9088-x. PMID 18663607.
- Czachorowski M, Lam-Yuk-Tseung S, Cellier M, Gros P (September 2009). "Transmembrane topology of the mammalian Slc11a2 iron transporter". Biochemistry. 48 (35): 8422–34. doi:10.1021/bi900606y. PMC 2736113. PMID 19621945.
As of 2 February 2016, this article is derived in whole or in part from Transporter Classification Database. The copyright holder has licensed the content in a manner that permits reuse under CC BY-SA 3.0 and GFDL. All relevant terms must be followed. The original text was at "2.A.55 The Metal Ion (Mn2+-iron) Transporter (Nramp) Family".