Natural Resistance-Associated Macrophage Proteins

Identifiers
Symbol ?
Pfam PF01566
TCDB 2.A.55
OPM superfamily 514
OPM protein 4wgv

Natural Resistance-Associated Macrophage Proteins (NRAMPs) are members of the Metal Ion (Mn2+-iron) Transporter (NRAMP) Family (TC# 2.A.55). The NRAMP family is a member of the large APC Superfamily of secondary carriers.[1] 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).[2] 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.[3]

NRAMP2

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.

NRAMP1

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.[4] 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.[5] 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.[6]

Transport Reaction

The generalized transport reaction catalyzed by NRAMP family proteins is:

Me2+ (out) + H+ (out) ⇌ Me2+ (in) + H+ (in).

See also

References

  1. ↑ Vastermark, Ake; Wollwage, Simon; Houle, Michael E.; Rio, Rita; Saier, Milton H. (2014-10-01). "Expansion of the APC superfamily of secondary carriers". Proteins. 82 (10): 2797–2811. ISSN 1097-0134. PMC 4177346 Freely accessible. PMID 25043943. doi:10.1002/prot.24643.
  2. ↑ Neves, João V.; Wilson, Jonathan M.; Kuhl, Heiner; Reinhardt, Richard; Castro, L. Filipe C.; Rodrigues, Pedro N. S. (2011-01-01). "Natural history of SLC11 genes in vertebrates: tales from the fish world". BMC evolutionary biology. 11: 106. ISSN 1471-2148. PMC 3103463 Freely accessible. PMID 21501491. doi:10.1186/1471-2148-11-106.
  3. ↑ Cellier, Mathieu F. M. (2012-01-01). "Nramp: from sequence to structure and mechanism of divalent metal import". Current Topics in Membranes. 69: 249–293. ISSN 1063-5823. PMID 23046654. doi:10.1016/B978-0-12-394390-3.00010-0.
  4. ↑ Techau, Michala Eichner; Valdez-Taubas, Javier; Popoff, Jean-François; Francis, Richard; Seaman, Matthew; Blackwell, Jenefer M. (2007-12-07). "Evolution of differences in transport function in Slc11a family members". The Journal of Biological Chemistry. 282 (49): 35646–35656. ISSN 0021-9258. PMID 17932044. doi:10.1074/jbc.M707057200.
  5. ↑ Wei, Wei; Chai, Tuanyao; Zhang, Yuxiu; Han, Lu; Xu, Jin; Guan, Ziqiu (2009-01-01). "The Thlaspi caerulescens NRAMP homologue TcNRAMP3 is capable of divalent cation transport". Molecular Biotechnology. 41 (1): 15–21. ISSN 1073-6085. PMID 18663607. doi:10.1007/s12033-008-9088-x.
  6. ↑ Czachorowski, Maciej; Lam-Yuk-Tseung, Steven; Cellier, Mathieu; Gros, Philippe (2009-09-08). "Transmembrane topology of the mammalian Slc11a2 iron transporter". Biochemistry. 48 (35): 8422–8434. ISSN 1520-4995. PMC 2736113 Freely accessible. PMID 19621945. doi:10.1021/bi900606y.

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