Natural resistance-associated macrophage protein

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NRAMP family
DraNramp membrane.png
Identifiers
Symbol?
Pfam PF01566
TCDB 2.A.55
OPM superfamily 64
OPM protein 4wgv

Natural resistance-associated macrophage proteins (Nramps), also known as metal ion (Mn2+-iron) transporters (TC# 2.A.55), are a family of metal transport proteins found throughout all domains of life. Taking on an eleven-helix LeuT fold, the Nramp family is a member of the large APC Superfamily of secondary carriers. [1] They transport a variety of transition metals such as manganese, cadmium, and manganese using an alternating access mechanism characteristic of secondary transporters. [2]

Contents

The name "natural resistance-associated" macrophage proteins arises from the role in resistance of intracellular bacterial pathogens played by some animal homologs. 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]

Human homologs

Humans and rodents possess two distinct Nramp proteins. The broad specificity NRAMP2 (DMT1) transports a range of divalent metal cations. Studies have shown that it 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. [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 homologs 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:

Internal rearrangements during DraNramp conformational changes Nramp.gif
Internal rearrangements during DraNramp conformational changes

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

Structure and Mechanism

All Nramp proteins have eleven to twelve transmembrane helices, the first ten of which form a canonical LeuT fold, common throughout the APC superfamily. Metal uptake in Nramp proteins is typically stimulated by acidic pH and accompanied by proton influx, [7] although many homologs have also shown proton uniport. [8] This has been explained in the Deinococcus radiodurans homolog as the result of spatially segregated metal and proton pathways that rely on a longer-range allosteric connection rather than the direct structural connection seen in canonical symporters. [9] Metal uptake requires alternating access bulk conformation change, in which the protein changes from an outward-open state to an inward-open state upon metal binding, while proton uptake can occur through a simpler channel-like mechanism. [2]

See also

Related Research Articles

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Transmembrane protein Protein spanning across a biological membrane

A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

Cotransporter

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

ATP-binding cassette transporter Gene family

The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

The Transporter Classification Database is an International Union of Biochemistry and Molecular Biology (IUBMB)-approved classification system for membrane transport proteins, including ion channels.

Magnesium transporters are proteins that transport magnesium across the cell membrane. All forms of life require magnesium, yet the molecular mechanisms of Mg2+ uptake from the environment and the distribution of this vital element within the organism are only slowly being elucidated.

Natural resistance-associated macrophage protein 2

Natural resistance-associated macrophage protein 2, also known as divalent metal transporter 1 (DMT1) and divalent cation transporter 1 (DCT1), is a protein that in humans is encoded by the SLC11A2 gene. DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.

Thiamine transporter 1

Thiamine transporter 1, also known as thiamine carrier 1 (TC1) or solute carrier family 19 member 2 (SLC19A2) is a protein that in humans is encoded by the SLC19A2 gene. SLC19A2 is a thiamine transporter. Mutations in this gene cause thiamine-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness.

Uncoupling protein Mitochondrial protein

An uncoupling protein (UCP) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH-powered pumping of protons from the mitochondrial matrix to the mitochondrial intermembrane space. The energy lost in dissipating the proton gradient via UCPs is not used to do biochemical work. Instead, heat is generated. This is what links UCP to thermogenesis. However, not every type of UCPs are related to thermogenesis. Although UCP2 and UCP3 are closely related to UCP1, UCP2 and UCP3 do not affect thermoregulatory abilities of vertebrates. UCPs are positioned in the same membrane as the ATP synthase, which is also a proton channel. The two proteins thus work in parallel with one generating heat and the other generating ATP from ADP and inorganic phosphate, the last step in oxidative phosphorylation. Mitochondria respiration is coupled to ATP synthesis but is regulated by UCPs. UCPs belong to the mitochondrial carrier (SLC25) family.

Peptide transporter 1 Mammalian protein found in Homo sapiens

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A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

Natural resistance-associated macrophage protein 1

Natural resistance-associated macrophage protein 1 is a protein that in humans is encoded by the SLC11A1 gene.

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4:HCO−
3 exchange, or more generally, anion:anion antiport. For example, the mouse homologue, SLC26A6, can transport sulfate, formate, oxalate, chloride and bicarbonate, exchanging any one of these anions for another. A cyanobacterial homologue can transport nitrate. Some members can function as channels. SLC26A3 and SLC26A6 can function as carriers or channels, depending on the transported anion. In these porters, mutating a glutamate, also involved in transport in the CIC family, created a channel out of the carrier. It also changed the stoichiometry from 2Cl−/HCO−
3 to 1Cl−/HCO−
3.

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References

  1. ↑ 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.
  2. 1 2 Bozzi, Aaron T; Zimanyi, Christina M; Nicoludis, John M; Lee, Brandon K; Zhang, Casey H; Gaudet, Rachelle (2019-02-04). Faraldo-Gómez, José D; Marletta, Michael A; Zhou, Ming; Slotboom, Dirk; Rudnick, Gary (eds.). "Structures in multiple conformations reveal distinct transition metal and proton pathways in an Nramp transporter". eLife. 8: e41124. doi:10.7554/eLife.41124. ISSN   2050-084X. PMC   6398981 . PMID   30714568.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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. S2CID   5455501.
  6. ↑ 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.
  7. ↑ Ehrnstorfer, Ines A.; Manatschal, Cristina; Arnold, Fabian M.; Laederach, Juerg; Dutzler, Raimund (2017-01-06). "Structural and mechanistic basis of proton-coupled metal ion transport in the SLC11/NRAMP family". Nature Communications. 8 (1): 14033. Bibcode:2017NatCo...814033E. doi:10.1038/ncomms14033. ISSN   2041-1723. PMC   5230734 . PMID   28059071.
  8. ↑ Gunshin, H.; Mackenzie, B.; Berger, U. V.; Gunshin, Y.; Romero, M. F.; Boron, W. F.; Nussberger, S.; Gollan, J. L.; Hediger, M. A. (1997-07-31). "Cloning and characterization of a mammalian proton-coupled metal-ion transporter". Nature. 388 (6641): 482–488. Bibcode:1997Natur.388..482G. doi:10.1038/41343. ISSN   0028-0836. PMID   9242408. S2CID   4416482.
  9. ↑ Bozzi, Aaron T.; Bane, Lukas B.; Zimanyi, Christina M.; Gaudet, Rachelle (2019-12-02). "Unique structural features in an Nramp metal transporter impart substrate-specific proton cotransport and a kinetic bias to favor import". Journal of General Physiology. 151 (12): 1413–1429. doi:10.1085/jgp.201912428. ISSN   0022-1295. PMC   6888756 . PMID   31619456.

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"

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