Cation diffusion facilitator

Last updated
Cation_efflux
Identifiers
SymbolCation_efflux
Pfam PF01545
Pfam clan CL0184
InterPro IPR002524
TCDB 2.A.4
OPM superfamily 183
OPM protein 3h90
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Cation diffusion facilitators (CDFs) are transmembrane proteins that provide tolerance of cells to divalent metal ions, such as cadmium, zinc, and cobalt. These proteins are considered to be efflux pumps that remove these divalent metal ions from cells. [1] [2] However, some members of the CDF superfamily are implicated in ion uptake. [3] All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners. [4] The Cation Diffusion Facilitator (CDF) Superfamily includes the following families: [4] [5]

Contents

The Cation Diffusion Facilitator (CDF) Family

The CDF family (TC# 2.A.4) is a ubiquitous family, members of which are found in bacteria, archaea and eukaryotes. [4] They transport heavy metal ions, such as cadmium, zinc, cobalt, nickel, copper and mercuric ions. There are 9 mammalian paralogues, ZnT1 - 8 and 10. [6] Most proteins from the family have six transmembrane helices, but MSC2 of S. cerevisiae ) and Znt5 and hZTL1 of H. sapiens have 15 and 12 predicted TMSs, respectively. [7] These proteins exhibit an unusual degree of sequence divergence and size variation (300-750 residues). Eukaryotic proteins exhibit differences in cell localization. Some catalyze heavy metal uptake from the cytoplasm into various intracellular eukaryotic organelles (ZnT2-7) while others (ZnT1) catalyze efflux from the cytoplasm across the plasma membrane into the extracellular medium. Thus, some are found in plasma membranes while others are in organellar membranes such as vacuoles of plants and yeast and the golgi of animals. [8] [9] [10] They catalyze cation:proton antiport, have a single essential zinc-binding site within the transmembrane domains of each monomer within the dimer, and have a binuclear zinc-sensing and binding site in the cytoplasmic C-terminal region. [11] A representative list of proteins belonging to the CDF family can be found in the Transporter Classification Database.

Phylogeny

Prokaryotic and eukaryotic proteins cluster separately but may function with the same polarity by similar mechanisms. These proteins are secondary carriers which utilize the proton motive force (pmf) and function by H+ antiport (for metal efflux). One member, CzcD of Bacillus subtilis (TC# 2.A.4.1.3) , has been shown to exchange the divalent cation (Zn2+ or Cd2+ ) for two monovalent cations (K+ and H+ ) in an electroneutral process energized by the transmembrane pH gradient. [12] Another, ZitB of E. coli (TC #2.A.4.1.4), has been reconstituted in proteoliposomes and studied kinetically. [13] It appears to function by simple Me2+:H+ antiport with a 1:1 stoichiometry.

Montanini et al. (2007) have conducted a phylogenetic analysis of CDF family members. Their analysis revealed three major and two minor phylogenetic groups. They suggest that the three major groups segregated according to metal ion specificity: [14]

  1. Mn2+
  2. Fe2+ and Zn2+ as well as other metal ions
  3. Zn2+ plus other metals, but not Iron.

Structure

X-ray structure of YiiP of E. coli represents a homodimer. [15] [16]

Coudray et al. (2013) used cryoelectron microscopy to determine a 13 Å resolution structure of a YiiP homolog from Shewanella oneidensis within a lipid bilayer in the absence of Zn2+. Starting from the x-ray structure in the presence of Zn2+, they used molecular dynamic flexible fitting to build a model. A comparison of the structures suggested a conformational change that involves pivoting of a transmembrane, four-helix bundle (M1, M2, M4, and M5) relative to the M3-M6 helix pair. Although the accessibility of transport sites in the x-ray model indicates that it represents an outward-facing state, their model was consistent with an inward-facing state, suggesting that the conformational change is relevant to the alternating access mechanism for transport. They speculated that the dimer may coordinate the rearrangement of the transmembrane helices. [17]

Involved in metal tolerance/resistance by efflux, most CDF proteins share a two-modular architecture consisting of a transmembrane domain (TMD) and a C-terminal domain (CTD) that protrudes into the cytoplasm. A Zn2+ and Cd2+ CDF transporter from the marine bacterium, Maricaulis maris, that does not possess the CTD is a member of a new, CTD-lacking subfamily of CDFs.

Transport Reaction

The generalized transport reaction for CDF family members is:

Me2+ (in) H+ (out) ± K+ (out) → Me2+ (out) H+ (in) ± K+ (in).

See also

Related Research Articles

<span class="mw-page-title-main">Facilitated diffusion</span> Biological process

Facilitated diffusion is the process of spontaneous passive transport of molecules or ions across a biological membrane via specific transmembrane integral proteins. Being passive, facilitated transport does not directly require chemical energy from ATP hydrolysis in the transport step itself; rather, molecules and ions move down their concentration gradient reflecting its diffusive nature.

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion or active transport. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.

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.

<span class="mw-page-title-main">Sphingomyelin phosphodiesterase</span> Class of enzymes

Sphingomyelin phosphodiesterase is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. SMase is a member of the DNase I superfamily of enzymes and is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide. The activation of SMase has been suggested as a major route for the production of ceramide in response to cellular stresses.

<span class="mw-page-title-main">Oxaloacetate decarboxylase</span> Enzyme

Oxaloacetate decarboxylase is a carboxy-lyase involved in the conversion of oxaloacetate into pyruvate.

<span class="mw-page-title-main">Ammonia transporter</span>

Ammonia transporters are structurally related membrane transport proteins called Amt proteins in bacteria and plants, methylammonium/ammonium permeases (MEPs) in yeast, or Rhesus (Rh) proteins in chordates. In humans, the RhAG, RhBG, and RhCG Rhesus proteins constitute solute carrier family 42 whilst RhD and RhCE form the Rh blood group system. The three-dimensional structure of the ammonia transport protein AmtB from Escherichia coli has been determined by x-ray crystallography revealing a hydrophobic ammonia channel. The human RhCG ammonia transporter was found to have a similar ammonia-conducting channel structure. It was proposed that the erythrocyte Rh complex is a heterotrimer of RhAG, RhD, and RhCE subunits in which RhD and RhCE might play roles in anchoring the ammonia-conducting RhAG subunit to the cytoskeleton. Based on reconstitution experiments, purified RhCG subunits alone can function to transport ammonia. RhCG is required for normal acid excretion by the mouse kidney and epididymis.

The cation-chloride cotransporter (CCC) family is part of the APC superfamily of secondary carriers. Members of the CCC family are found in animals, plants, fungi and bacteria. Most characterized CCC family proteins are from higher eukaryotes, but one has been partially characterized from Nicotiana tabacum, and homologous ORFs have been sequenced from Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast) and Synechococcus sp.. The latter proteins are of unknown function. These proteins show sequence similarity to members of the APC family. CCC family proteins are usually large, and possess 12 putative transmembrane spanners (TMSs) flanked by large N-terminal and C-terminal hydrophilic domains.

The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.

<span class="mw-page-title-main">Natural resistance-associated macrophage protein</span> Family of transport proteins

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. They transport a variety of transition metals such as manganese, cadmium, and manganese using an alternating access mechanism characteristic of secondary transporters.

The potassium (K+) uptake permease (KUP) family (TC# 2.A.72) is a member of the APC superfamily of secondary carriers. Proteins of the KUP/HAK/KT family include the KUP (TrkD) protein of E. coli and homologues in both Gram-positive and Gram-negative bacteria. High affinity (20 μM) K+ uptake systems (Hak1, TC# 2.A.72.2.1) of the yeast Debaryomyces occidentalis as well as the fungus, Neurospora crassa, and several homologues in plants have been characterized. Arabidopsis thaliana and other plants possess multiple KUP family paralogues. While many plant proteins cluster tightly together, the Hak1 proteins from yeast as well as the two Gram-positive and Gram-negative bacterial proteins are distantly related on the phylogenetic tree for the KUP family. All currently classified members of the KUP family can be found in the Transporter Classification Database.

The Ca2+:cation antiporter (CaCA) family (TC# 2.A.19) is a member of the cation diffusion facilitator (CDF) superfamily. This family should not be confused with the Ca2+:H+ Antiporter-2 (CaCA2) Family (TC# 2.A.106) which belongs to the Lysine Exporter (LysE) Superfamily. Proteins of the CaCA family are found ubiquitously, having been identified in animals, plants, yeast, archaea and divergent bacteria. Members of this family facilitate the antiport of calcium ion with another cation.

The bacterial murein precursor exporter (MPE) family is a member of the cation diffusion facilitator (CDF) superfamily of membrane transporters. Members of the MPE family are found in a large variety of Gram-negative and Gram-positive bacteria and facilitate the translocation of lipid-linked murein precursors. A representative list of proteins belonging to the MPE family can be found in the Transporter Classification Database.

The Nickel/Cobalt Transporter (NicO) Family is a member of the Lysine Exporter (LysE) Superfamily.

Arsenite resistance (Ars) efflux pumps of bacteria may consist of two proteins, ArsB and ArsA, or of one protein. ArsA proteins have two ATP binding domains and probably arose by a tandem gene duplication event. ArsB proteins all possess twelve transmembrane spanners and may also have arisen by a tandem gene duplication event. Structurally, the Ars pumps resemble ABC-type efflux pumps, but there is no significant sequence similarity between the Ars and ABC pumps. When only ArsB is present, the system operates by a pmf-dependent mechanism, and consequently belongs in TC subclass 2.A. When ArsA is also present, ATP hydrolysis drives efflux, and consequently the system belongs in TC subclass 3.A. ArsB therefore appears twice in the TC system but ArsA appears only once. These pumps actively expel both arsenite and antimonite.

The arsenical resistance-3 (ACR3) family is a member of the BART superfamily. Based on operon analyses, ARC3 homologues may function either as secondary carriers or as primary active transporters, similarly to the ArsB and ArsAB families. In the latter case ATP hydrolysis again energizes transport. ARC3 homologues transport the same anions as ArsA/AB homologues, though ArsB homologues are members of the IT Superfamily and homologues of the ARC3 family are within the BART Superfamily suggesting they may not be evolutionarily related.

<span class="mw-page-title-main">NhaA family</span> Family of transport proteins

Na+/H+ antiporter A (NhaA) family (TC# 2.A.33) contains a number of bacterial sodium-proton antiporter (SPAP) proteins. These are integral membrane proteins that catalyse the exchange of H+ for Na+ in a manner that is highly pH dependent. Homologues have been sequenced from a number of bacteria and archaea. Prokaryotes possess multiple paralogues. A representative list of the proteins that belong to the NhaA family can be found in the Transporter Classification Database.

The Monovalent Cation:Proton Antiporter-2 (CPA2) Family is a moderately large family of transporters belonging to the CPA superfamily. Members of the CPA2 family have been found in bacteria, archaea and eukaryotes. The proteins of the CPA2 family consist of between 333 and 900 amino acyl residues and exhibit 10-14 transmembrane α-helical spanners (TMSs).

<span class="mw-page-title-main">Resistance-nodulation-cell division superfamily</span>

Resistance-nodulation-division (RND) family transporters are a category of bacterial efflux pumps, especially identified in Gram-negative bacteria and located in the cytoplasmic membrane, that actively transport substrates. The RND superfamily includes seven families: the heavy metal efflux (HME), the hydrophobe/amphiphile efflux-1, the nodulation factor exporter family (NFE), the SecDF protein-secretion accessory protein family, the hydrophobe/amphiphile efflux-2 family, the eukaryotic sterol homeostasis family, and the hydrophobe/amphiphile efflux-3 family. These RND systems are involved in maintaining homeostasis of the cell, removal of toxic compounds, and export of virulence determinants. They have a broad substrate spectrum and can lead to the diminished activity of unrelated drug classes if over-expressed. The first reports of drug resistant bacterial infections were reported in the 1940s after the first mass production of antibiotics. Most of the RND superfamily transport systems are made of large polypeptide chains. RND proteins exist primarily in gram-negative bacteria but can also be found in gram-positive bacteria, archaea, and eukaryotes.

The Reduced Folate Carrier (RFC) Family is a group of transport proteins that is part of the major facilitator superfamily. RFCs take up folate, reduced folate, derivatives of reduced folate and the drug, methotrexate.

Metal transporter CNNM3 is a human transmembrane protein which is made up of 707 amino acids. Although CNNM3 is ubiquitous, it is mostly present in the kidney, brain, lung, spleen, heart and liver.

References

  1. ↑ Xiong A, Jayaswal RK (August 1998). "Molecular characterization of a chromosomal determinant conferring resistance to zinc and cobalt ions in Staphylococcus aureus". J. Bacteriol. 180 (16): 4024–9. doi:10.1128/JB.180.16.4024-4029.1998. PMC   107394 . PMID   9696746.
  2. ↑ Kunito T, Kusano T, Oyaizu H, Senoo K, Kanazawa S, Matsumoto S (April 1996). "Cloning and sequence analysis of czc genes in Alcaligenes sp. strain CT14". Biosci. Biotechnol. Biochem. 60 (4): 699–704. doi: 10.1271/bbb.60.699 . PMID   8829543.
  3. ↑ Conklin DS, McMaster JA, Culbertson MR, Kung C (September 1992). "COT1, a gene involved in cobalt accumulation in Saccharomyces cerevisiae". Mol. Cell. Biol. 12 (9): 3678–88. doi:10.1128/mcb.12.9.3678. PMC   360222 . PMID   1508175.
  4. 1 2 3 Paulson, IT; Saier, MH Jr. (1997). "A novel family of ubiquitous heavy metal ion transport proteins". Journal of Membrane Biology. 156 (2): 99–103. doi:10.1007/s002329900192. PMID   9075641. S2CID   23203104.
  5. ↑ Saier, MH Jr. "Cation Diffusion Facilitator (CDF) Superfamily". Transporter Classification Database.
  6. ↑ Cousins, Robert J.; Liuzzi, Juan P.; Lichten, Louis A. (2006-08-25). "Mammalian zinc transport, trafficking, and signals". The Journal of Biological Chemistry. 281 (34): 24085–24089. doi: 10.1074/jbc.R600011200 . ISSN   0021-9258. PMID   16793761.
  7. ↑ Cragg, Ruth A.; Christie, Graham R.; Phillips, Siôn R.; Russi, Rachel M.; Küry, Sébastien; Mathers, John C.; Taylor, Peter M.; Ford, Dianne (2002-06-21). "A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane". The Journal of Biological Chemistry. 277 (25): 22789–22797. doi: 10.1074/jbc.M200577200 . ISSN   0021-9258. PMID   11937503.
  8. ↑ Chao, Yang; Fu, Dax (2004-04-23). "Thermodynamic studies of the mechanism of metal binding to the Escherichia coli zinc transporter YiiP". The Journal of Biological Chemistry. 279 (17): 17173–17180. doi: 10.1074/jbc.M400208200 . ISSN   0021-9258. PMID   14960568.
  9. ↑ Haney, Christopher J.; Grass, Gregor; Franke, Sylvia; Rensing, Christopher (2005-06-01). "New developments in the understanding of the cation diffusion facilitator family". Journal of Industrial Microbiology & Biotechnology. 32 (6): 215–226. doi:10.1007/s10295-005-0224-3. ISSN   1367-5435. PMID   15889311. S2CID   8214762.
  10. ↑ MacDiarmid, Colin W.; Milanick, Mark A.; Eide, David J. (2003-04-25). "Induction of the ZRC1 metal tolerance gene in zinc-limited yeast confers resistance to zinc shock". The Journal of Biological Chemistry. 278 (17): 15065–15072. doi: 10.1074/jbc.M300568200 . ISSN   0021-9258. PMID   12556516.
  11. ↑ Kambe, Taiho (2012-01-01). "Molecular architecture and function of ZnT transporters" (PDF). Current Topics in Membranes. 69: 199–220. doi:10.1016/B978-0-12-394390-3.00008-2. hdl: 2433/160391 . ISBN   9780123943903. ISSN   1063-5823. PMID   23046652. S2CID   8185980.
  12. ↑ Guffanti, Arthur A.; Wei, Yi; Rood, Sacha V.; Krulwich, Terry A. (2002-07-01). "An antiport mechanism for a member of the cation diffusion facilitator family: divalent cations efflux in exchange for K+ and H+". Molecular Microbiology. 45 (1): 145–153. doi: 10.1046/j.1365-2958.2002.02998.x . ISSN   0950-382X. PMID   12100555. S2CID   28579708.
  13. ↑ Chao, Yang; Fu, Dax (2004-03-26). "Kinetic study of the antiport mechanism of an Escherichia coli zinc transporter, ZitB". The Journal of Biological Chemistry. 279 (13): 12043–12050. doi: 10.1074/jbc.M313510200 . ISSN   0021-9258. PMID   14715669.
  14. ↑ Montanini, Barbara; Blaudez, Damien; Jeandroz, Sylvain; Sanders, Dale; Chalot, Michel (2007-01-01). "Phylogenetic and functional analysis of the Cation Diffusion Facilitator (CDF) family: improved signature and prediction of substrate specificity". BMC Genomics. 8: 107. doi:10.1186/1471-2164-8-107. ISSN   1471-2164. PMC   1868760 . PMID   17448255.
  15. ↑ Wei, Yinan; Li, Huilin; Fu, Dax (2004-09-17). "Oligomeric state of the Escherichia coli metal transporter YiiP". The Journal of Biological Chemistry. 279 (38): 39251–39259. doi: 10.1074/jbc.M407044200 . ISSN   0021-9258. PMID   15258151.
  16. ↑ Lu, Min; Fu, Dax (2007-09-21). "Structure of the zinc transporter YiiP". Science. 317 (5845): 1746–1748. Bibcode:2007Sci...317.1746L. doi:10.1126/science.1143748. ISSN   1095-9203. PMID   17717154. S2CID   20136118.
  17. ↑ Coudray, Nicolas; Valvo, Salvatore; Hu, Minghui; Lasala, Ralph; Kim, Changki; Vink, Martin; Zhou, Ming; Provasi, Davide; Filizola, Marta (2013-02-05). "Inward-facing conformation of the zinc transporter YiiP revealed by cryoelectron microscopy". Proceedings of the National Academy of Sciences of the United States of America. 110 (6): 2140–2145. Bibcode:2013PNAS..110.2140C. doi: 10.1073/pnas.1215455110 . ISSN   1091-6490. PMC   3568326 . PMID   23341604.
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