View source for Cation diffusion facilitator

{{Short description|Large group of transport proteins}}
{{Infobox protein family
| Symbol = Cation_efflux
| Name = Cation_efflux
| image =
| width =
| caption = structural basis for the autoregulation of the zinc transporter yiip
| Pfam = PF01545
| Pfam_clan = CL0184
| InterPro = IPR002524
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB = 2.A.4
| OPM family = 183
| OPM protein = 3h90
| CAZy =
| CDD =
}}
'''Cation diffusion facilitators''' (CDFs) are [[transmembrane protein]]s that provide tolerance of cells to [[divalent]] metal ions, such as cadmium, zinc, and [[cobalt]]. These proteins are considered to be [[Efflux (microbiology)#Bacterial efflux pumps|efflux pump]]s that remove these divalent metal [[ions]] from [[Cell (biology)|cell]]s.<ref name="pmid9696746">{{cite journal |vauthors=Xiong A, Jayaswal RK | title = Molecular characterization of a chromosomal determinant conferring resistance to zinc and cobalt ions in Staphylococcus aureus | journal = J. Bacteriol. | volume = 180 | issue = 16 | pages = 4024–9 |date=August 1998 | pmid = 9696746 | pmc = 107394 | doi = 10.1128/JB.180.16.4024-4029.1998}}</ref><ref name="pmid8829543">{{cite journal |vauthors=Kunito T, Kusano T, Oyaizu H, Senoo K, Kanazawa S, Matsumoto S | title = Cloning and sequence analysis of czc genes in Alcaligenes sp. strain CT14 | journal = Biosci. Biotechnol. Biochem. | volume = 60 | issue = 4 | pages = 699–704 |date=April 1996 | pmid = 8829543 | doi = 10.1271/bbb.60.699| doi-access =  }}</ref> However, some members of the CDF superfamily are implicated in ion uptake.<ref name="pmid1508175">{{cite journal |vauthors=Conklin DS, McMaster JA, Culbertson MR, Kung C | title = COT1, a gene involved in cobalt accumulation in Saccharomyces cerevisiae | journal = Mol. Cell. Biol. | volume = 12 | issue = 9 | pages = 3678–88 |date=September 1992 | pmid = 1508175 | pmc = 360222 | doi = 10.1128/mcb.12.9.3678}}</ref> All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners.<ref name=":3" /> The Cation Diffusion Facilitator (CDF) Superfamily includes the following families:<ref name=":3" /><ref>{{Cite web|url = http://www.tcdb.org/superfamily.php?id=29|title = Cation Diffusion Facilitator (CDF) Superfamily|website = Transporter Classification Database|last = Saier|first = MH Jr}}</ref>
* [http://www.tcdb.org/search/result.php?tc=1.A.52 1.A.52] - [[Calcium release activated channel|The Ca<sup>2+</sup> Release-activated Ca<sup>2+</sup> (CRAC) Channel (CRAC-C) Family]]
* [http://www.tcdb.org/search/result.php?tc=2.A.4 2.A.4] - The Cation Diffusion Facilitator (CDF) Family
* [http://www.tcdb.org/search/result.php?tc=2.A.19 2.A.19] - [[Calcium:Cation Antiporter|The Ca<sup>2+</sup>:Cation Antiporter (CaCA) Family]]
* [http://www.tcdb.org/search/result.php?tc=2.A.103 2.A.103] - [[Bacterial Murein Precursor Exporter|The Bacterial Murein Precursor Exporter (MPE) Family]]
== The Cation Diffusion Facilitator (CDF) Family ==
The CDF family (TC# [http://www.tcdb.org/search/result.php?tc=2.A.4 2.A.4]) is a ubiquitous family, members of which are found in bacteria, archaea and eukaryotes.<ref name=":3">{{Cite journal|title = A novel family of ubiquitous heavy metal ion transport proteins.|last1 = Paulson|first1 = IT|date = 1997|journal = Journal of Membrane Biology|doi = 10.1007/s002329900192|pmid = 9075641|last2 = Saier|first2 = MH Jr.|issue = 2|volume = 156|pages = 99–103|s2cid = 23203104}}</ref> They transport heavy metal ions, such as [[cadmium]], [[zinc]], [[cobalt]], [[nickel]], [[copper]] and mercuric ions. There are 9 mammalian paralogues, ZnT1 - 8 and 10.<ref>{{Cite journal|title = Mammalian zinc transport, trafficking, and signals|journal = The Journal of Biological Chemistry|date = 2006-08-25|issn = 0021-9258|pmid = 16793761|pages = 24085–24089|volume = 281|issue = 34|doi = 10.1074/jbc.R600011200|first1 = Robert J.|last1 = Cousins|first2 = Juan P.|last2 = Liuzzi|first3 = Louis A.|last3 = Lichten|doi-access = free}}</ref> Most proteins from the family have six transmembrane helices, but MSC2 of ''[[Saccharomyces cerevisiae|S. cerevisiae]]'') and Znt5 and hZTL1 of ''[[Homo sapiens|H. sapiens]]'' have 15 and 12 predicted TMSs, respectively.<ref>{{Cite journal|title = A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane|journal = The Journal of Biological Chemistry|date = 2002-06-21|issn = 0021-9258|pmid = 11937503|pages = 22789–22797|volume = 277|issue = 25|doi = 10.1074/jbc.M200577200|first1 = Ruth A.|last1 = Cragg|first2 = Graham R.|last2 = Christie|first3 = Siôn R.|last3 = Phillips|first4 = Rachel M.|last4 = Russi|first5 = Sébastien|last5 = Küry|first6 = John C.|last6 = Mathers|first7 = Peter M.|last7 = Taylor|first8 = Dianne|last8 = Ford|doi-access = free}}</ref> 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.<ref name=":0">{{Cite journal|title = Thermodynamic studies of the mechanism of metal binding to the Escherichia coli zinc transporter YiiP|journal = The Journal of Biological Chemistry|date = 2004-04-23|issn = 0021-9258|pmid = 14960568|pages = 17173–17180|volume = 279|issue = 17|doi = 10.1074/jbc.M400208200|first1 = Yang|last1 = Chao|first2 = Dax|last2 = Fu|doi-access = free}}</ref><ref name=":1">{{Cite journal|title = New developments in the understanding of the cation diffusion facilitator family|journal = Journal of Industrial Microbiology & Biotechnology|date = 2005-06-01|issn = 1367-5435|pmid = 15889311|pages = 215–226|volume = 32|issue = 6|doi = 10.1007/s10295-005-0224-3|first1 = Christopher J.|last1 = Haney|first2 = Gregor|last2 = Grass|first3 = Sylvia|last3 = Franke|first4 = Christopher|last4 = Rensing|s2cid = 8214762}}</ref><ref>{{Cite journal|title = Induction of the ZRC1 metal tolerance gene in zinc-limited yeast confers resistance to zinc shock|journal = The Journal of Biological Chemistry|date = 2003-04-25|issn = 0021-9258|pmid = 12556516|pages = 15065–15072|volume = 278|issue = 17|doi = 10.1074/jbc.M300568200|first1 = Colin W.|last1 = MacDiarmid|first2 = Mark A.|last2 = Milanick|first3 = David J.|last3 = Eide|doi-access = free}}</ref> 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.<ref>{{Cite journal|title = Molecular architecture and function of ZnT transporters|journal = Current Topics in Membranes|date = 2012-01-01|issn = 1063-5823|pmid = 23046652|pages = 199–220|volume = 69|doi = 10.1016/B978-0-12-394390-3.00008-2|first = Taiho|last = Kambe|hdl = 2433/160391|isbn = 9780123943903| s2cid=8185980 |url = http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/160391/1/B978-0-12-394390-3.00008-2.pdf|hdl-access = free}}</ref> A representative list of proteins belonging to the CDF family can be found in the [http://www.tcdb.org/search/result.php?tc=2.A.4.8 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<sup>+</sup> antiport (for metal efflux). One member, CzcD of ''[[Bacillus subtilis]]'' ([http://www.tcdb.org/search/result.php?tc=2.A.4.1.3 TC# 2.A.4.1.3]) '','' has been shown to exchange the divalent cation (Zn<sup>2+</sup> or Cd<sup>2+</sup> ) for two monovalent cations (K<sup>+</sup> and H<sup>+</sup> ) in an electroneutral process energized by the transmembrane pH gradient.<ref>{{Cite journal|title = An antiport mechanism for a member of the cation diffusion facilitator family: divalent cations efflux in exchange for K+ and H+|journal = Molecular Microbiology|date = 2002-07-01|issn = 0950-382X|pmid = 12100555|pages = 145–153|volume = 45|issue = 1|first1 = Arthur A.|last1 = Guffanti|first2 = Yi|last2 = Wei|first3 = Sacha V.|last3 = Rood|first4 = Terry A.|last4 = Krulwich|doi=10.1046/j.1365-2958.2002.02998.x|s2cid = 28579708|doi-access = }}</ref> Another, ZitB of ''E. coli'' ([http://www.tcdb.org/search/result.php?tc=2.A.4.1.4 TC #2.A.4.1.4]), has been reconstituted in proteoliposomes and studied kinetically.<ref>{{Cite journal|title = Kinetic study of the antiport mechanism of an Escherichia coli zinc transporter, ZitB|journal = The Journal of Biological Chemistry|date = 2004-03-26|issn = 0021-9258|pmid = 14715669|pages = 12043–12050|volume = 279|issue = 13|doi = 10.1074/jbc.M313510200|first1 = Yang|last1 = Chao|first2 = Dax|last2 = Fu|doi-access = free}}</ref> It appears to function by simple Me<sup>2+</sup>:H<sup>+</sup> 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:<ref>{{Cite journal|title = Phylogenetic and functional analysis of the Cation Diffusion Facilitator (CDF) family: improved signature and prediction of substrate specificity|journal = BMC Genomics|date = 2007-01-01|issn = 1471-2164|pmc = 1868760|pmid = 17448255|pages = 107|volume = 8|doi = 10.1186/1471-2164-8-107|first1 = Barbara|last1 = Montanini|first2 = Damien|last2 = Blaudez|first3 = Sylvain|last3 = Jeandroz|first4 = Dale|last4 = Sanders|first5 = Michel|last5 = Chalot | doi-access=free }}</ref>
# Mn<sup>2+</sup>
# Fe<sup>2+</sup> and Zn<sup>2+</sup> as well as other metal ions
# Zn<sup>2+</sup> plus other metals, but not Iron.
=== Structure ===
X-ray structure of YiiP of ''E. coli'' represents a homodimer.<ref>{{Cite journal|title = Oligomeric state of the Escherichia coli metal transporter YiiP|journal = The Journal of Biological Chemistry|date = 2004-09-17|issn = 0021-9258|pmid = 15258151|pages = 39251–39259|volume = 279|issue = 38|doi = 10.1074/jbc.M407044200|first1 = Yinan|last1 = Wei|first2 = Huilin|last2 = Li|first3 = Dax|last3 = Fu|doi-access = free}}</ref><ref>{{Cite journal|title = Structure of the zinc transporter YiiP|journal = Science|date = 2007-09-21|issn = 1095-9203|pmid = 17717154|pages = 1746–1748|volume = 317|issue = 5845|doi = 10.1126/science.1143748|first1 = Min|last1 = Lu|first2 = Dax|last2 = Fu|bibcode = 2007Sci...317.1746L|s2cid = 20136118|url = https://zenodo.org/record/1230886|doi-access = free}}</ref>
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 Zn<sup>2+</sup>. Starting from the x-ray structure in the presence of Zn<sup>2+</sup>, 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.<ref>{{Cite journal|title = Inward-facing conformation of the zinc transporter YiiP revealed by cryoelectron microscopy|journal = Proceedings of the National Academy of Sciences of the United States of America|date = 2013-02-05|issn = 1091-6490|pmc = 3568326|pmid = 23341604|pages = 2140–2145|volume = 110|issue = 6|doi = 10.1073/pnas.1215455110|first1 = Nicolas|last1 = Coudray|first2 = Salvatore|last2 = Valvo|first3 = Minghui|last3 = Hu|first4 = Ralph|last4 = Lasala|first5 = Changki|last5 = Kim|first6 = Martin|last6 = Vink|first7 = Ming|last7 = Zhou|first8 = Davide|last8 = Provasi|first9 = Marta|last9 = Filizola|bibcode = 2013PNAS..110.2140C|doi-access = free}}</ref>
Involved in metal tolerance/resistance by efflux, most CDF proteins share a two-modular architecture consisting of a [[transmembrane domain]] (TMD) and a [[C-terminus|C-terminal domain]] (CTD) that protrudes into the cytoplasm. A Zn<sup>2+</sup> and Cd<sup>2+</sup> 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:
Me<sup>2+</sup> (in) H<sup>+</sup> (out) ± K<sup>+</sup> (out) → Me<sup>2+</sup> (out) H<sup>+</sup> (in) ± K<sup>+</sup> (in).
==See also==
* [[Integral membrane protein]]
* [[Ion channel]]
* [[Transporter Classification Database]]
* [[Protein superfamily]]
* [[Protein family]]
==References==
{{reflist|30em}}
{{InterPro content|IPR002524}}
{{Portal bar|Biology|border=no}}
[[Category:Cell biology]]
[[Category:Protein families]]
[[Category:Membrane proteins]]
[[Category:Transmembrane proteins]]
[[Category:Transmembrane transporters]]
[[Category:Transport proteins]]
[[Category:Integral membrane proteins]]