Cation diffusion facilitators (CDFs) are integral membrane proteins that increase tolerance 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. However, some members of the CDF superfamily are implicated in ion uptake. All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners. The Cation Diffusion Facillitator (CDF) Superfamily includes the following families:

The CDF family (TC# 2.A.4) is a ubiquitous family, members of which are found in bacteria, archaea and eukaryotes. They transport heavy metals including cobalt, cadmium, zinc and possibly nickel, copper and mercuric ions. There are 9 mammalian paralogues, ZnT1 - 8 and 10. Most members of the CDF family possess six putative transmembrane spanners with N- and C-termini on the cytoplasmic side of the membrane, but MSC2 of S. cerevisiae (TC# 2.A.4.4.1) and Znt5 and hZTL1 (TC# 2.A.4.4.3) of H. sapiens exhibit 15 and 12 putative TMSs, respectively. 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. 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 cytoplamsic C-terminal region. A representative list of proteins belonging to the CDF family can be found in the Transporter Classification Database.

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