The ZIP family was named after its founding members, Zrt1p and Zrt2p in yeast and IRT1 in A. thaliana (Eide et al., 1996; Zhao and Eide, 1996a, 1996b). As we will discuss below, IRT1 is the major iron transporter responsible for iron uptake from the soil and Zrt1p and Zrt2p are zinc transporters. There are now more than 100 members of this family found in many diverse organisms including bacteria (Grass et al., 2002), Drosophila (Mathews et al., 2005), mammals (Dufner-Beattie et al., 2003; Eide, 2003;
Taylor and Nicholson, 2003) and zebrafish (Yamashita et al., 2004). Various members of the ZIP family have been shown to transport iron, manganese, zinc, copper and cadmium. All ZIP proteins are predicted to be integral membrane proteins; most family members are predicted to have eight transmembrane domains with a variable region between transmembrane domains III and IV (Eng et al., 1998; Guerinot, 2000). The variable region is often histidine-rich and has been shown to localize to the cytoplasm in yeast (Gitan and Eide, 2000) and in humans (Gaither and Eide, 2000; Gaither and Eide, 2001). Where characterized, ZIP proteins have been found to transport metal ions from the cell exterior or lumen of intracellular organelles into the cytoplasm. The sole exception is GmZIP1 which has been localized to the peribacteroid membrane of soybean nodules (Moreau et al., 2002). Antibodies to GmZIP1 inhibited zinc uptake by symbiosomes, suggesting that this protein is responsible for transporting metal ions from the cytosol into the symbiosome. However, GmZIP1 was also shown to rescue the zinc uptake mutant of yeast i.e. it is capable of transporting zinc into the cytosol. If GmZIP1 has the same orientation in both the peribacteroid and yeast membranes, then it must be capable of bidirectional transport.
The ZIP family has been divided into four sub-groups based on amino acid sequence similarity: Subfamily I, Subfamily II, LIV-1, and gufA (gene of unknown function) (Gaither and Eide, 2001; Taylor et al., 2003). The LIV-1 subfamily is named after its founder member, an estrogen-regulated gene involved in the formation of breast cancer. This sub-family has been recently re-named LZT, for LIV-1 subfamily of ZIP zinc Transporters (Taylor et al., 2003). LZT proteins are similar to other ZIP proteins with respect to predicted secondary structure but they have a unique motif (HEXPHEXGD) in transmembrane V. Embedded within this motif is the consensus sequence of the catalytic zinc binding site of metalloproteases (HEXXH). This domain had been previously recognized in some presumptive ZIP family members (Begum et al., 2002; Suzuki and Endo, 2002), with Suzuki and Endo (2002) referring to it as the HELP domain. The LZT sub-family includes members from at least 12 different species including humans, mouse, drosophila, plants, yeast and bacteria. The one characterized member of the LZT family from Arabidopsis, IAR1, has been localized to the ER and may play a role in zinc homeostasis (Lasswell et al., 2000). IAR1 was originally identified as a mutant that was resistant to the inhibitory effects of several IAA-amino acid conjugates.
Arabidopsis is predicted to have 15 ZIP genes which belong to subfamily I (Maser et al., 2001). One obvious question to ask is why does Arabidopsis need so many ZIP transporters? We know that metals are transported from the soil into the root and then must cross both cellular and organellar membranes as they are distributed throughout the plant. Thus, we might expect different ZIP transporters to be functioning in different tissues. We can also expect that different members might function at different membranes; we have now localized various ZIP family members to the plasma membrane, to endocytotic vesicles and to the ER. In addition to functioning at different locations, some of the ZIP transporters may have different substrate specificities as well as different affinities for metals: high-affinity systems that are active in metal limiting conditions and low-affinity systems that function when substrates are more abundant. In yeast, ZIP family Zrt1p is a high affinity zinc transporter whereas ZIP family member Zrt2p is a low affinity zinc transporter (Zhao and Eide, 1996a, 1996b). Various molecular approaches ultimately can tell us not only in what tissue and cell type certain transporters are expressed but also where within a cell each is expressed. We have also identified plant mutants carrying insertions in all of the Arabidopsis ZIP transporter genes; this will greatly help in assigning functions. Having cloned genes in hand is also allowing us to undertake structure-function studies on the encoded proteins themselves (Rogers et al., 2000). Finally, moving beyond how any one transporter functions, we need to keep in mind that we want to understand metal transport at the whole plant level and to use such knowledge to develop plants with enhanced mineral content as well as plants that bioaccumulate or exclude potentially toxic cations. Such understanding will require knowledge of how metal levels are sensed by plants and how metals control gene expression.
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