ABC Proteins That Transport Lipid Soluble Substrates May Operate by a Flippase Mechanism

The substrates of mammalian MDR1 are primarily planar, lipid-soluble molecules with one or more positive charges;

▲ FIGURE 7-11 Structural model of E. coli lipid flippase, an ABC protein homologous to mammalian MDR1. The

V-shaped protein encloses a "chamber" within the bilayer where it is hypothesized that bound substrates are flipped across the membrane, as depicted in Figure 7-12. Each identical subunit in this homodimeric protein has one transmembrane domain, comprising six a helices, and one cytosolic domain where ATP binding occurs. [Adapted from G. Chang and C. Roth, 2001, Science 293:1793.]

they all compete with one another for transport by MDR1, suggesting that they bind to the same site or sites on the protein. In contrast to bacterial ABC proteins, all four domains of MDR1 are fused into a single 170,000-MW protein. The recently determined three-dimensional structure of a homologous E. coli lipid-transport protein reveals that the molecule is V shaped, with the apex in the membrane and the arms containing the ATP-binding sites protruding into the cytosol (Figure 7-11).

Although the mechanism of transport by MDR1 and similar ABC proteins has not been definitively demonstrated, a likely candidate is the flippase model depicted in Figure 7-12. According to this model, MDR1 "flips" a charged substrate molecule from the cytosolic to the exoplasmic leaflet, an energetically unfavorable reaction powered by the coupled ATPase activity of the protein. Support for the flippase model of transport by MDR1 comes from MDR2, a homologous protein present in the region of the liver cell plasma membrane that faces the bile duct. As detailed in Chapter 18, MDR2 has been shown to flip phospholipids from the cytosolic-facing leaflet of the plasma membrane to the exo-plasmic leaflet, thereby generating an excess of phospho-lipids in the exoplasmic leaflet; these phospholipids then peel off into the bile duct and form an essential part of the bile.

► FIGURE 7-12 Flippase model of transport by MDR1 and similar ABC proteins. Step |1|: The hydrophobic portion (black) of a substrate molecule moves spontaneously from the cytosol into the cytosolic-facing leaflet of the lipid bilayer, while the charged end (red) remains in the cytosol. Step |2|: The substrate diffuses laterally until encountering and binding to a site on the MDR1 protein within the bilayer. Step □: The protein then "flips" the charged substrate molecule into the exoplasmic leaflet, an energetically unfavorable reaction powered by the coupled hydrolysis of ATP by the cytosolic domain. Steps |4| and |5|: Once in the exoplasmic face, the substrate again can diffuse laterally in the membrane and ultimately moves into the aqueous phase on the outside of the cell. [Adapted from P Borst, N. Zelcer, and A. van Helvoort, 2000, Biochim. Biophys. Acta 1486:128.]

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