Five major hexose transporters have been identified and cloned since the characterization of the first, GLUT 1, by molecular cloning ( 9). They are numbered GLUT 1
to 5 in the order of their discovery and are all proteins with similar molecular structures containing between 492 and 524 amino acid residues. Mueckler et al. ( 9), using hydropathic and secondary structure predictions, proposed a two-dimensional orientation model of GLUT 1 in the plasma membrane ( Fig, 3.3). The molecule has three major domains: (a) 12 a-helices spanning the membrane with the N and C termini of the protein on the cytoplasmic side of the cell membrane, (b) an intracellular domain of 65 hydrophilic amino acids (between M6 and M7), and (c) an extracellular 33-amino-acid segment (between M1 and M2) containing the site for an asparagine-linked oligosaccharide at asparagine 45.
Figure 3.3. Highly schematic diagram illustrating the predicted secondary structure model of the glucose transporter molecule (GLUT 1) in the cell membrane (shaded). The putative membrane-spanning a-helices are shown as rectangles numbered 1-12 connected by chains (lines) of linked amino acids. (Adapted from Mueckler M, Caruso C, Baldwin SA, et al. Science 1985;229:941-5.)
The prediction was that the polypeptide backbone of the molecule traverses or spans the plasma membrane 12 times. Both the amino- and carboxy-terminal ends of the molecule are on the cytoplasmic side of the membrane, while an N-glycosylation site is present on the first extracytoplasmic loop (M1 and M2). These basic topologic features have been confirmed by studies using proteolytic digestion and sequence-specific antibodies. GLUT 1, purified from human red cells and reconstituted in liposomes, appears to be predominantly in the a-helical form, and the transmembrane segments form a-helixes at right angles to the plane of the lipid membrane (10). The molecular structure of GLUT 1, shown in Figures...^, is, of course, a two-dimensional model. At present, the three-dimensional structure of the carrier in the membrane is not known. Studies using radiation inactivation of the carrier in intact red cells have indicated that GLUT 1 probably exists as homotetramer (11).
The structures, properties, expression sites, and roles of each of the five facilitative glucose transporter isoforms are briefly described below and summarized in Table
3.4. Because of the recognized importance of these transporters in health and disease, there have been numerous reviews (12, 13, 14 and 16), which should be consulted for greater detail.
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