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The Human Genome Encodes a Family of Sugar-Transporting GLUT Proteins

المؤلف:  Harvey Lodish, Arnold Berk, Chris A. Kaiser, Monty Krieger, Anthony Bretscher, Hidde Ploegh, Angelika Amon, and Kelsey C. Martin.

المصدر:  Molecular Cell Biology

الجزء والصفحة:  8th E , P480

2026-05-21

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The Human Genome Encodes a Family of Sugar-Transporting GLUT Proteins The human genome encodes at least 14 highly homologous GLUT proteins, GLUT1–GLUT14, that are all thought to contain 12 membrane-spanning α helices, suggesting that they evolved from a single ancestral transport protein. In the human GLUT1 protein, the transmembrane α helices are predominantly hydrophobic; several helices, however, bear amino acid residues (e.g., serine, threonine, asparagine, and glutamine) whose side chains can form hydrogen bonds with the hydroxyl groups on glucose. These residues are thought to form the inward-facing and outward facing glucose- binding sites in the interior of the protein.

The structures of all GLUT isoforms are thought to be quite similar, and all of them transport sugars. Nonetheless, their differential expression in various cell types, the regulation of their numbers on cell surfaces, and isoform-specific functional properties enable different body cells to regulate glucose metabolism differently and at the same time allow a constant concentration of glucose in the blood to be maintained. For instance, GLUT3 is found in neuronal cells of the brain. Neurons depend on a constant influx of glucose for metabolism, and the low Km of GLUT3 for glucose (1.5 mM), like that of GLUT1, ensures that these cells incorporate glucose from brain extra cellular fluids at a high and constant rate.

GLUT2, expressed in liver cells and in the insulin-secreting β islet cells of the pancreas, has a Km of ~20 mM, about 13 times higher than the Km of GLUT1. As a result, when blood glucose rises after a meal from its basal level of 5 mM to 10 mM or so, the rate of glucose influx will almost double in GLUT2-expressing cells, whereas it will increase only slightly in GLUT1-expressing cells. In the liver, the “excess” glucose brought into the cell is stored as the polymer glycogen. In β islet cells, the rise in glucose triggers secretion of the hormone insulin, which in turn lowers blood glucose by increasing glucose uptake and metabolism in muscle and by inhibiting glucose production in the liver. Indeed, cell-specific inactivation of GLUT2 in pancreatic β islet cells prevents glucose-stimulated insulin secretion and disrupts the regulated expression of glucose-sensitive genes in liver cells (hepatocytes).

Another GLUT isoform, GLUT4, is expressed only in fat and muscle cells, which respond to insulin by increasing their uptake of glucose, thereby removing glucose from the blood. In the absence of insulin, GLUT4 resides in intracellular membranes, not the plasma membrane, and is unable to facilitate glucose uptake from the extracellular fluid. By a process detailed in Figure 1, insulin causes these GLUT4 rich internal membranes to fuse with the plasma membrane, increasing the number of GLUT4 molecules present on the cell surface and thus the rate of glucose uptake. This is one principal mechanism by which insulin lowers blood glucose; defects in the movement of GLUT4 to the plasma membrane are one of the causes of adult-onset, or type II, diabetes, a disease marked by continuously high blood glucose.

Fig1. Insulin stimulation of fat cells induces translocation of GLUT4 from intracellular vesicles to the plasma mem brane. (a) Cultured adipose cells engineered to express a chimeric protein comprising GLUT4 with a green fluorescent protein (GFP) fused to its C-terminus were visualized with a confocal fluorescence microscope. In the absence of insulin, virtually all of the GLUT4 is in intracellular mem branes. Treatment with insulin triggers fusion of the GLUT4 containing membranes with the plasma membrane. Arrows highlight GLUT4 present at the plasma membrane; N indicates the position of the nucleus. (b) In fat and muscle cells, insulin signaling acts in multiple steps to increase the level of GLUT4 at the plasma membrane. In resting cells, the majority of the GLUT4 protein is localized to specialized GLUT4 storage vesicles (GSVs), tethered to Golgi matrix proteins by the TUG protein. Binding of insulin to the insulin receptor leads to activation of a protease (step 1) that cleaves the TUG protein, releasing GLUT4-containing vesicles (step 2), which then move along microtubules, powered by a kinesin motor (see Chapter 18), to the cell surface. Insulin also activates PKB (step 3; see Figure 16-29). PKB then phosphorylates the Rab GAP protein AS160 (step 4), inhibiting its ability to accelerate GTP hydrolysis by Rab8, Rab10, and Rab14. These Rab proteins accumulate in their active GTP-bound states (step 5) and allow the GLUT4 storage vesicles to move along microtubules to the cell surface (steps 6a and 6b). Finally, these GSVs fuse with the plasma membrane (step 7). This step is catalyzed by the exocyst and also by another monomeric GTP-binding protein, RALA. PKB stimulates this membrane fusion event by phosphorylating and thus inactivating the RALA GAP protein RGC (step 8), allowing RALA to accumulate in its active GTP-bound state (step 9). The resultant increase in plasma membrane GLUT4 allows the cell to incorporate glucose from the extracellular fluids at a rate about 10 times that of unstimulated cells (step 10). Following removal of insulin, the plasma membrane GLUT4 is internalized by endocytosis (step 11) and eventually transported to GSVs (step 12). Many other proteins, not shown here, participate in these signaling and vesicle budding and fusion events. See J. Bogan, 2012, Annu. Rev. Biochem. 81:507, D. Leto and A. Saltiel, 2012, Nat. Rev. Mol. Cell Biol. 13:383, and J. Belman et al., 2014, Rev. Endocr. Metab. Disord. 15:55. [Part (a) C. Yu et al., 2007, J. Biol. Chem 282:7710; ©2007 American Society for Biochemistry and Molecular Biology.]

GLUT5 is the only GLUT protein with a high specificity (preference) for fructose; its principal site of expression is the apical membrane of intestinal epithelial cells, where it transports dietary fructose from the intestinal lumen to the inside of the cells.