1).ĭespite extensive efforts, we simply could not obtain diffracting crystals for GLUT4. However, the unique sequences that mediate GLUT4’s membrane trafficking capability, including an FQQI motif on the amino (N) terminus and the LL and TELEY motifs on the carboxyl (C) terminus 14, 15, 16, 17, 18, are not conserved in the SLC2A family, entailing the need to solve the high-resolution structure of GLUT4 (Supplementary Fig. We solved crystal structures of human GLUT1 and GLUT3 in the inward- and outward-facing conformations a few years ago 12, 13. Among the SLC2A members, GLUT4 is most closely related to GLUT1, with a sequence identity and similarity of 65% and 79%, respectively. GLUT4, encoded by SLC2A4, is one of the 14 members of the SLC2A family. Therefore, elucidating the structure and working mechanism of GLUT4 will both facilitate our understanding of the fundamental energy metabolism, and shed light on the development of potential intervention strategies for the deleterious disease 11. Impairment of cellular glucose uptake due to compromised insulin availability or sensing underlies diabetes mellitus 10. Upon insulin stimulation, GLUT4 is quickly transported from these intracellular structures to the plasma membrane, resulting in rapid consumption of glucose from blood 9. The major facilitator superfamily (MFS) glucose transporter GLUT4 mediates the rate-limiting glucose cellular uptake in adipocytes and muscle cells, and thus plays a vital role in insulin-responsive glucose metabolism 3, 4, 5, 6.Īt basal state, GLUT4 is primarily distributed on the membranes of the trans-Golgi network (TGN), endosomes and 50–70 nm tubulo-vesicular structures known as the GLUT4 storage vesicles (GSVs) 7, 8. Insulin lowers blood sugar level by triggering cellular uptake of glucose 2. Glucose, being the primary fuel, a versatile bio-precursor, and a signaling molecule, is tightly controlled for metabolic homeostasis via various mechanisms, such as hormonal regulation by insulin and glucagon 1.
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