Cryo-EM structure of human glucose transporter GLUT4

Small solute carriers remain difficult to study by single particle cryo-EM. Here, the authors report the cryo-EM structure of human insulin-responsive glucose transporter GLUT4 (55 kDa) without rigid soluble domains or binders. GLUT4 is the primary glucose transporter in adipose and skeletal muscle tissues. Its cellular trafficking is regulated by insulin signaling. Failed or reduced plasma membrane localization of GLUT4 is associated with diabetes. Here, we report the cryo-EM structures of human GLUT4 bound to a small molecule inhibitor cytochalasin B (CCB) at resolutions of 3.3 angstrom in both detergent micelles and lipid nanodiscs. CCB-bound GLUT4 exhibits an inward-open conformation. Despite the nearly identical conformation of the transmembrane domain to GLUT1, the cryo-EM structure reveals an extracellular glycosylation site and an intracellular helix that is invisible in the crystal structure of GLUT1. The structural study presented here lays the foundation for further mechanistic investigation of the modulation of GLUT4 trafficking. Our methods for cryo-EM analysis of GLUT4 will also facilitate structural determination of many other small size solute carriers.

Automated summary

In this study, the authors reveal the cryo-EM structure of human GLUT4 and compare it with GLUT1. They also lay the foundation for further investigation of GLUT4 trafficking and provide methods for cryo-EM analysis of other small solute carriers.