Structural Interpretation of the Alternating Access Mechanism of Glucose Transporters Gluts

Abstract

Glucose is the primary fuel to life on earth. Cellular uptake of glucose is a fundamental process for metabolism, growth, and homeostasis. The major facilitator superfamily glucose transporters, exemplified by human GLUT1-4, are prototypes in the study of solute transport. We were able to determine the atomic structures of human GLUTs in multiple conformations during a transport cycle, which reveal the molecular basis for ligand recognition and transport. The crystal structure of human GLUT1 at 3.2 angstrom resolution in the inward-open conformation allows accurate mapping and potential mechanistic understanding of disease-associated mutations in GLUT1. Comparison of the GLUT structures in the outward-open, outward-occluded, and inward-open states provides insights into the alternating access cycle for GLUTs, whereby the C domain provides the primary substrate binding site and the amino terminal domain undergoes rigid-body rotation with respect to C domain. We also determined the crystal structure of XylE, an E. coli homologue of GLUT1-4. Whereas GLUT1-4 are facilitative uniporters, XylE is a proton-driven symporter. Structural comparison and biochemical analysis of GLUTs and XylE allow examination of transport mechanisms by passive facilitators versus active transporters.