Extracellular gating of glucose transport through GLUT 1

Abstract

The ubiquitous glucose transporter 1 (GLUT1) is physiologically and pathologically relevant in energy metabolism of the CNS, skeletal muscles, cancer cells etc. Extensive experiments on GLUT1 produced thorough understandings of its expressions, functions, and structures which were recently resolved to atomic accuracy. However, theoretical understandings are still controversial about how GLUT1 facilitates glucose diffusion across the cell membrane. Molecular dynamics (MD) simulations of the current literature have GLUT1 embedded in a symmetric bilayer of a single lipid type. They provide atomistic illustrations of the alternating access theory (AAT), but the simulation results are inconsistent with the undisputed experimental data of kinetics showing rapid transport of glucose at near-physiological temperatures, high Arrhenius activation barrier in zero-trans uptake, and large trans-acceleration at sub-physiological temperatures. In this research, we embedded GLUT1 in an asymmetric bilayer of multiple lipids to better mimic the erythrocyte membrane. We ran unbiased MD simulations at 37°C and at 5°C and found a new mechanism of glucose transport via GLUT1: The extracellular (EC) gate opened wide for EC glucopyranose at 37°C and, only in the presence of intracellular (IC) glucose, at 5°C. In the absence of IC glucose at 5°C, the EC gate opened narrowly for acyclic glucose, gating out glucopyranose. This EC-gating mechanism is simpler than AAT and yet it well explains for the rapid glucose transport at near-physiological temperatures and large trans-acceleration at subphysiological temperatures. It also explains why zero-trans uptake (involving the pyranose-toaldehyde transformation) has an Arrhenius barrier ~20 kcal/mol higher than the equilibrium exchange transport.

Quantitative characterization of the path of glucose diffusion facilitated by human glucose transporter 1

“…Qualitatively, the GLUT1 dynamics are similar to the case studied in Ref. (53) where GLUT1 was embedded in a single membrane patch that had similar lipid compositions. Quantitatively, the EC gate is open for ~10% of the time which is much shorter than in the single-membrane model where the gate is nearly open all the time at 37°C.…”

“…They do not heed the known facts that the structure and activities of GLUTs are sensitive to the membrane lipid compositions. (52)(53)(54)(55)(56) In particular, glucose transport across erythrocyte membranes was found, long ago, to be reduced by 75% by exposure to phospholipase A2 which hydrolyzes fatty acyl groups from the sn-2 position of glycerophospholipids. (54,56) In general, lipid-protein interactions are significant determinants of the membrane protein functions.…”

Up-Regulation of Glycogen Synthesis and Degradation Enzyme Level Maintained Myocardial Glycogen in Huddling Brandt’s Voles Under Cool Environments

“…Glycogen synthesis and decomposition also depend on changes in glucose metabolism ( Chen and Phelix, 2019 ). In this study, the protein expression levels of glucose transporters GLUT1 and GLUT4 in the CS group males were significantly higher than in the CON group males, which may contribute to intracellular glucose accumulation and glycogen content increase.…”

In silicosimulations of erythrocyte aquaporins with quantitativein vitrovalidation

“…[32][33][34][35][36][37][38][39] Now the copy numbers of the AQPs natively expressed in the human erythrocyte are known quantitatively, 40 can we make quantitatively accurate predictions of their transport characteristics from the all-atom MD simulations? Is it necessary to model the erythrocyte membrane with appropriate lipid compositions in its inner and outer leaets [41][42][43][44][45][46] ? In another word, what difference would it be if the membrane is simply modelled as a lipid bilayer of a single lipid type as it is in the current literature?…”