Kinetic Basis of Cis- and Trans-Allostery in GLUT1-Mediated Sugar Transport

J Membr Biol. 2018 Feb;251(1):131-152. doi: 10.1007/s00232-017-0006-7. Epub 2017 Dec 5.

Abstract

A growing body of evidence demonstrates that GLUT1-mediated erythrocyte sugar transport is more complex than widely assumed and that contemporary interpretations of emergent GLUT1 structural data are incompatible with the available transport and biochemical data. This study examines the kinetic basis of one such incompatibility-transport allostery-and in doing so suggests how the results of studies examining GLUT1 structure and function may be reconciled. Three types of allostery are observed in GLUT1-mediated, human erythrocyte sugar transport: (1) exofacial cis-allostery in which low concentrations of extracellular inhibitors stimulate sugar uptake while high concentrations inhibit transport; (2) endofacial cis-allostery in which low concentrations of intracellular inhibitors enhance cytochalasin B binding to GLUT1 while high concentrations inhibit binding, and (3) trans-allostery in which low concentrations of ligands acting at one cell surface stimulate ligand binding at or sugar transport from the other surface while high concentrations inhibit these processes. We consider several kinetic models to account for these phenomena. Our results show that an inhibitor can only stimulate then inhibit sugar uptake if (1) the transporter binds two or more molecules of inhibitor; (2) high-affinity binding to the first site stimulates transport, and (3) low-affinity binding to the second site inhibits transport. Reviewing the available structural, transport, and ligand binding data, we propose that exofacial cis-allostery results from cross-talk between multiple, co-existent ligand interaction sites present in the exofacial cavity of each GLUT1 protein, whereas trans-allostery and endofacial cis-allostery require ligand-induced subunit-subunit interactions.

Keywords: Allostery; Facilitated diffusion; Glucose transport; Kinetic analysis; Membrane transport protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Transport / physiology
  • Cytochalasin B / metabolism
  • Erythrocytes / metabolism
  • Glucose / metabolism
  • Glucose Transporter Type 1 / metabolism*
  • Humans
  • Kinetics
  • Protein Binding

Substances

  • Glucose Transporter Type 1
  • Cytochalasin B
  • Glucose