Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family

  • Life Sci Alliance. 2021 Feb 3;4(4):e202000858. doi: 10.26508/lsa.202000858.
Tânia Filipa Custódio  1 ,  Peter Aasted Paulsen  1 ,  Kelly May Frain  1 ,  Bjørn Panyella Pedersen  2  3
Affiliations
  • 1. Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark.
  • 2. Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark [email protected].
  • 3. Aarhus Institute of Advanced Studies, Aarhus University, Aarhus C, Denmark.
PMID: 33536238 DOI: 10.26508/lsa.202000858
Abstract

The human glucose transporters GLUT1 and GLUT3 have a central role in glucose uptake as canonical members of the Sugar Porter (SP) family. GLUT1 and GLUT3 share a fully conserved substrate-binding site with identical substrate coordination, but differ significantly in transport affinity in line with their physiological function. Here, we present a 2.4 Å crystal structure of GLUT1 in an inward open conformation and compare it with GLUT3 using both structural and functional data. Our work shows that interactions between a cytosolic "SP motif" and a conserved "A motif" stabilize the outward conformational state and increases substrate apparent affinity. Furthermore, we identify a previously undescribed Cl- ion site in GLUT1 and an endofacial lipid/glucose binding site which modulate GLUT kinetics. The results provide a possible explanation for the difference between GLUT1 and GLUT3 glucose affinity, imply a general model for the kinetic regulation in GLUTs and suggest a physiological function for the defining SP sequence motif in the SP family.