Crystal Structure of the Human Glucose Transporter GLUT1

The long-sought after crystal structure of Glucose Transporter GLUT1 has been solved by Nieng Yan’s group at Tsinghua University in Beijing.  Resolved to 3.2A˚, this is the first structure solved from one of the largest and most universal secondary transporter super families. The structure provided insights in to the alternating access mechanism of GLUT1 as well as other Major Facilitator Superfamilies (MFS). The structure is an essential step for understanding how the MFS transport glucose and, how mutated, cause disease.

 Technical Challenges

The glucose transporter GLUT1 has an essential role for glucose supply to the brain and other organs. It is highly active and undoubtedly exhibits multiple, interchangeable conformations that make crystallizing and solving the structure improbable. To overcome this challenge, the Yan group identified and crystallized two mutants, N45T and E329Q, which arrested GLUT1 activity. The mutants were known to freeze GLUT1 in an inward-facing conformation. 

Interesting Structural Features
A faulty encoding gene (SLC2A1) or inactivation of GLUT1 results in compromised transport activities for glucose and is the cause of a number of diseases. Structural mapping of the known genetic mutations mapped to three clusters in the membrane protein. The first cluster concerns the amino acid residues involved in substrate binding. The other two clusters are thought to facilitate the transport mechanism of GLUT1 as well as other sugar porter subfamilies. 
To determine the transport mechanism of GLUT1, the team compared the newly solved GLUT1 structure to its bacterial homologue, XylE, which is a proton-coupled xylose symporter. Some key findings are listed below:

  • The GLUT1 protein may prefer an outward-open configuration.
  • Two actions cause the translocation of glucose and the conformational switch to inward-open conformation: Substrate binding & binding affinity between the extracellular side and the intercellular side.
  • Comparison of GLUT1 and XylE show protonation of a key residue that triggers the outward to inward translocation.
  •  Detailed mechanistic understanding of the transport mechanisms of uniporters and symporters requires additional biochemical and biophysical investigations.
For a complete account of the structure of GLUT1 and its potential functional characteristics, please review, Crystal structure of the human glucose transporter GLUT1 published in the June 5th, 2014 print edition of Nature or the May 18th, 2014 on-line edition.

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