First Crystal Structure of Human GLUT1 Solved

Innovation That Matters

An article published in the prestigious Nature magazine this summer by a group led by one of a 2012 recipient of WuXi Life Science and Chemistry Awards, Dr. Nieng Yan of Tsinghua University, made a great contribution toward the understanding of GLUT1 functions and implications in disease intervention by solving the first crystal structure of human GLUT1.  The article is titled “Crystal structure of the human glucose transporter GLUT1” (Nature 510, 121-125, PMID: 24847886).

Glucose is the essential energy source for human cell metabolism.  To transport glucose across the plasma membrane, cells reply on a family of membrane proteins called glucose transporters (GLUTs), encoded by solute carrier 2A gene family (SLC2A).  These transporters allow glucose uptake across the plasma membrane through facilitative diffusion.  Fourteen members have been identified in this family of glucose transporters and they are responsible for glucose uptake in different cell types and tissues in humans.  Glucose homeostasis is vital for metabolism supplying energy source for essential cellular functions via respiration, and providing building blocks and reducing power required for cellular growth and proliferation via several well-characterized biochemical pathways.  Perturbation of glucose uptake causes many diseases.

GLUT1 (glucose transporter 1) is one of the members of GLUT family.  It is mainly expressed in erythrocytes and in the endothelial cells of blood-tissue barrier, such as blood-brain barrier and placenta.  Mutations in GLUT1 cause several rare hereditary diseases including GLUT1 deficiency syndrome 1 and 2, Dystonia 9, and idiopathic generalized epilepsy-12.  Disregulation, mainly over-expression of GLUT1 is associated with a number of cancers, cancer progression and poor prognosis.  Therefore, characterizing the structure of GLUT1 and deciphering the mechanisms involved in regulation of glucose transport would provide structural basis for understanding the physiology and pathophysiology of glucose uptake-associated functions and diseases.

Although structures of homologous GLUT1 from bacteria have been solved, these GLUT1 transporters are proton-driven symporters.  Human GLUT1 is a proton-independent uniporter that transport glucose down its concentration-gradient through facilitative diffusion.  This paper provided the first crystal structure for a uniporter GLUT1.  According to the paper, “Structure resolution of the human GLUT1 serves as a framework for understanding its functional mechanism.”  By comparison to the structures reported for bacterial GLUT1, insights regarding the differences between proton-driven active versus facilitative diffusion could be gained and be applicable to similar uniporters.

There are practical implications from this work as well.  For instance, by mapping variants observed in GLUT1 on to the crystal structure, functional consequence could be deduced providing support to classification of genetic variants and diagnosis of rare diseases associated with GLUT1 mutations.  GLUT1 is one of the members of glucose transporters whose expression is frequently upregulated in malignant cancers to increase glucose uptake to support malignant growth and proliferation.  Crystal structure of GLUT1 will provide clues for therapeutic development aiming at either blocking the transporter or utilizing the transporter to deliver chemotherapeutic drugs.  As the authors stated, “the structure also serves as a guiding principle for the development of potential therapeutic agents that target GLUT1 and other physiologically important MSF (major facilitator superfamily) sugar transporters.”  In addition, GLUT1 has been shown to interact with the receptor-binding domains of the human T-cell leukemia virus (HTLV)-1 and -2 envelope glycoproteins.  The crystal structure resolution of GLUT1 could also result in novel therapeutic interventions for HTLV infections.

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