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J. Biol. Chem., Vol. 283, Issue 24, 16732-16742, June 13, 2008

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Structural Signatures and Membrane Helix 4 in GLUT1

INFERENCES FROM HUMAN BLOOD-BRAIN GLUCOSE TRANSPORT MUTANTS^*

Juan M. Pascual¹, Dong Wang, Ru Yang, Lei Shi^¶, Hong Yang, and Darryl C. De Vivo^||

From the Departments of Neurology, Physiology, and Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, Departments of Neurology and ^||Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and ^¶Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College, Cornell University, New York, New York 10021

Exon IV of SLC2A1, a multiple facilitator superfamily (MFS) transporter gene, is particularly susceptible to mutations that cause GLUT1 deficiency syndrome, a human encephalopathy that results from decreased glucose flux through the blood-brain barrier. Genotyping of 100 patients revealed that in a third of them who harbor missense mutations in the GLUT1 transporter, transmembrane domain 4 (TM4), encoded by SLC2A1 exon IV, contains mutant residues that have the periodicity of one face of a kinked -helix. Arg-126, located at the amino terminus of TM4, is the locus for most of the mutations followed by other arginine and glycine residues located elsewhere in the transporter but conserved among MFS proteins. The Arg-126 mutants were constructed and assayed for protein expression, targeting, and transport capacity in Xenopus oocytes. The role of charge at position 126, as well as its accessibility, was investigated in R126H by determining its activity as a function of extracellular pH. The results indicate that intracellular charges at the MFS TM2–3 and TM8–9 signature loops and flanking TMs 3, 5, and 6 are critical for the structure of GLUT1 as are TM glycines and that TM4, located at the catalytic core of MFS proteins, forms a helix that surfaces into the extracellular solution where another proton facilitates transport.

Received for publication, February 21, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS037949 and NS001698 (to J. M. P., D. W., and D. C. D.). This work was also supported by the Colleen Giblin Foundation and the Will Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Depts. of Neurology, Physiology, and Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8813. Tel.: 214-648-5818; Fax: 214-645-6238; E-mail: Juan.Pascual{at}UTSouthwestern.edu.

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