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Identification of an exofacial substrate selectivity structure within the facilitative hexose transporter protein family (SLC2A)

GLUTs 2, 5, 7 & 9, which transport both glucose and fructose, appear to have a unique motif in TM7 (NAI) as a key component of a substrate selectivity filter within the exofacial vestibule. In non fructose transporting GLUT isoforms (GLUTs 1, 3 & 4) the Ile is replaced by a Val residue. One exception to this “rule” is GLUT11, a glucose/ fructose transporter which has a Val residue at position 299 equivalent to Val290 of GLUT1, but within a DSV motif. We hypothesized that the proximity of the Asn to Ile or Val could alter the effect of Ile or Val in this filter. We tested the functional properties of GLUT11 D297N, S298A and V299I mutants. D297N and S298A had no effect on glucose and fructose transport. However, mutation of the Val 299 to Ile dramatically reduced both glucose and fructose permeation. This marked reduction was then rescued when the DSV motif was replaced by NAI. Comparison of sequence alignments indicates that the NxI/V motif is highly conserved in the orthologs of human hexose transporters found in many species, including Taenia Solium, Schistosoma Mansoni, Saccharomyces cerevisiae, Trypanosoma, and Plasmodium falciparum. These findings support the hypothesis that this hydrophobic region of TM7 at the opening of the extracellular vestibule in facilitated hexose transporters may be an important structural component for determining substrate selectivity upstream of the binding site/s.