title: Pathogenic mutations causing glucose transport defects in GLUT1 transporter: The role of intermolecular forces in protein structure-function.
abstract: Two families of glucose transporter - the Na(+)-dependent glucose cotransporter-1 (SGLT family) and the facilitated diffusion glucose transporter family (GLUT family) - play a crucial role in the translocation of glucose across the epithelial cell membrane. How genetic mutations cause life-threatening diseases like GLUT1-deficiency syndrome (GLUT1-DS) is not well understood. In this review, we have combined previous functional data with our in silico analyses of the bacterial homologue of GLUT members, XylE (an outward-facing, partly occluded conformation) and previously proposed GLUT1 homology model (an inward-facing conformation). A variety of native and mutant side chain interactions were modeled to highlight the potential roles of mutations in destabilizing protein-protein interaction hence triggering structural and functional defects. This study sets the stage for future studies of the structural properties that mediate GLUT1 dysfunction and further suggests that both SGLT and GLUT families share conserved domains that stabilize the transporter structure/function via a similar mechanism.
authors: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany; Molecular Structure and Function, The Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada. Electronic address: mobeen.raja@sickkids.ca.
authors: Mobeen
authors: M
authors: Raja
authors: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany. Electronic address: rolf.kinne@mpi-dortmund.mpg.de.
authors: Rolf K H
authors: RK
authors: Kinne
mesh_terms: D051272:Glucose Transporter Type 1 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human
keywords: GLUT1-deficiency syndrome; Glucose transporter; Intermolecular interactions; Loss-of-function mutations; Protein stability; Sugar transport defects