Mammalian glucose transporter activity is dependent upon anionic and conical phospholipids

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The regulated movement of glucose across mammalian cell membranes is mediated by facilitative glucose transporters (GLUTs) embedded in lipid bilayers. Despite the known impor-tance of phospholipids in regulating protein structure and activ-ity, the lipid-induced effects on the GLUTs remain poorly understood. We systematically examined the effects of physio-logically relevant phospholipids on glucose transport in lipo-somes containing purified GLUT4 and GLUT3. The anionic phospholipids, phosphatidic acid, phosphatidylserine, phos-phatidylglycerol, and phosphatidylinositol, were found to be essential for transporter function by activating it and stabilizing its structure. Conical lipids, phosphatidylethanolamine and dia-cylglycerol, enhanced transporter activity up to 3-fold in the presence of anionic phospholipids but did not stabilize protein structure. Kinetic analyses revealed that both lipids increase the k cat of transport without changing the K m values. These results allowed us to elucidate the activation of GLUT by plasma mem-brane phospholipids and to extend the field of membrane pro-tein-lipid interactions to the family of structurally and function-ally related human solute carriers. Membrane proteins are embedded in a lipid bilayer that cov-ers a large percentage of their exposed surface. Lipid bilayers in typical human cells consist of hundreds of different lipid types that modulate cell signaling and protein function (1). Mem-brane lipid composition changes in several disease states and varies markedly over different cellular compartments. This influences the activity of transmembrane proteins by direct interactions with specific lipids or through changes in the bio-physical properties of the membrane (e.g. fluidity, permeability, curvature, and lateral pressure) (2, 3). Each membrane protein interacts with several lipid molecules at any given time, yet understanding the functional and structural effects of these contacts has been previously limited. With the advent of several methodological advances in isolating and studying membrane proteins, the significance of individual lipid components has begun to emerge. Human and bacterial ion channels, aquaporin Z, LacY, and the nicotinic acetylcholine receptor, are among the growing list of membrane proteins that have been shown to require specific lipids like anionic phospholipids, phosphati-dylethanolamine (PE), 6 cholesterol, or signaling lipids like phosphatidylinositol bisphosphate for optimal activity or proper folding (4 –11). The solute carriers (SLCs) consist of over 400 family mem-bers in humans. A quarter of these are associated with disease, making them excellent targets for clinical research (12). Although highly important in nutrient uptake, drug transport, and waste removal, this class of proteins remains relatively understudied (12). Elucidation of the lipid requirement for activity of mammalian solute carriers remains of paramount interest for drug discovery and general understanding of trans-port mechanisms. Members of the SLC2A family of facilitative hexose trans-porters are essential in regulating cellular metabolism by selec-tively transporting glucose down a concentration gradient without the use of energy. To date, 14 distinct human SLC2A isoforms (GLUTs) have been identified (13), and for several of these proteins the cellular function in health and disease has been established. Regulation of the insulin-responsive facilita-tive glucose transporter GLUT4 (SLC2A4), which is primarily responsible for mediating peripheral glucose disposal in insu-lin-sensitive tissues such as skeletal and cardiac muscle as well as adipose tissue (14), has been intensively studied in relation to the pathophysiology of type 2 diabetes mellitus (15). Under basal conditions, the majority of GLUT4 remains sequestered within the cytosol in specialized membrane vesicles. Upon




Hresko, R. C., Kraft, T. E., Quigley, A., Carpenter, E. P., & Hruz, P. W. (2016). Mammalian glucose transporter activity is dependent upon anionic and conical phospholipids. Journal of Biological Chemistry, 291(33), 17271–17282.

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