Lecture 11 W24 Transport Across Biological Membranes II (March 27) - PDF

LECTURE 11 W24 Membrane topology of glucose transporters Major Facilitator (MF) superfamily Integral membrane protein with 12 TM segments. 4 (maybe 5) amphipathic α-helices are packed to form a hydrophilic channel through which glucose can pass in these helices, charged/polar amino acids are found o...

LECTURE 11 W24 Membrane topology of glucose transporters Major Facilitator (MF) superfamily Integral membrane protein with 12 TM segments. 4 (maybe 5) amphipathic α-helices are packed to form a hydrophilic channel through which glucose can pass in these helices, charged/polar amino acids are found on one face of α-helix and line the channel; the hydrophobic amino acids are found on the other face and interacts with the membrane can be seen on helical wheel plot (3.6 Channel lined with polar amino acids/turn of α-helix) (and charged) residues Yellow – hydrophobic; Blue – hydrophilic. Glucose Transport occurs via a Gated Pore Mechanism – GLUT 1 cycles between two conformations: – T1 form: glucose-binding site exposed on the outer membrane surface – T2 form: glucose-binding site exposed on the inner surface empty transporter reverts to outward-facing conformation 12 glucose transporters are encoded by the human genome GLUTs are a major facilitator (MF) superfamily of sugar transporters found in all organisms from bacteria to humans. 12 GLUT family members exist in the human genome (GLUT1-GLUT12), with different tissue distribution, kinetic properties and regulation. GLUT1 is found in erythrocytes and the Blood Brain Barrier In addition to transporting glucose into erythrocytes, also transport glucose across the blood brain barrier. Hence essential for normal brain metabolism In rare cases of defective GLUT1, patients present with brain related symptoms Standard care include a ketogenic diet. Can you explain why? GLUT2 – Liver, Kidney and Pancreas Large Kt = 17 mM Transport glucose into liver and kidney when blood [glucose] high Transport glucose OUT of hepatocytes during glycogenolysis to replenish blood [glucose]. Since Kt=17 mM can increase rate of transport in response to increased intracellular [glucose]. In pancreas, movement of glucose regulates the release of insulin. Glucose transport via GLUT4 into cardiac and skeletal muscles and adipocytes Unlike GLUT1 of RBC, ~90% of GLUT4 transporters are stored in storage vesicles inside the cell. High blood [glucose] after a meal releases insulin triggering the exocytosis of GLUT4 to the membrane surface & increasing the uptake of glucose into cells When [insulin] decreases, GLUT4s are removed from the membrane by endocytosis. In type 1 diabetes, a lack of insulin leads to high blood [glucose] for prolonged periods. Basis for “Glucose Tolerance Test”