نبذة مختصرة : The Band 3 (AE1, SLC4A1) membrane protein is found in red blood cells and in kidney where it functions as an electro-neutral chloride/bicarbonate exchanger. In this study, we have used molecular dynamics simulations to provide the first realistic model of the dimeric membrane domain of human Band 3 in an asymmetric lipid bilayer containing a full complement of phospholipids, including phosphatidylinositol 4,5–bisphosphate (PIP2) and cholesterol, and its partner membrane protein Glycophorin A (GPA). The simulations show that the annular layer in the inner leaflet surrounding Band 3 was enriched in phosphatidylserine and PIP2 molecules. Cholesterol was also enriched around Band 3 but also at the dimer interface. The interaction of these lipids with specific sites on Band 3 may play a role in the folding and function of this anion transport membrane protein. GPA associates with Band 3 to form the Wright (Wr) blood group antigen, an interaction that involves an ionic bond between Glu658 in Band 3 and Arg61 in GPA. We were able to recreate this complex by performing simulations to allow the dimeric transmembrane portion of GPA to interact with Band 3 in a model membrane. Large-scale simulations showed that the GPA dimer can bridge Band 3 dimers resulting in the dynamic formation of long strands of alternating Band 3 and GPA dimers.
Author summary Human Band 3 (AE1, SLC4A1), an abundant 911 amino acid glycoprotein, catalyzes the exchange of bicarbonate and chloride across the red blood cell membrane, a process necessary for efficient respiration. Malfunction of Band 3 leads to inherited diseases such as Southeast Asian Ovalocytosis, hereditary spherocytosis and distal renal tubular acidosis. Despite much available structural and functional data about Band 3, key questions about the conformational changes associated with transport and the molecular details of its interaction with lipids and other proteins remain unanswered. In this study, we have used computer simulations to investigate the dynamics of Band 3 in lipid bilayers that resemble the red blood cell plasma membrane. Our results suggest that negatively charged phospholipids and cholesterol interact strongly with Band 3 forming an annulus around the protein. Glycophorin A (GPA) interacts with Band 3 to form the Wright (Wr) blood group antigen. We were able to recreate this complex and show that GPA promotes the clustering of Band 3 in red blood cell membranes. Understanding the molecular details of the interaction of Band 3 with GPA has provided new insights into the nature of the Wright blood group antigen.
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