The crystal structure of the dimeric membrane domain of human Band 3(1), the red cell chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1), provides a structural context for over four decades of studies into this historic and important membrane glycoprotein. In this review, we highlight the key structural features responsible for anion binding and translocation and have integrated the following topological markers within the Band 3 structure: blood group antigens, N-glycosylation site, protease cleavage sites, inhibitor and chemical labeling sites, and the results of scanning cysteine and N-glycosylation mutagenesis. Locations of mutations linked to human disease, including those responsible for Southeast Asian ovalocytosis, hereditary stomatocytosis, hereditary spherocytosis, and distal renal tubular acidosis, provide molecular insights into their effect on Band 3 folding. Finally, molecular dynamics simulations of phosphatidylcholine self-assembled around Band 3 provide a view of this membrane protein within a lipid bilayer.
Keywords: Anion exchanger; Band 3; Bicarbonate transport; Chloride/bicarbonate exchange; Distal renal tubular acidosis (dRTA); Glycoprotein; Hereditary spherocytosis (HS); Hereditary stomatocytosis (HSt); Membrane proteins; Molecular dynamics; N-glycosylation; Protein folding; Protein quality control; Solute carrier 4 (SLC4); Southeast Asian ovalocytosis (SAO); Trafficking; Transporters.
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