Background: There is still no high resolution three-dimensional structure available for the membrane-spanning domain of anion exchanger 1 (AE1). Results: A three-dimensional model of AE1 membrane-spanning domain has been generated in silico and experimentally assessed. Conclusion: Transmembrane segments forming AE1 transport site have been identified. Significance: This is the first three-dimensional model of AE1 membrane-spanning domain based on a cation symporter.The anion exchanger 1 (AE1), a member of bicarbonate transporter family SLC4, mediates an electroneutral chloride/bicarbonate exchange in physiological conditions. However, some point mutations in AE1 membrane-spanning domain convert the electroneutral anion exchanger into a Na ؉ and K ؉ conductance or induce a cation leak in a still functional anion exchanger. The molecular determinants that govern ion movement through this transporter are still unknown. The present study was intended to identify the ion translocation pathway within AE1. In the absence of a resolutive three-dimensional structure of AE1 membrane-spanning domain, in silico modeling combined with site-directed mutagenesis experiments was done. A structural model of AE1 membrane-spanning domain is proposed, and this model is based on the structure of a uracilproton symporter. This model was used to design cysteine-scanning mutagenesis on transmembrane (TM) segments 3 and 5. By measuring AE1 anion exchange activity or cation leak, it is proposed that there is a unique transport site comprising TM3-5 and TM8 that should function as an anion exchanger and a cation leak.The anion exchanger 1 (AE1, 2 SLC4A1, or band 3) is the main membrane protein in vertebrate red cells. It fulfills different tasks in these cells: a structural role by linking plasma membrane to cytoskeleton, a respiratory role by improving CO 2 transport capacity of red cells, and an antigenic function (Diego blood group and senescence), and it is also involved in cytokinesis and red cell volume regulation (1). At the molecular level, this protein is divided into two main structural domains: a cytoplasmic N-terminal domain (about 400 amino acids) and a membrane-spanning domain (about 450 amino acids) with a short C-terminal tail in the cytoplasm. These two entities seem to function independently: the large cytoplasmic domain is involved in interactions with enzymes, hemoglobin, and structural proteins, whereas the membrane-spanning domain is responsible for the transport activity of the protein (2, 3). In addition to red cells, AE1 is also expressed in kidney ␣-intercalated cells and cardiac myocytes (4). In physiological conditions, AE1 exchanges one chloride for one bicarbonate by an electroneutral transport mechanism with the driving force for ion movement provided by their electrochemical gradient. A few years ago, some specific point mutations were characterized and proposed to convert the electroneutral anion exchanger into a cation-conductive pathway (5, 6). These mutations are associated with human pathologies (hered...
Missense mutations in the erythroid band 3 protein (Anion Exchanger 1) have been associated with hereditary stomatocytosis. Features of cation leaky red cells combined with functional expression of the mutated protein led to the conclusion that the AE1 point mutations were responsible for Na+ and K+ leak through a conductive mechanism. A molecular mechanism explaining mutated AE1-linked stomatocytosis involves changes in AE1 transport properties that become leaky to Na+ and K+. However, another explanation suggests that point-mutated AE1 could regulate a cation leak through other transporters. This short paper intends to discuss these two alternatives.
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