Band 3, the human red cell chloride/bicarbonate anion exchanger (AE1, SLC4A1), in a structural context

Abstract

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.

Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3

“…S1), and the highly conserved 509-GSFLVR-514 peptide was surprisingly found in an exposed region of the cytoplasmic loop connecting membrane-spanning helices 4 and 5 ( Fig. S2) (26,27). Moreover, the weakly conserved sequences flanking GSFLVR in classical SH2 domains were absent from the sequences flanking 509-GSFLVR-514 in band 3.…”

“…Thus, the amino acid sequence that encompasses the SH2 signature motif specifically forms the bridge that precisely spans between the two halves of the membrane-spanning domain of band 3. Because these two halves of band 3 must pivot back and forth to catalyze anion transport (26,27), binding of cdb3-PO4 solely to one of the two conformations would be expected to lock the anion transporter in that conformation and thereby inhibit anion transport.…”

“…Based on analysis of the crystal structure of band 3 (26,27), the GSFLVR bridging peptide can be seen to exist in an α-helical conformation when the transport site faces outwards, but must extend to an elongated conformation when the transport site opens up to the cytoplasm. Given that the GSFLVR sequence in SH2 domains exists in an elongated conformation, one would predict that cdb3-PO 4 (or phosphorylated Y904) might only bind to the inward facing conformation of band 3.…”

It takes two to transport via an elevator

“…Importantly, UraA and the other NATs, are structurally homologous to the SLC4 family of anion exchangers [8] and the SLC26 family of anion transporters [9]. Mutations in these transporters are associated with a number of disease states [10,11]. Thus, the information provided by this new UraA structure may be relevant for both a deeper understanding of how these transporters function and of the molecular basis of the associated diseases, and may ultimately contribute to the design of drugs to treat them.…”

A Family with Autosomal Dominant Distal Renal Tubular Acidosis Presents with Atypical Phenotype Caused by a Missence Mutation (R388C) of the Human Kidney Anion Exchanger

“…The SLC4A1 mutation R388C has never been reported in the literature. R388 is located in the amphipathic helix 1 (H1) of N-terminal of the kAE1 protein and form the trio of arginies with R387 and R389, which has extensive interactions with the cytosolic ends of TM9 (Lys691-Leu704) in the core domain [21] (Fig. 1b, 3).…”