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

https://doi.org/10.1016/j.bbamem.2016.03.030Get rights and content
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Highlights

  • The Band 3 chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1) is one of the best-studied human membrane transport proteins.

  • A recent 3.5 Å crystal structure of the Band 3 membrane domain provides new insights into its mechanism of action.

  • This review places over 40 year of research on Band 3 into a structural context and explains why mutations lead to disease.

  • Molecular dynamics simulations produced the first molecular model of Band 3 in a lipid bilayer.

Abstract

The crystal structure of the dimeric membrane domain of human Band 31, 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.

Graphical abstract

Human Band 3 dimer in a lipid bilayer. Each subunit is colored using the rainbow color (blue to red) from N-terminal to C-terminal and the positions of the lipid phosphate groups shown as gray spheres.

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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

Cited by (0)

This article is dedicated to the (great) grandfathers in the Band 3 field: mentor Guido Guidotti, Bob Gunn, Harvey Lodish, Hermann Passow, Aser Rothstein, Ted Steck, and Michael Tanner who all inspired future generations of scientists including colleagues Seth Alper, Lesley Bruce, Naotaka Hamasaki, Mike Jennings, Phil Knauf, Ron Kopito, Phil Low, Jim Salhany, Ashley Toye, and others to devote their continued interest to this membrane transport glycoprotein with such a poor name.

☆☆

For the purpose of this review, Band 3 refers to the native protein as found in red blood cells, AE1 to the protein expressed from its cDNA, SLC4A1 as the gene and SLC4A1 as the gene product.