Abstract
Anion exchanger 1 (AE1) is responsible for the exchange of bicarbonate and chloride across the erythrocyte plasma membrane. Human AE1 consists of a cytoplasmic and a membrane domain joined by a 33-residue flexible linker. Crystal structures of the individual domains have been determined, but the intact AE1 structure remains elusive. In this study, we use molecular dynamics simulations and modeling to build intact AE1 structures in a complex lipid bilayer that resembles the native erythrocyte plasma membrane. AE1 models were evaluated using available experimental data to provide an atomistic view of the interaction and dynamics of the cytoplasmic domain, the membrane domain, and the connecting linker in a complete model of AE1 in a lipid bilayer. Anionic lipids were found to interact strongly with AE1 at specific amino acid residues that are linked to diseases and blood group antigens. Cholesterol was found in the dimeric interface of AE1, suggesting that it may regulate subunit interactions and anion transport.
Highlights
The red blood cell anion exchanger 1 (AE1, Band 3, SLC4A1) is responsible for the rapid exchange of bicarbonate and chloride across the red blood cell plasma membrane, a process necessary for efficient respiration [1,2]
Our results suggest that Anion exchanger 1 (AE1) strongly interacts with specific lipids in the red blood cell membrane and highlight residues that, when mutated, may result in diseases
Human AE1 is a 911 residue glycoprotein consisting of a N-terminal cytoplasmic domain that interacts with cytoplasmic proteins and a C-terminal membrane domain responsible for its transport function [3]
Summary
The red blood cell anion exchanger 1 (AE1, Band 3, SLC4A1) is responsible for the rapid exchange of bicarbonate and chloride across the red blood cell plasma membrane, a process necessary for efficient respiration [1,2]. Human AE1 is a 911 residue glycoprotein consisting of a N-terminal cytoplasmic domain (cdAE1) that interacts with cytoplasmic proteins and a C-terminal membrane domain (mdAE1) responsible for its transport function [3]. A poorly conserved linker region connects the mdAE1 with the cdAE1 that can be readily cleaved by trypsin at Lys360 separating the two domains [6]. The mdAE1 monomer consists of 14 transmembrane (TM) helices organized as two inverted 7-helix repeat. CdAE1 functions primarily as an anchoring site for cytoskeletal proteins such as ankyrin and is a major organization center of the red blood cell membrane [8]. Mutations have previously been reported to alter AE1 function and localization to the plasma membrane, causing various diseases and conditions such as hereditary spherocytosis [6]. Understanding the mechanistic details of the function of AE1 is physiologically and medically relevant
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