The cover image for the October 1 issue of Biophysical Journal is an artistic rendering of our model of the anion exchanger 1 (AE1) transport protein embedded in a model red cell membrane inspired by the computer simulations we ran for our study. This snapshot was taken from our molecular dynamics simulations. In the image, the AE1 cytoplasmic domain is facing the cytoplasm whereas the membrane domain (in an outward-facing conformation) is embedded in a complex asymmetric bilayer. AE1 is critical for maintaining the proper functional shape of red cells, which are schematically shown on the right. The linker regions that connect the AE1 cytoplasmic with the AE1 membrane domain, modelled in our study, are shown in blue and red. Lipids (PIP2 in green and cholesterol in yellow) that were found to make significant interactions with AE1 are also shown. The image was created by Dario De Vecchis using the software VMD (http://www.ks.uiuc.edu/Research/vmd/) and Inkscape (https://inkscape.org/).
Our cover captures a key element of our research. What is the 3D structure of the full-length AE1 and does the membrane lipid environment have a role in its dynamics? The anion exchanger 1 (AE1, Band 3, SLC4A1), which is the founding member of the SLC4 family of proteins, is responsible for the rapid exchange of bicarbonate and chloride across the red blood cell membrane, which is a process critical for efficient respiration. By combining our simulations with available structural and functional data, we were able to highlight key lipid interaction sites and protein residues that result in human disease when mutated.
Our study shows that anionic lipids interact strongly with AE1 at specific amino acid and that cholesterol was found in the dimeric interface of AE1. This image provides a realistic model of intact AE1 in a native membrane. Mutations in the AE1 gene are linked to anemias and kidney disease. We will use this model to determine the effect of these mutations on the structure and dynamics of this membrane protein.
For more information, the authors’ websites are:
https://medicinehealth.leeds.ac.uk/medicine/staff/485/dr-antreas-kalli
http://biochemistry.utoronto.ca/person/reinhart-af-reithmeier/
- Dario De Vecchis, Reinhart A. F. Reithmeier and Antreas C. Kalli