Impact of anionic lipids on the energy landscape of conformational transition in anion exchanger 1 (AE1).
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41298479.
- Also identified by DOI 10.1038/s41467-025-66786-6 and PMC identifier 12748791.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Anion Exchanger 1 (AE1) is an elevator-type transporter that plays a key role in acid-base homeostasis of erythrocytes. Here, we report three high-resolution cryo-electron microscopy (cryo-EM) structures of distinct states of AE1: two inward-facing (IF1 and IF2) and one outward-facing (OF). Uptake assay revealed the modulatory effect of phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>) lipids on AE1. Molecular dynamics simulations are conducted on these structures to determine the anion binding sites in AE1. We then use advanced enhanced sampling to study the OF⇌IF transition in AE1 in three systems: apo, HCO<sub>3</sub><sup>-</sup>-bound, and an AE1 system in which cryo-EM-determined PIP<sub>2</sub> lipids had been removed. The transition pathways were then used to calculate the free energy of the OF⇌IF transition in AE1 under different conditions. The results show how substrate reduces the transition barrier against transport. Furthermore, they capture the inhibitory effect of PIP<sub>2</sub> lipids and provide a molecular mechanism for this inhibitory effect.
Medical subject headings
- Phosphatidylinositol 4,5-Diphosphate
- Anion Exchange Protein 1, Erythrocyte
- Lipids