Chen T et al., Nat Commun - Cryo-EM structures, uptake assays, and molecular dynamics show that PIP2 lipids bind at the AE1 dimer interface and inhibit the OF⇌IF conformational transition while substrate binding lowers the transition barrier. Key terms: AE1, PIP2, bicarbonate transport, cryo-EM, molecular dynamics.
Study Highlights:Three high-resolution cryo-EM states were solved: two inward-facing (IF1, IF2) and one outward-facing (OF). Proteoliposome uptake assays show that depleting or masking PIP2 increases HCO3– and I– transport. MD simulations identify recurring anion binding in the lumen with R730 as a key coordinating residue and estimate tighter HCO3– binding than Cl–. Enhanced-sampling free energy profiles reveal that HCO3– binding lowers the OF⇌IF barrier by ~3 kcal/mol while removing PIP2 lowers it by ~2 kcal/mol. Mechanistically, HCO3– stabilizes a transition-state conformation by promoting R730 contact with the scaffold domain.
Conclusion:PIP2 stabilizes AE1 in a conformation that raises the transport transition barrier and inhibits activity, whereas substrate binding promotes the transition and facilitates transport.
Music:Enjoy the music based on this article at the end of the episode.
Reference:Chen T, Vallese F, Gil-Iturbe E, Kim K, Calì T, Quick M, Clarke OB, Tajkhorshid E. Impact of anionic lipids on the energy landscape of conformational transition in anion exchanger 1 (AE1). Nature Communications. 2025. https://doi.org/10.1038/s41467-025-66786-6
License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
Official website https://basebybase.com
On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Episode link: https://basebybase.castos.com/episodes/pipt2-inhibits-ae1
Episode Slug: pipt2-inhibits-ae1

Ver todos los episodios