Anion exchange protein 2

Structure

The cryo electron microscopic studies revealed that human AE2 protein forms a homodimer and stays in resting state of inward-facing conformation at physiological pH. A loop between transmembrane (TM) helices 10 and 11 extends from TM domain into its cytoplamic domain, forming a "trigger" locking the TM helices in the resting state. In addition, the C-terminal loop (CTD loop) inserts into the anion binding pocket to further block its activities.

Mechanism of ion exchange

During the process of acid secretion, the cellular pH increases, triggering the release of the "trigger" loop from the cytoplasmic domain. This allows for the re-arrangement of the TM helices, while the CTD loop is forced out, enabling binding. Further conformational changes then turn the AE2 protein into an outward-facing conformation, releasing into the extracellular environment and capturing into the binding pocket. Finally, the AE2 protein returns to its inward-facing conformation and releases into the cytosol. This working cycle of the AE2 protein replaces a weak acid anion with a strong acid anion, thereby lowering the cellular pH and re-balancing pH homeostasis.

References

References

1. (January 1993). "Molecular and cellular biology of the erythrocyte anion exchanger (AE1)". Seminars in Hematology.
2. "Entrez Gene: SLC4A2 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1)".
3. (April 2010). "AE2 Cl-/HCO3- exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon". American Journal of Physiology. Gastrointestinal and Liver Physiology.
4. (December 2003). "Anion exchanger 2 is essential for spermiogenesis in mice". Proceedings of the National Academy of Sciences of the United States of America.
5. (November 2008). "HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function". Proceedings of the National Academy of Sciences of the United States of America.
6. (February 2009). "Targeted disruption of the Cl-/HCO3- exchanger Ae2 results in osteopetrosis in mice". Proceedings of the National Academy of Sciences of the United States of America.
7. (March 2009). "Putative re-entrant loop 1 of AE2 transmembrane domain has a major role in acute regulation of anion exchange by pH". The Journal of Biological Chemistry.
8. (June 2010). "Involvement of anion exchanger-2 in apoptosis of endothelial cells induced by high glucose through an mPTP-ROS-Caspase-3 dependent pathway". Apoptosis.
9. (2023-03-31). "The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2". Nature Communications.
10. (November 2008). "HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function". Proceedings of the National Academy of Sciences of the United States of America.