Anion exchange protein 2

Anion exchange protein 2 (AE2) is a membrane transport protein that in humans is encoded by the SLC4A2 gene.[5][6] AE2 is functionally similar to the Band 3 Cl−/HCO3− exchange protein.

SLC4A2
Identifiers
AliasesSLC4A2, AE2, BND3L, EPB3L1, HKB3, NBND3, solute carrier family 4 member 2
External IDsOMIM: 109280 MGI: 109351 HomoloGene: 128699 GeneCards: SLC4A2
Orthologs
SpeciesHumanMouse
Entrez

6522

20535

Ensembl

ENSG00000164889

ENSMUSG00000028962

UniProt

P04920

P13808

RefSeq (mRNA)

NM_001199692
NM_001199693
NM_001199694
NM_003040

NM_001253892
NM_009207

RefSeq (protein)

NP_001186621
NP_001186622
NP_001186623
NP_003031

NP_001240821
NP_033233

Location (UCSC)Chr 7: 151.06 – 151.08 MbChr 5: 24.63 – 24.65 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mice have been used to explore the function of AE2. AE2 contributes to basolateral membrane HCO3− transport in the gastrointestinal tract.[7] AE2 is required for spermiogenesis in mice.[8] AE2 is required for normal osteoclast function.[9][10] The activity of AE2 is sensitive to pH.[11]

AE3 has been suggested as a target for prevention of diabetic vasculopathy.[12]

Structure

The cryo electron microsopic studies revealed that human AE2 protein forms a homodimer and stays in resting state of inward-facing conformation at physiological pH.[13] 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.[14] This allows for the re-arrangement of the TM helices, while the CTD loop is forced out, enabling HCO3- binding. Further conformational changes then turn the AE2 protein into an outward-facing conformation, releasing HCO3- into the extracellular environment and capturing Cl- into the binding pocket. Finally, the AE2 protein returns to its inward-facing conformation and releases Cl- 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.

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000164889 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000028962 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Tanner MJ (January 1993). "Molecular and cellular biology of the erythrocyte anion exchanger (AE1)". Seminars in Hematology. 30 (1): 34–57. PMID 8434259.
  6. "Entrez Gene: SLC4A2 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1)".
  7. Gawenis LR, Bradford EM, Alper SL, Prasad V, Shull GE (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. 298 (4): G493–G503. doi:10.1152/ajpgi.00178.2009. PMC 2853300. PMID 20110461.
  8. Medina JF, Recalde S, Prieto J, Lecanda J, Saez E, Funk CD, et al. (December 2003). "Anion exchanger 2 is essential for spermiogenesis in mice". Proceedings of the National Academy of Sciences of the United States of America. 100 (26): 15847–15852. Bibcode:2003PNAS..10015847M. doi:10.1073/pnas.2536127100. PMC 307656. PMID 14673081.
  9. Wu J, Glimcher LH, Aliprantis AO (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. 105 (44): 16934–16939. Bibcode:2008PNAS..10516934W. doi:10.1073/pnas.0808763105. PMC 2579356. PMID 18971331.
  10. Josephsen K, Praetorius J, Frische S, Gawenis LR, Kwon TH, Agre P, et al. (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. 106 (5): 1638–1641. doi:10.1073/pnas.0811682106. PMC 2635809. PMID 19164575.
  11. Stewart AK, Kurschat CE, Vaughan-Jones RD, Alper SL (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. 284 (10): 6126–6139. doi:10.1074/jbc.M802051200. PMC 2649077. PMID 19103596.
  12. Huang QR, Li Q, Chen YH, Li L, Liu LL, Lei SH, et al. (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. 15 (6): 693–704. doi:10.1007/s10495-010-0477-9. PMID 20180022. S2CID 25917589.
  13. Zhang Q, Jian L, Yao D, Rao B, Xia Y, Hu K, et al. (2023-03-31). "The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2". Nature Communications. 14 (1): 1812. doi:10.1038/s41467-023-37557-y. ISSN 2041-1723. PMC 10066210. PMID 37002221. S2CID 257858182.
  14. Wu J, Glimcher LH, Aliprantis AO (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. 105 (44): 16934–16939. Bibcode:2008PNAS..10516934W. doi:10.1073/pnas.0808763105. PMC 2579356. PMID 18971331.

Further reading

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