Biology:Anion exchange protein 2
 Generic protein structure example |
Anion exchange protein 2 (AE2) is a membrane transport protein that in humans is encoded by the SLC4A2 gene.[1][2] AE2 is functionally similar to the Band 3 Cl−/HCO3− exchange protein.
Mice have been used to explore the function of AE2. AE2 contributes to basolateral membrane HCO3− transport in the gastrointestinal tract.[3] AE2 is required for spermiogenesis in mice.[4] AE2 is required for normal osteoclast function.[5][6] The activity of AE2 is sensitive to pH.[7]
AE3 has been suggested as a target for prevention of diabetic vasculopathy.[8]
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.[9] 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.[10] 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
- ↑ "Molecular and cellular biology of the erythrocyte anion exchanger (AE1)". Seminars in Hematology 30 (1): 34–57. January 1993. PMID 8434259.
- ↑ "Entrez Gene: SLC4A2 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6522.
- ↑ "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. April 2010. doi:10.1152/ajpgi.00178.2009. PMID 20110461.
- ↑ "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. December 2003. doi:10.1073/pnas.2536127100. PMID 14673081. Bibcode: 2003PNAS..10015847M.
- ↑ "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. November 2008. doi:10.1073/pnas.0808763105. PMID 18971331. Bibcode: 2008PNAS..10516934W.
- ↑ "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. February 2009. doi:10.1073/pnas.0811682106. PMID 19164575.
- ↑ "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. March 2009. doi:10.1074/jbc.M802051200. PMID 19103596.
- ↑ "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. June 2010. doi:10.1007/s10495-010-0477-9. PMID 20180022.
- ↑ "The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2" (in en). Nature Communications 14 (1): 1812. 2023-03-31. doi:10.1038/s41467-023-37557-y. ISSN 2041-1723. PMID 37002221.
- ↑ "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. November 2008. doi:10.1073/pnas.0808763105. PMID 18971331. Bibcode: 2008PNAS..10516934W.
Further reading
- "Complete nucleotide sequence of band 3 related anion transport protein AE2 from human kidney". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1130 (3): 326–328. April 1992. doi:10.1016/0167-4781(92)90446-7. PMID 1562608.
- "Associations of human erythrocyte band 4.2. Binding to ankyrin and to the cytoplasmic domain of band 3". The Journal of Biological Chemistry 263 (21): 10212–10218. July 1988. doi:10.1016/S0021-9258(19)81500-4. PMID 2968981.
- "Cloning and structural characterization of a human non-erythroid band 3-like protein". The EMBO Journal 5 (6): 1205–1214. June 1986. doi:10.1002/j.1460-2075.1986.tb04348.x. PMID 3015590.
- "Chromosomal localization of a human band 3-like gene to region 7q35----7q36". American Journal of Human Genetics 39 (3): 307–316. September 1986. PMID 3020980.
- "Identification of a band-3 binding site near the N-terminus of erythrocyte membrane protein 4.2". The Biochemical Journal. 309 309 ( Pt 2) (Pt 2): 677–681. July 1995. doi:10.1042/bj3090677. PMID 7626035.
- "Expression of the anion exchanger (AE) gene family in human brain. Identification of a new AE protein: AE0". Brain Research. Molecular Brain Research 25 (1–2): 97–104. August 1994. doi:10.1016/0169-328X(94)90283-6. PMID 7984058.
- "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548.
- "Molecular cloning and characterization of the human AE2 anion exchanger (SLC4A2) gene". Genomics 39 (1): 74–85. January 1997. doi:10.1006/geno.1996.4467. PMID 9027488.
- "In situ detection of AE2 anion-exchanger mRNA in the human liver". Cell and Tissue Research 291 (3): 481–488. March 1998. doi:10.1007/s004410051017. PMID 9477304.
- "Anion exchanger 2 (AE2) binds to erythrocyte ankyrin and is colocalized with ankyrin along the basolateral plasma membrane of human gastric parietal cells". European Journal of Cell Biology 75 (3): 232–236. March 1998. doi:10.1016/s0171-9335(98)80117-9. PMID 9587054.
- "Expression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblasts". Cell Biology International 22 (7–8): 551–562. 1999. doi:10.1006/cbir.1998.0299. PMID 10452823.
- "Chloride-bicarbonate exchangers in the human fetal pancreas". Biochemical and Biophysical Research Communications 263 (2): 315–321. September 1999. doi:10.1006/bbrc.1999.1367. PMID 10491290.
- "Primary structure of a sperm cell anion exchanger and its messenger ribonucleic acid expression during spermatogenesis". Biology of Reproduction 61 (4): 981–986. October 1999. doi:10.1095/biolreprod61.4.981. PMID 10491633.
- "Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34". American Journal of Human Genetics 65 (6): 1656–1665. December 1999. doi:10.1086/302679. PMID 10577919.
- "Tissue-specific N-terminal isoforms from overlapping alternate promoters of the human AE2 anion exchanger gene". Biochemical and Biophysical Research Communications 267 (1): 228–235. January 2000. doi:10.1006/bbrc.1999.1951. PMID 10623603.
- "Identification of the carbonic anhydrase II binding site in the Cl(-)/HCO(3)(-) anion exchanger AE1". Biochemistry 39 (18): 5527–5533. May 2000. doi:10.1021/bi992564p. PMID 10820026.
- "Identification of the full-length AE2 (AE2a) isoform as the Golgi-associated anion exchanger in fibroblasts". The Journal of Histochemistry and Cytochemistry 49 (2): 259–269. February 2001. doi:10.1177/002215540104900213. PMID 11156694.
- "Pendrin: an apical Cl−/OH−/HCO3− exchanger in the kidney cortex.". American Journal of Physiology. Renal Physiology 280 (2): F356–F364. February 2001. doi:10.1152/ajprenal.2001.280.2.f356. PMID 11208611.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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