Anion exchange protein 2 explained

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 microscopic 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

• Solute carrier family

Further reading

• Gehrig H, Müller W, Appelhans H . 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 . 1562608 . 10.1016/0167-4781(92)90446-7 .
• Korsgren C, Cohen CM . 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 . 2968981 . 10.1016/S0021-9258(19)81500-4 . free .
• Demuth DR, Showe LC, Ballantine M, Palumbo A, Fraser PJ, Cioe L, Rovera G, Curtis PJ . 6 . Cloning and structural characterization of a human non-erythroid band 3-like protein . The EMBO Journal . 5 . 6 . 1205–1214 . June 1986 . 3015590 . 1166929 . 10.1002/j.1460-2075.1986.tb04348.x .
• Palumbo AP, Isobe M, Huebner K, Shane S, Rovera G, Demuth D, Curtis PJ, Ballantine M, Croce CM, Showe LC . 6 . Chromosomal localization of a human band 3-like gene to region 7q35----7q36 . American Journal of Human Genetics . 39 . 3 . 307–316 . September 1986 . 3020980 . 1683956 .
• Rybicki AC, Musto S, Schwartz RS . Identification of a band-3 binding site near the N-terminus of erythrocyte membrane protein 4.2 . The Biochemical Journal . 309 (Pt 2) . Pt 2 . 677–681 . July 1995 . 7626035 . 1135783 . 10.1042/bj3090677 . 309 .
• Havenga MJ, Bosman GJ, Appelhans H, De Grip WJ . 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 . 7984058 . 10.1016/0169-328X(94)90283-6 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Medina JF, Acín A, Prieto J . Molecular cloning and characterization of the human AE2 anion exchanger (SLC4A2) gene . Genomics . 39 . 1 . 74–85 . January 1997 . 9027488 . 10.1006/geno.1996.4467 . 223493 .
• García C, Montuenga LM, Medina JF, Prieto J . In situ detection of AE2 anion-exchanger mRNA in the human liver . Cell and Tissue Research . 291 . 3 . 481–488 . March 1998 . 9477304 . 10.1007/s004410051017 . free . 22738717 . 10171/20151 .
• Jöns T, Drenckhahn D . 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 . 9587054 . 10.1016/s0171-9335(98)80117-9 .
• Mobasheri A, Golding S, Pagakis SN, Corkey K, Pocock AE, Fermor B, O'Brien MJ, Wilkins RJ, Ellory JC, Francis MJ . 6 . 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 . 10452823 . 10.1006/cbir.1998.0299 . 12201584 .
• Hyde K, Harrison D, Hollingsworth MA, Harris A . Chloride-bicarbonate exchangers in the human fetal pancreas . Biochemical and Biophysical Research Communications . 263 . 2 . 315–321 . September 1999 . 10491290 . 10.1006/bbrc.1999.1367 .
• Holappa K, Mustonen M, Parvinen M, Vihko P, Rajaniemi H, Kellokumpu S . 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 . 10491633 . 10.1095/biolreprod61.4.981 . free .
• Karet FE, Finberg KE, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Medina JF, Lifton RP . 6 . 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 . 10577919 . 1288376 . 10.1086/302679 .
• Medina JF, Lecanda J, Acín A, Ciesielczyk P, Prieto J . 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 . 10623603 . 10.1006/bbrc.1999.1951 . 26957969 .
• Vince JW, Reithmeier RA . Identification of the carbonic anhydrase II binding site in the Cl(-)/HCO(3)(-) anion exchanger AE1 . Biochemistry . 39 . 18 . 5527–5533 . May 2000 . 10820026 . 10.1021/bi992564p .
• Holappa K, Suokas M, Soininen P, Kellokumpu S . 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 . 11156694 . 10.1177/002215540104900213 . free .
• Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE . Pendrin: an apical Cl⁻/OH⁻/HCO³⁻ exchanger in the kidney cortex. . American Journal of Physiology. Renal Physiology . 280 . 2 . F356–F364 . February 2001 . 11208611 . 10.1152/ajprenal.2001.280.2.f356 .

Notes and References

1. Tanner MJ . Molecular and cellular biology of the erythrocyte anion exchanger (AE1) . Seminars in Hematology . 30 . 1 . 34–57 . January 1993 . 8434259 .
2. Web site: Entrez Gene: SLC4A2 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1).
3. Gawenis LR, Bradford EM, Alper SL, Prasad V, Shull GE . 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 . 20110461 . 2853300 . 10.1152/ajpgi.00178.2009 .
4. Medina JF, Recalde S, Prieto J, Lecanda J, Saez E, Funk CD, Vecino P, van Roon MA, Ottenhoff R, Bosma PJ, Bakker CT, Elferink RP . 6 . 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 . 14673081 . 307656 . 10.1073/pnas.2536127100 . free . 2003PNAS..10015847M .
5. Wu J, Glimcher LH, Aliprantis AO . 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 . 18971331 . 2579356 . 10.1073/pnas.0808763105 . free . 2008PNAS..10516934W .
6. Josephsen K, Praetorius J, Frische S, Gawenis LR, Kwon TH, Agre P, Nielsen S, Fejerskov O . 6 . 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 . 19164575 . 2635809 . 10.1073/pnas.0811682106 . free .
7. Stewart AK, Kurschat CE, Vaughan-Jones RD, Alper SL . 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 . 19103596 . 2649077 . 10.1074/jbc.M802051200 . free .
8. Huang QR, Li Q, Chen YH, Li L, Liu LL, Lei SH, Chen HP, Peng WJ, He M . 6 . 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 . 20180022 . 10.1007/s10495-010-0477-9 . 25917589 .
9. Zhang Q, Jian L, Yao D, Rao B, Xia Y, Hu K, Li S, Shen Y, Cao M, Qin A, Zhao J, Cao Y . 6 . 2023-03-31 . The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2 . Nature Communications . en . 14 . 1 . 1812 . 10.1038/s41467-023-37557-y . 37002221 . 257858182 . 2041-1723. 10066210 .
10. Wu J, Glimcher LH, Aliprantis AO . 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 . 18971331 . 2579356 . 10.1073/pnas.0808763105 . 2008PNAS..10516934W . free .