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
Aliases	SLC4A2, AE2, BND3L, EPB3L1, HKB3, NBND3, solute carrier family 4 member 2
External IDs	OMIM: 109280; MGI: 109351; HomoloGene: 128699; GeneCards: SLC4A2; OMA:SLC4A2 - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q36.1 Start 151,057,210 bp[1] End 151,076,526 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 A3|5 11.74 cM Start 24,628,835 bp[2] End 24,645,948 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in body of stomach muscle layer of sigmoid colon canal of the cervix right lobe of liver mucosa of transverse colon body of uterus body of pancreas stromal cell of endometrium left uterine tube right ovary Top expressed in choroid plexus of fourth ventricle epithelium of stomach Epithelium of choroid plexus vestibular membrane of cochlear duct yolk sac mucous cell of stomach retinal pigment epithelium pyloric antrum molar granulocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function enzyme binding anion transmembrane transporter activity antiporter activity transporter activity inorganic anion exchanger activity sodium:bicarbonate symporter activity Cellular component integral component of membrane plasma membrane basolateral plasma membrane apical plasma membrane membrane focal adhesion integral component of plasma membrane Biological process digestive tract development anion transport spermatogenesis ion transport regulation of intracellular pH inorganic anion transport transmembrane transport anion transmembrane transport bicarbonate transport sodium ion transmembrane transport transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 5: 24.63 – 24.65 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/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 microscopic 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 HCO−3 binding. Further conformational changes then turn the AE2 protein into an outward-facing conformation, releasing HCO−3 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

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

• Gehrig H, Müller W, Appelhans H (April 1992). "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. doi:10.1016/0167-4781(92)90446-7. PMID 1562608.
• Korsgren C, Cohen CM (July 1988). "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. doi:10.1016/S0021-9258(19)81500-4. PMID 2968981.
• Demuth DR, Showe LC, Ballantine M, Palumbo A, Fraser PJ, Cioe L, et al. (June 1986). "Cloning and structural characterization of a human non-erythroid band 3-like protein". The EMBO Journal. 5 (6): 1205–1214. doi:10.1002/j.1460-2075.1986.tb04348.x. PMC 1166929. PMID 3015590.
• Palumbo AP, Isobe M, Huebner K, Shane S, Rovera G, Demuth D, et al. (September 1986). "Chromosomal localization of a human band 3-like gene to region 7q35----7q36". American Journal of Human Genetics. 39 (3): 307–316. PMC 1683956. PMID 3020980.
• Rybicki AC, Musto S, Schwartz RS (July 1995). "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. doi:10.1042/bj3090677. PMC 1135783. PMID 7626035.
• Havenga MJ, Bosman GJ, Appelhans H, De Grip WJ (August 1994). "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. doi:10.1016/0169-328X(94)90283-6. PMID 7984058.
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Medina JF, Acín A, Prieto J (January 1997). "Molecular cloning and characterization of the human AE2 anion exchanger (SLC4A2) gene". Genomics. 39 (1): 74–85. doi:10.1006/geno.1996.4467. PMID 9027488. S2CID 223493.
• García C, Montuenga LM, Medina JF, Prieto J (March 1998). "In situ detection of AE2 anion-exchanger mRNA in the human liver". Cell and Tissue Research. 291 (3): 481–488. doi:10.1007/s004410051017. hdl:10171/20151. PMID 9477304. S2CID 22738717.
• Jöns T, Drenckhahn D (March 1998). "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. doi:10.1016/s0171-9335(98)80117-9. PMID 9587054.
• Mobasheri A, Golding S, Pagakis SN, Corkey K, Pocock AE, Fermor B, et al. (1999). "Expression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblasts". Cell Biology International. 22 (7–8): 551–562. doi:10.1006/cbir.1998.0299. PMID 10452823. S2CID 12201584.
• Hyde K, Harrison D, Hollingsworth MA, Harris A (September 1999). "Chloride-bicarbonate exchangers in the human fetal pancreas". Biochemical and Biophysical Research Communications. 263 (2): 315–321. doi:10.1006/bbrc.1999.1367. PMID 10491290.
• Holappa K, Mustonen M, Parvinen M, Vihko P, Rajaniemi H, Kellokumpu S (October 1999). "Primary structure of a sperm cell anion exchanger and its messenger ribonucleic acid expression during spermatogenesis". Biology of Reproduction. 61 (4): 981–986. doi:10.1095/biolreprod61.4.981. PMID 10491633.
• Karet FE, Finberg KE, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, et al. (December 1999). "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. doi:10.1086/302679. PMC 1288376. PMID 10577919.
• Medina JF, Lecanda J, Acín A, Ciesielczyk P, Prieto J (January 2000). "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. doi:10.1006/bbrc.1999.1951. PMID 10623603. S2CID 26957969.
• Vince JW, Reithmeier RA (May 2000). "Identification of the carbonic anhydrase II binding site in the Cl(-)/HCO(3)(-) anion exchanger AE1". Biochemistry. 39 (18): 5527–5533. doi:10.1021/bi992564p. PMID 10820026.
• Holappa K, Suokas M, Soininen P, Kellokumpu S (February 2001). "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. doi:10.1177/002215540104900213. PMID 11156694.
• Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE (February 2001). "Pendrin: an apical Cl⁻/OH⁻/HCO³⁻ exchanger in the kidney cortex". American Journal of Physiology. Renal Physiology. 280 (2): F356–F364. 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.