Anion exchange protein 2
(Redirected from SLC4A2)
| SLC4A2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | SLC4A2, AE2, BND3L, EPB3L1, HKB3, NBND3, solute carrier family 4 member 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 109280 MGI: 109351 HomoloGene: 128699 GeneCards: SLC4A2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
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[edit]
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[edit]
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[edit]
References[edit]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000164889 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028962 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Tanner MJ (January 1993). "Molecular and cellular biology of the erythrocyte anion exchanger (AE1)". Seminars in Hematology. 30 (1): 34–57. PMID 8434259.
- ^ "Entrez Gene: SLC4A2 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1)".
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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[edit]
- 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.
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