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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Anion exchange protein 2''' (AE2) is a [[membrane transport protein]] that in humans is encoded by the ''SLC4A2'' [[gene]].<ref name="pmid8434259">{{cite journal | author = Tanner MJ | title = Molecular and cellular biology of the erythrocyte anion exchanger (AE1) | journal = Semin Hematol | volume = 30 | issue = 1 | pages = 34–57 |date=Mar 1993 | pmid = 8434259}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC4A2 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6522}}</ref> AE2 is functionally similar to the [[Band 3]] [[chloride|Cl<sup>−</sup>]]/[[bicarbonate|HCO3<sup>−</sup>]] [[Secondary active transport#Antiport|exchange]] protein.
'''Anion exchange protein 2''' (AE2) is a [[membrane transport protein]] that in humans is encoded by the ''SLC4A2'' [[gene]].<ref name="pmid8434259">{{cite journal | vauthors = Tanner MJ | title = Molecular and cellular biology of the erythrocyte anion exchanger (AE1) | journal = Seminars in Hematology | volume = 30 | issue = 1 | pages = 34–57 | date = January 1993 | pmid = 8434259 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SLC4A2 solute carrier family 4, anion exchanger, member 2 (erythrocyte membrane protein band 3-like 1)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6522}}</ref> AE2 is functionally similar to the [[Band 3]] [[chloride|Cl<sup>−</sup>]]/[[bicarbonate|HCO3<sup>−</sup>]] [[Secondary active transport#Antiport|exchange]] protein.


[[Mice#Laboratory mice|Mice]] have been used to explore the function of AE2. AE2 contributes to [[Epithelial polarity#Basolateral membranes|basolateral membrane]] HCO<sub>3</sub><sup>−</sup> transport in the [[gastrointestinal tract]].<ref name="pmid20110461">{{cite journal | vauthors = Gawenis LR, Bradford EM, Alper SL, Prasad V, Shull GE | title = AE2 Cl<sup>−</sup>/HCO<sub>3</sub><sup>−</sup> exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon | journal = Am. J. Physiol. Gastrointest. Liver Physiol. | volume = 298 | issue = 4 | pages = G493–503 |date=April 2010 | pmid = 20110461 | pmc = 2853300 | doi = 10.1152/ajpgi.00178.2009 }}</ref> AE2 is required for [[spermiogenesis]] in mice.<ref name="pmid14673081">{{cite journal | vauthors = 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 | title = Anion exchanger 2 is essential for spermiogenesis in mice | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 26 | pages = 15847–52 |date=December 2003 | pmid = 14673081 | pmc = 307656 | doi = 10.1073/pnas.2536127100 | bibcode = 2003PNAS..10015847M | doi-access = free }}</ref> AE2 is required for normal [[osteoclast]] function.<ref name="pmid18971331">{{cite journal | vauthors = Wu J, Glimcher LH, Aliprantis AO | title = HCO<sub>3</sub><sup>−</sup>/Cl<sup>−</sup> anion exchanger SLC4A2 is required for proper osteoclast differentiation and function | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 44 | pages = 16934–9 |date=November 2008 | pmid = 18971331 | pmc = 2579356 | doi = 10.1073/pnas.0808763105 | bibcode = 2008PNAS..10516934W | doi-access = free }}</ref><ref name="pmid19164575">{{cite journal | vauthors = Josephsen K, Praetorius J, Frische S, Gawenis LR, Kwon TH, Agre P, Nielsen S, Fejerskov O | title = Targeted disruption of the Cl<sup>−</sup>/HCO<sub>3</sub><sup>−</sup> exchanger Ae2 results in osteopetrosis in mice | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 5 | pages = 1638–41 |date=February 2009 | pmid = 19164575 | pmc = 2635809 | doi = 10.1073/pnas.0811682106 | doi-access = free }}</ref> The activity of AE2 is sensitive to [[pH]].<ref name="pmid19103596">{{cite journal | vauthors = Stewart AK, Kurschat CE, Vaughan-Jones RD, Alper SL | title = Putative re-entrant loop 1 of AE2 transmembrane domain has a major role in acute regulation of anion exchange by pH | journal = J. Biol. Chem. | volume = 284 | issue = 10 | pages = 6126–39 |date=March 2009 | pmid = 19103596 | pmc = 2649077 | doi = 10.1074/jbc.M802051200 | doi-access = free }}</ref>
[[Mice#Laboratory mice|Mice]] have been used to explore the function of AE2. AE2 contributes to [[Epithelial polarity#Basolateral membranes|basolateral membrane]] HCO<sub>3</sub><sup>−</sup> transport in the [[gastrointestinal tract]].<ref name="pmid20110461">{{cite journal | vauthors = Gawenis LR, Bradford EM, Alper SL, Prasad V, Shull GE | title = AE2 Cl-/HCO3- exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 298 | issue = 4 | pages = G493–G503 | date = April 2010 | pmid = 20110461 | pmc = 2853300 | doi = 10.1152/ajpgi.00178.2009 }}</ref> AE2 is required for [[spermiogenesis]] in mice.<ref name="pmid14673081">{{cite journal | vauthors = 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 | display-authors = 6 | title = Anion exchanger 2 is essential for spermiogenesis in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 26 | pages = 15847–15852 | date = December 2003 | pmid = 14673081 | pmc = 307656 | doi = 10.1073/pnas.2536127100 | doi-access = free | bibcode = 2003PNAS..10015847M }}</ref> AE2 is required for normal [[osteoclast]] function.<ref name="pmid18971331">{{cite journal | vauthors = Wu J, Glimcher LH, Aliprantis AO | title = HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 44 | pages = 16934–16939 | date = November 2008 | pmid = 18971331 | pmc = 2579356 | doi = 10.1073/pnas.0808763105 | doi-access = free | bibcode = 2008PNAS..10516934W }}</ref><ref name="pmid19164575">{{cite journal | vauthors = Josephsen K, Praetorius J, Frische S, Gawenis LR, Kwon TH, Agre P, Nielsen S, Fejerskov O | display-authors = 6 | title = Targeted disruption of the Cl-/HCO3- exchanger Ae2 results in osteopetrosis in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 5 | pages = 1638–1641 | date = February 2009 | pmid = 19164575 | pmc = 2635809 | doi = 10.1073/pnas.0811682106 | doi-access = free }}</ref> The activity of AE2 is sensitive to [[pH]].<ref name="pmid19103596">{{cite journal | vauthors = Stewart AK, Kurschat CE, Vaughan-Jones RD, Alper SL | title = Putative re-entrant loop 1 of AE2 transmembrane domain has a major role in acute regulation of anion exchange by pH | journal = The Journal of Biological Chemistry | volume = 284 | issue = 10 | pages = 6126–6139 | date = March 2009 | pmid = 19103596 | pmc = 2649077 | doi = 10.1074/jbc.M802051200 | doi-access = free }}</ref>


AE3 has been suggested as a target for prevention of [[Diabetes mellitus|diabetic vasculopathy]].<ref name="pmid20180022">{{cite journal | vauthors = Huang QR, Li Q, Chen YH, Li L, Liu LL, Lei SH, Chen HP, Peng WJ, He M | title = Involvement of anion exchanger-2 in apoptosis of endothelial cells induced by high glucose through an mPTP-ROS-Caspase-3 dependent pathway | journal = Apoptosis | volume = 15 | issue = 6 | pages = 693–704 |date=June 2010 | pmid = 20180022 | doi = 10.1007/s10495-010-0477-9 | s2cid = 25917589 }}</ref>
AE3 has been suggested as a target for prevention of [[Diabetes mellitus|diabetic vasculopathy]].<ref name="pmid20180022">{{cite journal | vauthors = Huang QR, Li Q, Chen YH, Li L, Liu LL, Lei SH, Chen HP, Peng WJ, He M | display-authors = 6 | title = Involvement of anion exchanger-2 in apoptosis of endothelial cells induced by high glucose through an mPTP-ROS-Caspase-3 dependent pathway | journal = Apoptosis | volume = 15 | issue = 6 | pages = 693–704 | date = June 2010 | pmid = 20180022 | doi = 10.1007/s10495-010-0477-9 | s2cid = 25917589 }}</ref>


==See also==
== 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.<ref>{{Cite journal | vauthors = Zhang Q, Jian L, Yao D, Rao B, Xia Y, Hu K, Li S, Shen Y, Cao M, Qin A, Zhao J, Cao Y | display-authors = 6 |date=2023-03-31 |title=The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2 |journal=Nature Communications |language=en |volume=14 |issue=1 |pages=1812 |doi=10.1038/s41467-023-37557-y | pmid = 37002221 | s2cid = 257858182 |issn=2041-1723|pmc=10066210 }}</ref> 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.
⚫
* [[Solute carrier family]]


== Mechanism of ion exchange ==
⚫
==References==
During the process of acid secretion, the cellular pH increases, triggering the release of the "trigger" loop from the cytoplasmic domain.<ref>{{cite journal | vauthors = Wu J, Glimcher LH, Aliprantis AO | title = HCO3-/Cl- anion exchanger SLC4A2 is required for proper osteoclast differentiation and function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 44 | pages = 16934–16939 | date = November 2008 | pmid = 18971331 | pmc = 2579356 | doi = 10.1073/pnas.0808763105 | bibcode = 2008PNAS..10516934W | doi-access = free }}</ref> 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]]
{{clear}}
⚫
== References ==
{{reflist}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|30em}}
*{{cite journal | vauthors=Gehrig H, Müller W, Appelhans H |title=Complete nucleotide sequence of band 3 related anion transport protein AE2 from human kidney. |journal=Biochim. Biophys. Acta |volume=1130 |issue= 3 |pages= 326–8 |year= 1992 |pmid= 1562608 |doi=10.1016/0167-4781(92)90446-7}}
* {{cite journal | vauthors = Gehrig H, Müller W, Appelhans H | title = Complete nucleotide sequence of band 3 related anion transport protein AE2 from human kidney | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1130 | issue = 3 | pages = 326–328 | date = April 1992 | pmid = 1562608 | doi = 10.1016/0167-4781(92)90446-7 }}
*{{cite journal | vauthors=Korsgren C, Cohen CM |title=Associations of human erythrocyte band 4.2. Binding to ankyrin and to the cytoplasmic domain of band 3. |journal=J. Biol. Chem. |volume=263 |issue= 21 |pages= 10212–8 |year= 1988 |doi=10.1016/S0021-9258(19)81500-4 |pmid= 2968981 |doi-access=free }}
* {{cite journal | vauthors = Korsgren C, Cohen CM | title = Associations of human erythrocyte band 4.2. Binding to ankyrin and to the cytoplasmic domain of band 3 | journal = The Journal of Biological Chemistry | volume = 263 | issue = 21 | pages = 10212–10218 | date = July 1988 | pmid = 2968981 | doi = 10.1016/S0021-9258(19)81500-4 | doi-access = free }}
*{{cite journal |vauthors=Demuth DR, Showe LC, Ballantine M, etal |title=Cloning and structural characterization of a human non-erythroid band 3-like protein. |journal=EMBO J. |volume=5 |issue= 6 |pages= 1205–14 |year= 1986 |pmid= 3015590 | pmc=1166929 |doi=10.1002/j.1460-2075.1986.tb04348.x }}
* {{cite journal | vauthors = Demuth DR, Showe LC, Ballantine M, Palumbo A, Fraser PJ, Cioe L, Rovera G, Curtis PJ | display-authors = 6 | title = Cloning and structural characterization of a human non-erythroid band 3-like protein | journal = The EMBO Journal | volume = 5 | issue = 6 | pages = 1205–1214 | date = June 1986 | pmid = 3015590 | pmc = 1166929 | doi = 10.1002/j.1460-2075.1986.tb04348.x }}
*{{cite journal |vauthors=Palumbo AP, Isobe M, Huebner K, etal |title=Chromosomal localization of a human band 3-like gene to region 7q35----7q36. |journal=Am. J. Hum. Genet. |volume=39 |issue= 3 |pages= 307–16 |year= 1986 |pmid= 3020980 | pmc=1683956 }}
* {{cite journal | vauthors = Palumbo AP, Isobe M, Huebner K, Shane S, Rovera G, Demuth D, Curtis PJ, Ballantine M, Croce CM, Showe LC | display-authors = 6 | title = Chromosomal localization of a human band 3-like gene to region 7q35----7q36 | journal = American Journal of Human Genetics | volume = 39 | issue = 3 | pages = 307–316 | date = September 1986 | pmid = 3020980 | pmc = 1683956 }}
*{{cite journal | vauthors=Rybicki AC, Musto S, Schwartz RS |title=Identification of a band-3 binding site near the N-terminus of erythrocyte membrane protein 4.2. | series=309 |journal=Biochem. J. |volume=( Pt 2) |issue= 2|pages= 677–81 |year= 1995 |pmid= 7626035 | pmc=1135783 |doi=10.1042/bj3090677 }}
* {{cite journal | vauthors = Rybicki AC, Musto S, Schwartz RS | title = Identification of a band-3 binding site near the N-terminus of erythrocyte membrane protein 4.2 | journal = The Biochemical Journal | volume = 309 ( Pt 2) | issue = Pt 2 | pages = 677–681 | date = July 1995 | pmid = 7626035 | pmc = 1135783 | doi = 10.1042/bj3090677 | series = 309 }}
*{{cite journal | vauthors=Havenga MJ, Bosman GJ, Appelhans H, De Grip WJ |title=Expression of the anion exchanger (AE) gene family in human brain. Identification of a new AE protein: AE0. |journal=Brain Res. Mol. Brain Res. |volume=25 |issue= 1–2 |pages= 97–104 |year= 1995 |pmid= 7984058 |doi=10.1016/0169-328X(94)90283-6 }}
* {{cite journal | vauthors = Havenga MJ, Bosman GJ, Appelhans H, De Grip WJ | title = Expression of the anion exchanger (AE) gene family in human brain. Identification of a new AE protein: AE0 | journal = Brain Research. Molecular Brain Research | volume = 25 | issue = 1–2 | pages = 97–104 | date = August 1994 | pmid = 7984058 | doi = 10.1016/0169-328X(94)90283-6 }}
*{{cite journal | vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 |doi-access=free }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }}
*{{cite journal | vauthors=Medina JF, Acín A, Prieto J |title=Molecular cloning and characterization of the human AE2 anion exchanger (SLC4A2) gene. |journal=Genomics |volume=39 |issue= 1 |pages= 74–85 |year= 1997 |pmid= 9027488 |doi=10.1006/geno.1996.4467 }}
* {{cite journal | vauthors = Medina JF, Acín A, Prieto J | title = Molecular cloning and characterization of the human AE2 anion exchanger (SLC4A2) gene | journal = Genomics | volume = 39 | issue = 1 | pages = 74–85 | date = January 1997 | pmid = 9027488 | doi = 10.1006/geno.1996.4467 | s2cid = 223493 }}
*{{cite journal | vauthors=García C, Montuenga LM, Medina JF, Prieto J |title=In situ detection of AE2 anion-exchanger mRNA in the human liver. |journal=Cell Tissue Res. |volume=291 |issue= 3 |pages= 481–8 |year= 1998 |pmid= 9477304 |doi=10.1007/s004410051017 |hdl=10171/20151 |s2cid=22738717 |hdl-access=free }}
* {{cite journal | vauthors = García C, Montuenga LM, Medina JF, Prieto J | title = In situ detection of AE2 anion-exchanger mRNA in the human liver | journal = Cell and Tissue Research | volume = 291 | issue = 3 | pages = 481–488 | date = March 1998 | pmid = 9477304 | doi = 10.1007/s004410051017 | hdl-access = free | s2cid = 22738717 | hdl = 10171/20151 }}
*{{cite journal | vauthors=Jöns T, Drenckhahn D |title=Anion exchanger 2 (AE2) binds to erythrocyte ankyrin and is colocalized with ankyrin along the basolateral plasma membrane of human gastric parietal cells. |journal=Eur. J. Cell Biol. |volume=75 |issue= 3 |pages= 232–6 |year= 1998 |pmid= 9587054 |doi=10.1016/s0171-9335(98)80117-9}}
* {{cite journal | vauthors = Jöns T, Drenckhahn D | title = Anion exchanger 2 (AE2) binds to erythrocyte ankyrin and is colocalized with ankyrin along the basolateral plasma membrane of human gastric parietal cells | journal = European Journal of Cell Biology | volume = 75 | issue = 3 | pages = 232–236 | date = March 1998 | pmid = 9587054 | doi = 10.1016/s0171-9335(98)80117-9 }}
*{{cite journal |vauthors=Mobasheri A, Golding S, Pagakis SN, etal |title=Expression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblasts. |journal=Cell Biol. Int. |volume=22 |issue= 7–8 |pages= 551–62 |year= 1999 |pmid= 10452823 |doi= 10.1006/cbir.1998.0299 |s2cid=12201584 }}
* {{cite journal | vauthors = Mobasheri A, Golding S, Pagakis SN, Corkey K, Pocock AE, Fermor B, O'Brien MJ, Wilkins RJ, Ellory JC, Francis MJ | display-authors = 6 | title = Expression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblasts | journal = Cell Biology International | volume = 22 | issue = 7–8 | pages = 551–562 | year = 1999 | pmid = 10452823 | doi = 10.1006/cbir.1998.0299 | s2cid = 12201584 }}
*{{cite journal | vauthors=Hyde K, Harrison D, Hollingsworth MA, Harris A |title=Chloride-bicarbonate exchangers in the human fetal pancreas. |journal=Biochem. Biophys. Res. Commun. |volume=263 |issue= 2 |pages= 315–21 |year= 1999 |pmid= 10491290 |doi= 10.1006/bbrc.1999.1367 }}
* {{cite journal | vauthors = Hyde K, Harrison D, Hollingsworth MA, Harris A | title = Chloride-bicarbonate exchangers in the human fetal pancreas | journal = Biochemical and Biophysical Research Communications | volume = 263 | issue = 2 | pages = 315–321 | date = September 1999 | pmid = 10491290 | doi = 10.1006/bbrc.1999.1367 }}
*{{cite journal |vauthors=Holappa K, Mustonen M, Parvinen M, etal |title=Primary structure of a sperm cell anion exchanger and its messenger ribonucleic acid expression during spermatogenesis. |journal=Biol. Reprod. |volume=61 |issue= 4 |pages= 981–6 |year= 1999 |pmid= 10491633 |doi=10.1095/biolreprod61.4.981 |doi-access=free }}
* {{cite journal | vauthors = Holappa K, Mustonen M, Parvinen M, Vihko P, Rajaniemi H, Kellokumpu S | title = Primary structure of a sperm cell anion exchanger and its messenger ribonucleic acid expression during spermatogenesis | journal = Biology of Reproduction | volume = 61 | issue = 4 | pages = 981–986 | date = October 1999 | pmid = 10491633 | doi = 10.1095/biolreprod61.4.981 | doi-access = free }}
*{{cite journal |vauthors=Karet FE, Finberg KE, Nayir A, etal |title=Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34. |journal=Am. J. Hum. Genet. |volume=65 |issue= 6 |pages= 1656–65 |year= 2000 |pmid= 10577919 |doi=10.1086/302679 | pmc=1288376 }}
* {{cite journal | vauthors = Karet FE, Finberg KE, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Medina JF, Lifton RP | display-authors = 6 | title = Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34 | journal = American Journal of Human Genetics | volume = 65 | issue = 6 | pages = 1656–1665 | date = December 1999 | pmid = 10577919 | pmc = 1288376 | doi = 10.1086/302679 }}
*{{cite journal |vauthors=Medina JF, Lecanda J, Acín A, etal |title=Tissue-specific N-terminal isoforms from overlapping alternate promoters of the human AE2 anion exchanger gene. |journal=Biochem. Biophys. Res. Commun. |volume=267 |issue= 1 |pages= 228–35 |year= 2000 |pmid= 10623603 |doi= 10.1006/bbrc.1999.1951 }}
* {{cite journal | vauthors = Medina JF, Lecanda J, Acín A, Ciesielczyk P, Prieto J | title = Tissue-specific N-terminal isoforms from overlapping alternate promoters of the human AE2 anion exchanger gene | journal = Biochemical and Biophysical Research Communications | volume = 267 | issue = 1 | pages = 228–235 | date = January 2000 | pmid = 10623603 | doi = 10.1006/bbrc.1999.1951 | s2cid = 26957969 }}
*{{cite journal | vauthors=Vince JW, Reithmeier RA |title=Identification of the Carbonic Anhydrase II Binding Site in the Cl<sup>−</sup>/HCO<sub>3</sub><sup>−</sup> Anion Exchanger AE1. |journal=Biochemistry |volume=39 |issue= 18 |pages= 5527–33 |year= 2000 |pmid= 10820026 |doi=10.1021/bi992564p }}
* {{cite journal | vauthors = Vince JW, Reithmeier RA | title = Identification of the carbonic anhydrase II binding site in the Cl(-)/HCO(3)(-) anion exchanger AE1 | journal = Biochemistry | volume = 39 | issue = 18 | pages = 5527–5533 | date = May 2000 | pmid = 10820026 | doi = 10.1021/bi992564p }}
*{{cite journal | vauthors=Holappa K, Suokas M, Soininen P, Kellokumpu S |title=Identification of the full-length AE2 (AE2a) isoform as the Golgi-associated anion exchanger in fibroblasts. |journal=J. Histochem. Cytochem. |volume=49 |issue= 2 |pages= 259–69 |year= 2001 |pmid= 11156694 |doi=10.1177/002215540104900213|doi-access=free }}
* {{cite journal | vauthors = Holappa K, Suokas M, Soininen P, Kellokumpu S | title = Identification of the full-length AE2 (AE2a) isoform as the Golgi-associated anion exchanger in fibroblasts | journal = The Journal of Histochemistry and Cytochemistry | volume = 49 | issue = 2 | pages = 259–269 | date = February 2001 | pmid = 11156694 | doi = 10.1177/002215540104900213 | doi-access = free }}
*{{cite journal |vauthors=Soleimani M, Greeley T, Petrovic S, etal |title=Pendrin: an apical Cl<sup>−</sup>/OH<sup>−</sup>/HCO<sup>3</sup><sup>−</sup> exchanger in the kidney cortex. |journal=Am. J. Physiol. Renal Physiol. |volume=280 |issue= 2 |pages= F356–64 |year= 2001 |pmid= 11208611 |doi=10.1152/ajprenal.2001.280.2.f356}}
* {{cite journal | vauthors = Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE | title = Pendrin: an apical Cl<sup>−</sup>/OH<sup>−</sup>/HCO<sup>3−</sup> exchanger in the kidney cortex. | journal = American Journal of Physiology. Renal Physiology | volume = 280 | issue = 2 | pages = F356–F364 | date = February 2001 | pmid = 11208611 | doi = 10.1152/ajprenal.2001.280.2.f356 }}
{{refend}}
{{refend}}


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[[Category:Solute carrier family]]
[[Category:Solute carrier family]]



{{membrane-protein-stub}}
{{membrane-protein-stub}}

Latest revision as of 13:55, 13 August 2023

SLC4A2
Identifiers
AliasesSLC4A2, AE2, BND3L, EPB3L1, HKB3, NBND3, solute carrier family 4 member 2
External IDsOMIM: 109280; MGI: 109351; HomoloGene: 128699; GeneCards: SLC4A2; OMA:SLC4A2 - orthologs
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

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]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000164889 – Ensembl, May 2017
  2. ^ a b c 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[edit]

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