Anion exchange protein 2

Protein-coding gene in the species Homo sapiens

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]
Band	7q36.1	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]
Band	5 A3\|5 11.74 cM	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

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

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

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.

References

^ ^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.

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.

Membrane proteins, carrier proteins: membrane transport proteins solute carrier (TC 2A)

By group

SLC1–10

(1):	high affinity glutamate and neutral amino-acid transporter SLC1A1 2 3 4 5 6 7
(2):	facilitative GLUT transporter SLC2A1 2 3 4 5 6 7 8 9 10 11 12 13 14
(3):	heavy subunits of heterodimeric amino-acid transporters SLC3A1 2
(4):	bicarbonate transporter SLC4A1 2 3 4 5 6 7 8 9 10 11
(5):	sodium glucose cotransporter SLC5A1 2 3 4 5 6 7 8 9 10 11 12
(6):	sodium- and chloride- dependent sodium:neurotransmitter symporters SLC6A1 SLC6A2 SLC6A3 SLC6A4 SLC6A5 SLC6A6 SLC6A7 SLC6A8 SLC6A9 SLC6A10 SLC6A11 SLC6A12 SLC6A13 SLC6A14 SLC6A15 SLC6A16 SLC6A17 SLC6A18 SLC6A19 SLC6A20
(7):	cationic amino-acid transporter/glycoprotein-associated SLC7A1 SLC7A2 SLC7A3 SLC7A4 glycoprotein-associated/light or catalytic subunits of heterodimeric amino-acid transporters SLC7A5 SLC7A6 SLC7A7 SLC7A8 SLC7A9 SLC7A10 SLC7A11 SLC7A13 SLC7A14
(8):	Na⁺/Ca²⁺ exchanger SLC8A1 SLC8A2 SLC8A3
(9):	Na⁺/H⁺ exchanger SLC9A1 SLC9A2 SLC9A3 SLC9A4 SLC9A5 SLC9A6 SLC9A7 SLC9A8 SLC9A9 SLC9A10 SLC9A11
(10):	sodium bile salt cotransport SLC10A1 SLC10A2 SLC10A3 SLC10A4 SLC10A5 SLC10A6 SLC10A7 10A1 10A2 10A3 10A7

SLC11–20

(11):	proton coupled metal ion transporter SLC11A1 SLC11A2 11A3
(12):	electroneutral cation-Cl cotransporter SLC12A1 SLC12A2 SLC12A3 SLC12A4 SLC12A5 SLC12A6 SLC12A7 SLC12A8 SLC12A9
(13):	human Na⁺-sulfate/carboxylate cotransporter SLC13A1 SLC13A2 SLC13A3 SLC13A4 SLC13A5
(14):	urea transporter SLC14A1 SLC14A2
(15):	proton oligopeptide cotransporter SLC15A1 SLC15A2 SLC15A3 SLC15A4
(16):	monocarboxylate transporter SLC16A1 SLC16A2 SLC16A3 SLC16A4 SLC16A5 SLC16A6 SLC16A7 SLC16A8 SLC16A9 SLC16A10 SLC16A11 SLC16A12 SLC16A13 SLC16A14
(17):	Vesicular glutamate transporter 1 SLC17A1 SLC17A2 SLC17A3 SLC17A4 SLC17A5 SLC17A6 SLC17A7 SLC17A8 SLC17A9
(18):	vesicular monoamine transporter SLC18A1 SLC18A2 SLC18A3
(19):	folate/thiamine transporter SLC19A1 SLC19A2 SLC19A3
(20):	type III Na⁺-phosphate cotransporter SLC20A1 SLC20A2

SLC21–30

(21):	Organic anion-transporting polypeptide SLCO1A2 SLCO1B1 SLCO1B3 SLCO1B4 SLCO1C1 SLCO2A1 SLCO2B1 SLCO3A1 SLCO4A1 SLCO4C1 SLCO5A1(SLCO6A1)
(22):	organic cation/anion/zwitterion transporter SLC22A1 SLC22A2 SLC22A3 SLC22A4 SLC22A5 SLC22A6 SLC22A7 SLC22A8 SLC22A9 SLC22A10 SLC22A11 SLC22A12 SLC22A13 SLC22A14 SLC22A15 SLC22A16 SLC22A17 SLC22A18 SLC22A19 SLC22A20
(23):	Na+-dependent ascorbic acid transporter SLC23A1 SLC23A2 SLC23A3 SLC23A4
(24):	Na⁺/(Ca²⁺-K⁺) exchanger SLC24A1 SLC24A2 SLC24A3 SLC24A4 SLC24A5 SLC24A6
(25):	mitochondrial carrier SLC25A1 SLC25A2 SLC25A3 SLC25A4 SLC25A5 SLC25A6 SLC25A7 SLC25A8 SLC25A9 SLC25A10 SLC25A11 SLC25A12 SLC25A13 SLC25A14 SLC25A15 SLC25A16 SLC25A17 SLC25A18 SLC25A19 SLC25A20 SLC25A21 SLC25A22 SLC25A23 SLC25A24 SLC25A25 SLC25A26 SLC25A27 SLC25A28 SLC25A29 SLC25A30 SLC25A31 SLC25A32 SLC25A33 SLC25A34 SLC25A35 SLC25A36 SLC25A37 SLC25A38 SLC25A39 SLC25A40 SLC25A41 SLC25A42 SLC25A43 SLC25A44 SLC25A45 SLC25A46
(26):	multifunctional anion exchanger SLC26A1 SLC26A2 SLC26A3 SLC26A4 SLC26A5 SLC26A6 SLC26A7 SLC26A8 SLC26A9 SLC26A10 SLC26A11
(27):	fatty acid transport proteins SLC27A1 SLC27A2 SLC27A3 SLC27A4 SLC27A5 SLC27A6
(28):	Na⁺-coupled nucleoside transport (SLC28A1 SLC28A2 SLC28A3
(29):	facilitative nucleoside transporter SLC29A1 SLC29A2 SLC29A3 SLC29A4
(30):	zinc efflux SLC30A1 SLC30A2 SLC30A3 SLC30A4 SLC30A5 SLC30A6 SLC30A7 SLC30A8 SLC30A9 SLC30A10

SLC31–40

(31):	copper transporter SLC31A1
(32):	Vesicular glutamate transporter 1 SLC32A1
(33):	Acetyl-CoA transporter SLC33A1
(34):	type II Na⁺-phosphate cotransporter SLC34A1 SLC34A2 SLC34A3
(35):	nucleoside-sugar transporter SLC35A1 SLC35A2 SLC35A3 SLC35A4 SLC35A5 SLC35B1 SLC35B2 SLC35B3 SLC35B4 SLC35C1 SLC35C2 SLC35D1 SLC35D2 SLC35D3 SLC35E1 SLC35E2 SLC35E3 SLC35E4
(36):	proton-coupled amino-acid transporter SLC36A1 SLC36A2 SLC36A3 SLC36A436A2
(37):	sugar-phosphate/phosphate exchanger SLC37A1 SLC37A2 SLC37A3 SLC37A4
(38):	System A & N, sodium-coupled neutral amino-acid transporter SLC38A1 SLC38A2 SLC38A3 SLC38A4 SLC38A5 SLC38A6 SLC38A10
(39):	metal ion transporter SLC39A1 SLC39A2 SLC39A3 SLC39A4 SLC39A5 SLC39A6 SLC39A7 SLC39A8 SLC39A9 SLC39A10 SLC39A11 SLC39A12 SLC39A13 SLC39A14
(40):	basolateral iron transporter SLC40A1

SLC41–48

(41):	Magnesium transporter E SLC41A1 SLC41A2 SLC41A3
(42):	Ammonia transporter RhAG RhBG RhCG
(43):	Na⁺-independent, system-L like amino-acid transporter SLC43A1 SLC43A2 SLC43A3
(44):	Choline-like transporter SLC44A1 SLC44A2 SLC44A3 SLC44A4 SLC44A5
(45):	Putative sugar transporter SLC45A1 SLC45A2 SLC54A3 SLC45A4
(46):	Folate transporter SLC46A1 SLC46A2
(47):	multidrug and toxin extrusion SLC47A1 SLC47A2
(48):	Heme transporter

SLCO1–4
O1A2 O1B1 O1B3 O2B1 O431 O4A1

Ion pumps

Symporter, Cotransporter	Na⁺/K⁺,Cl⁻ Na⁺/P_i3 Na⁺/Cl⁻ Na⁺/glucose Na⁺/I⁻ Cl⁻/K⁺ 4 5
Antiporter (exchanger)	Na⁺/H⁺ Na⁺/Ca²⁺ Na⁺/(Ca²⁺-K⁺) - Cl⁻/HCO⁻ ₃ (Band 3) Cl⁻-formate Cl⁻-oxalate