Anion exchange protein 1 (Anion_exchange_1)
Type: Family

Bicarbonate (HCO
3
-
) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3
-
transport modes. Anion exchanger proteins exchange HCO
3
-
for Cl
-
in a reversible, electroneutral manner . Na
+
/HCO
3
-
co-transport proteins mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes, often in an electrogenic manner . Na
+
driven Cl
-
/HCO
3
-
exchange and K
+
/HCO
3
-
exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO
3
-
transporters that have been cloned to date (the anion exchangers and Na
+
/HCO
3
-
co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3
-
and are inhibited by a class of pharmacological agents called disulphonic stilbenes . They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.

Anion exchange proteins participate in pH and cell volume regulation. They are glycosylated, plasma-membrane transport proteins that exchange hydrogen carbonate (HCO
3
-
) for chloride (Cl
-
) in a reversible, electroneutral manner . To date three anion exchanger isoforms have been identified (AE1-3), AE1 being the previously-characterised erythrocyte band 3 protein. They share a predicted topology of 12-14 transmembrane (TM) domains, but have differing distribution patterns and cellular localisation. The best characterised isoform, AE1, is known to be the most abundant membrane protein in mature erythrocytes. It has a molecular mass of ~95kDa and consists of two major domains. The N-terminal 390 residues form a water-soluble, highly elongated domain that serves as an attachment site for the binding of the membrane skeleton and other cytoplasmic proteins. The remainder of the protein is a 55kDa hydrophobic domain that is responsible for catalysing anion exchange. The function of the analogous domains of AE2 and AE3 remains to be determined .

Naturally-occuring mutations have been characterised in the AE1 gene, which give rise to forms of several inherited human diseases. Around 20% of hereditary spherocytosis cases arise from heterozygosity for AE1 mutations, and result in the absence or decrease of the mutant protein in the red cell membrane. Similarly, familial distal renal tubular acidosis, a condition associated with kidney stones, has been shown to be associated with mutations of AE1 of the renal collecting duct alpha-intercalated cell, and it has been postulated that such mutations may affect the targeting of the AE1 protein, which is usually directed to the basolateral membrane of these cells .

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Band 3 anion transport protein (Anion exchange protein 1) belongs to the Diego blood group system and is associated with Di(a/b), Wr(a/b), Wd(a), Rb(a and WARR antigens.