CD233 SLC4A1( soluble carrier family 4, anion exchanger, member 1), EPB3(erythrocyte membrane protein band 3), AE1 (anion exchange protein 1), Diego blood group, Band 3
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Lineage Restricted Molecule
Type 3 glycoprotein, 12 span
Kidney
Plasma Cell
Erythrocyte
95 / 95
110 / 110

Expression
CD233 is strongly expressed on erythrocyte plasma membrane and on the basolateral membrane of a-intercalated cells of the distal tubules and collecting ducts of the kidney.  A truncated form of CD233 is involved in acid secretion.  CD233 is not known to be expressed on any other cells.


Structure
MOLECULAR FAMILY NAME: Belongs to the anion exchanger family.

CD233 is a multi-pass type-3 12 span glycoprotein.  It contains 2 structurally and functionally distinct domains, a transmembrane domain and a cytoplasmic domain.  The C-terminal transmembrane domain is located inside the membrane, provides binding sites for cytoskeletal proteins, glycolytic enzymes and hemoglobulin. and mediates the stilbene disulphonate-sensitive anion exchange transport.  The N-terminal domain is located in the cytoplasmic domain outside the membrane mediates an exchange of inorganic anions across the membrane and has attachment sites for several red cell proteins including band 4.2 glyceraldehyde 3-phosphate dehydrogenase, hemoglobin, several other glycolytic enzymes and ankyrin, a component of the red cell cytoskeleton. several other glycolytic enzymes.  The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase 2.  A single N-linked glycosylation site occurs at Asn 642.  CD233 is highly polymorphic.  CD233 is primarily dimeric but forms tetrameters in the presence of ankyrin.  Ankyrin induces the formation of the band 3 tetramers and is part of the anion exchanger (AE) family.  The band 3 anion exchanger (AE1), an erythrocyte membrane protein, is categorized as a bicarbonate transporter.  It is crucial for O2/CO2 gas exchange between lungs and tissues by mediating the exchange of biocarbonate chloride across the erythrocyte membrane.  Association of CD233 with the cytoskeleton is critical for the maintenance of red cell morphology.   

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Erythrocytes 95-110 kDa 95-110 kDa Smear due to heterogeneous glycosylation

There are low resolution structures of the C-terminal membrane-associated domain, 20A resolution of cryo-electron microscopy.  There is a high resolution structure of the N-terminal cytoplasmic domain.

POST-TRANSCRIPTIONAL MODIFICATION

Intron 3 of the CD233 gene contains an internal promoter which gives rise to the isoform expressed in the kidney.  The isoform is comprised of part of the intron 3 together with exons 4-20 of the gene, producing a truncated protein in the kidney of 65 aa at the N-terminus.

POST-TRANSLATIONAL MODIFICATION

CD233 has 1 N-glycan chain at Asn-642 of the poly N-acetyl-lactosamine type.  The glycan is heterogeneous in size due to variability in the number of N-acetyl-lactosamine repeats.  In CD233 phosphorylation, Tyr-8 is the major site which blocks the binding of hemoglobin and glycolytic enzymes, and the red cell casein kinase I phosphorylates band 3 on Thr-42.  CD233 is palmitoylated at Cys-843 but this modification is of unknown functional signifance.  Treatment of red cells with proteases cleaves CD233 at sites within the extracellular loop between membrane spans 5 and 6.  For example, chymotrypsin treatment of red cells results in cleavage of CD233 at Tyr-553 and Tyr-558.  CD233 is very sensitive to protease cleavage at cytoplasmic sites, resulting in separation of the N-terminal cytoplasmic domain and C-terminal membrane domain.  Chymotrypsin cleaves at Tyr-359 and Tyr-46 and trypsin cleaves at Lys-360.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD233
Molecule Comment
glycophorin A Band 3 interacts with glycophorin A and this interaction facilitates the movement of band 3 to the cell surface.  The interaction also results in the formation of the Wrb blood group antigen.
ankyrin The tetrameric form of band 3 attaches to the red cell sytoskeleton via ankyrin
protein 4.1 Protein 4.1 modulates the band 3-ankyrin interaction
protein 4.2 Protein 4.2 strengthens the band 3-cytoskelton link
carbonic anhydrase II Carbonic anhydrase II binds to the carboxyl terminus band 3
hemoglobin Hemoglobin interacts with the cytoplasmic domain of band 3
glycolytic enzymes The activity of glycolytic enzymes is regulated by binding to band 3


Function
CD233 is considered as a multifunctional transport protein of the erythrocyte membrane.   The N-terminal cytoplasmic domain of CD233 links the erythrocyte membrane to the underlying spectrin/actin-cytoskeleton.  This assists in maintenance of the integrity of the erythrocyte.  The C-terminal transmembrane domain mediates exchange of most monovalent anions but chloride and bicarbonate anions are the predominant substrates.  It is involved in carbon dioxide transport from tissues to lungs and as an anion exchanger that acts as an attachment site for the underlying cytoskeleton.  High anion transport activity and optimal surface expression of CD233 requires the presence of CD235a.  CD233 has 2 major functions in erythrocytes which exchange of inorganic anions which transport of chloride and bicarbonate across the membrane and the cytoplasmic domain which provides binding sites for the linkage of the red cell skeleton proteins to the membrane by binding to ankyrin.  During acid secretion by the a-intercalated cells of the distal nephron, an N-terminally-truncated form of erythroid CD233 moves bicarbonate into the blood in exchange for plasma chloride.  Perhaps of lesser importance, CD233 participates in senescent and damaged red cell clearance by mediating recognition of such altered cells by macrophages.

BIOCHEMICAL ACTIVITY

CD233 is an obigatory 1-for-1 anion exchanger.  It exchanges most monovalent anions, but in the physiological situation the predominant substrates exchanged are chloride with bicarbonate and chloride with chloride.  Inorganic divalent anions are also exchanged but much more slowly than inorganic monovalent anions.

DISEASE RELEVANCE AND FUNCTION OF CD233 IN INTACT ANIMAL

CD233 maintains red cell morphology.  CD233 is associated with acanthocytosis, one form of Elliptocytosis, Malaysian-Melanesian type, hemolytic anemia due to band 3 defect, renal tubular acidosis, distal Spherocytosis, and hereditary.  ed cell CD233 functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs.  It helps maintain the mechanical properties and integrity of the red cell by acting as the major linkage between the spectrin/actin skeleton and the membrane lipid bilayer.  A CD233 isoform is responsible for transporting bicarbonate out of the cell and into the blood in exchange for plasma chloride.  This function plays a part in maintaining whole body pH homeostasis because of its role in acid secretion by the distal nephron.  Many CD233 mutations are known in man.  CD233 defects can lead to 3 types of disease.  They are Elliptocytosis, a hematologic disorder, the destabilization of the red cell membrane leading to hereditary Spherocytosis and defective kidney acid secretion leading to familial distal renal tubular acidosis.  Other CD233 mutations that do not give rise to disease result in novel blood group antigens.  The Diego blood group system comprises 18  novel blood group antigens all derived from polymorphosm in the CD233 gene.  Incompatibility of the 2 most prevalent Diego antigens, Di b and Di a,  is a common cause of hemolytic disease of the newborn in the indigenous people of America.  Southeast Asian ovalocytosis, SAO, Melanesian ovalocytosis, is associated with abnormally rigid, stomatocytic erythrocytes and is also asymptomatic.  The condition results from the heterozygous presence of a deletion in the CD233 protein and is common in areas where Plasmodium falciparum malaria is endemic.  Children with South East Asian SAO have very rigid red blood cells due to a heterozygous deletion of CD233 and are less susceptible to infection with cerebral maleria (P. falciparum).  CD233 knockout mice have a high mortality and severe hemolytic anemia due to unstable erythrocytes.  Naturally occurring band 3 null cattle have a similar phenotype to CD233 knockout mice.  Also known is 1 band 3 null human with a very severe anemia and nephrocalcinosis.  This has an uncertain prognosis and is maintained by regular blood transfusions and bicarbonate supplements. 


Comments

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD233: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD233

Enzyme Comment
p72syk Tyrosine kinase phosphorylation of band 3
casein kinease I Threonine phosphorylation of band 3


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 6521P02730
Antibodies

Revised June 25, 2008


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