UniProt functional annotation for P02730



	UniProt functional annotation for P02730

UniProt code: P02730.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Major integral membrane glycoprotein of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride- bicarbonate exchange in the kidney, and is required for normal acidification of the urine. {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:14734552, ECO:0000269|PubMed:1538405, ECO:0000269|PubMed:20151848, ECO:0000269|PubMed:24121512}.

Activity regulation: Phenyl isothiocyanate inhibits anion transport in vitro.

Subunit: A dimer in solution, but in its membrane environment, it exists primarily as a mixture of dimers and tetramers and spans the membrane asymmetrically. Interacts (via cytoplasmic N-terminal domain) with ANK1 (via N-terminal ANK repeats); tetramer formation is critical for ankyrin association. Interacts with STOM. Isoform 2 interacts with TM139 (PubMed:26049106). {ECO:0000269|PubMed:11049968, ECO:0000269|PubMed:20151848, ECO:0000269|PubMed:23219802, ECO:0000269|PubMed:26049106, ECO:0000269|PubMed:7665627}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:24121512, ECO:0000269|PubMed:26542571, ECO:0000269|PubMed:7506871}; Multi-pass membrane protein {ECO:0000269|PubMed:26542571}. Basolateral cell membrane {ECO:0000269|PubMed:7506871}; Multi-pass membrane protein {ECO:0000269|PubMed:7506871}. Note=Detected in the erythrocyte cell membrane and on the basolateral membrane of alpha-intercalated cells in the collecting duct in the kidney. {ECO:0000269|PubMed:7506871}.

Tissue specificity: Detected in erythrocytes (at protein level) (PubMed:7506871, PubMed:26542571). Isoform 2 is expressed in kidney (at protein level) (PubMed:7506871). {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:1538405, ECO:0000269|PubMed:23219802, ECO:0000269|PubMed:26542571, ECO:0000269|PubMed:7506871}.

Ptm: Phosphorylated on Tyr-8 and Tyr-21 most likely by SYK. PP1- resistant phosphorylation that precedes Tyr-359 and Tyr-904 phosphorylation. {ECO:0000269|PubMed:10942405, ECO:0000269|PubMed:1998697}.

Ptm: Phosphorylated on Tyr-359 and Tyr-904 most likely by LYN. PP1- inhibited phosphorylation that follows Tyr-8 and Tyr-21 phosphorylation. {ECO:0000269|PubMed:10942405, ECO:0000269|PubMed:1998697}.

Ptm: N-glycosylated. {ECO:0000269|PubMed:26542571}.

Polymorphism: SLC4A1 is responsible for the Diego blood group system [MIM:110500]. The molecular basis of the Di(a)=Di1/Di(b)/Di2 blood group antigens is a single variation in position 854; Leu-854 corresponds to Di(a) and Pro-854 to Di(b). The molecular basis of the Wr(a)=Di3/Wr(b)/Di4 blood group antigens is a single variation in position 658; Lys-658 corresponds to Wr(a) and Glu-658 to Wr(b). The blood group antigens Wd(a)=Di5 (Waldner-type) has Met-557; Rb(a)=Di6 has Leu-548 and WARR=Di7 has Ile-552.

Polymorphism: SLC4A1 is responsible for the Swann blood group system (SW) [MIM:601550]. Sw(a+) has a Gln or a Trp at position 646 and Sw(a-) has an Arg.

Polymorphism: SLC4A1 is responsible for the Froese blood group system (FR) [MIM:601551]. FR(a+) has a Lys at position 480 and FR(a-) has a Glu.

Polymorphism: Genetic variations in SLC4A1 are involved in resistance to malaria [MIM:611162].

Disease: Ovalocytosis, Southeast Asian (SAO) [MIM:166900]: A hereditary hematologic disorder characterized by ovalocytic erythrocytes that are rigid and exhibit reduced expression of many erythrocyte antigens. Clinical manifestations include mild hemolysis, intermittent jaundice and gallstones. However, the disorder is most often asymptomatic. {ECO:0000269|PubMed:1538405, ECO:0000269|PubMed:1722314}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Spherocytosis 4 (SPH4) [MIM:612653]: Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. {ECO:0000269|PubMed:10580570, ECO:0000269|PubMed:10745622, ECO:0000269|PubMed:10942416, ECO:0000269|PubMed:11380459, ECO:0000269|PubMed:1378323, ECO:0000269|PubMed:15813913, ECO:0000269|PubMed:16227998, ECO:0000269|PubMed:7530501, ECO:0000269|PubMed:8547122, ECO:0000269|PubMed:8640229, ECO:0000269|PubMed:8943874, ECO:0000269|PubMed:9012689, ECO:0000269|PubMed:9207478, ECO:0000269|PubMed:9233560, ECO:0000269|PubMed:9973643}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Renal tubular acidosis, distal, autosomal dominant (AD-dRTA) [MIM:179800]: An autosomal dominant disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Renal tubular acidosis, distal, with hemolytic anemia (dRTA- HA) [MIM:611590]: A disease characterized by the association of hemolytic anemia with distal renal tubular acidosis, the reduced ability to acidify urine resulting in variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. {ECO:0000269|PubMed:10926824, ECO:0000269|PubMed:15211439, ECO:0000269|PubMed:9854053}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Renal tubular acidosis, distal, with normal red cell morphology (dRTA-NRC) [MIM:611590]: A disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. {ECO:0000269|PubMed:15211439}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Cryohydrocytosis (CHC) [MIM:185020]: An autosomal dominant disorder of red cell membrane permeability characterized by cold- induced changes in cell volume, resulting in cold-sensitive stomatocytosis, and increased erythrocyte osmotic fragility and autohemolysis at 4 degrees Celsius. Patients present with mild to moderate hemolytic anemia, splenomegaly, fatigue, and pseudohyperkalemia due to a potassium leak from the erythrocytes. {ECO:0000269|PubMed:16227998}. Note=The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Similarity: Belongs to the anion exchanger (TC 2.A.31) family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Major integral membrane glycoprotein of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride- bicarbonate exchange in the kidney, and is required for normal acidification of the urine. {ECO:0000269\|PubMed:10926824, ECO:0000269\|PubMed:14734552, ECO:0000269\|PubMed:1538405, ECO:0000269\|PubMed:20151848, ECO:0000269\|PubMed:24121512}.


Activity regulation:		Phenyl isothiocyanate inhibits anion transport in vitro.
Subunit:		A dimer in solution, but in its membrane environment, it exists primarily as a mixture of dimers and tetramers and spans the membrane asymmetrically. Interacts (via cytoplasmic N-terminal domain) with ANK1 (via N-terminal ANK repeats); tetramer formation is critical for ankyrin association. Interacts with STOM. Isoform 2 interacts with TM139 (PubMed:26049106). {ECO:0000269\|PubMed:11049968, ECO:0000269\|PubMed:20151848, ECO:0000269\|PubMed:23219802, ECO:0000269\|PubMed:26049106, ECO:0000269\|PubMed:7665627}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:10926824, ECO:0000269\|PubMed:24121512, ECO:0000269\|PubMed:26542571, ECO:0000269\|PubMed:7506871}; Multi-pass membrane protein {ECO:0000269\|PubMed:26542571}. Basolateral cell membrane {ECO:0000269\|PubMed:7506871}; Multi-pass membrane protein {ECO:0000269\|PubMed:7506871}. Note=Detected in the erythrocyte cell membrane and on the basolateral membrane of alpha-intercalated cells in the collecting duct in the kidney. {ECO:0000269\|PubMed:7506871}.
Tissue specificity:		Detected in erythrocytes (at protein level) (PubMed:7506871, PubMed:26542571). Isoform 2 is expressed in kidney (at protein level) (PubMed:7506871). {ECO:0000269\|PubMed:10926824, ECO:0000269\|PubMed:1538405, ECO:0000269\|PubMed:23219802, ECO:0000269\|PubMed:26542571, ECO:0000269\|PubMed:7506871}.
Ptm:		Phosphorylated on Tyr-8 and Tyr-21 most likely by SYK. PP1- resistant phosphorylation that precedes Tyr-359 and Tyr-904 phosphorylation. {ECO:0000269\|PubMed:10942405, ECO:0000269\|PubMed:1998697}.
Ptm:		Phosphorylated on Tyr-359 and Tyr-904 most likely by LYN. PP1- inhibited phosphorylation that follows Tyr-8 and Tyr-21 phosphorylation. {ECO:0000269\|PubMed:10942405, ECO:0000269\|PubMed:1998697}.
Ptm:		N-glycosylated. {ECO:0000269\|PubMed:26542571}.
Polymorphism:		SLC4A1 is responsible for the Diego blood group system [MIM:110500]. The molecular basis of the Di(a)=Di1/Di(b)/Di2 blood group antigens is a single variation in position 854; Leu-854 corresponds to Di(a) and Pro-854 to Di(b). The molecular basis of the Wr(a)=Di3/Wr(b)/Di4 blood group antigens is a single variation in position 658; Lys-658 corresponds to Wr(a) and Glu-658 to Wr(b). The blood group antigens Wd(a)=Di5 (Waldner-type) has Met-557; Rb(a)=Di6 has Leu-548 and WARR=Di7 has Ile-552.
Polymorphism:		SLC4A1 is responsible for the Swann blood group system (SW) [MIM:601550]. Sw(a+) has a Gln or a Trp at position 646 and Sw(a-) has an Arg.
Polymorphism:		SLC4A1 is responsible for the Froese blood group system (FR) [MIM:601551]. FR(a+) has a Lys at position 480 and FR(a-) has a Glu.
Polymorphism:		Genetic variations in SLC4A1 are involved in resistance to malaria [MIM:611162].
Disease:		Ovalocytosis, Southeast Asian (SAO) [MIM:166900]: A hereditary hematologic disorder characterized by ovalocytic erythrocytes that are rigid and exhibit reduced expression of many erythrocyte antigens. Clinical manifestations include mild hemolysis, intermittent jaundice and gallstones. However, the disorder is most often asymptomatic. {ECO:0000269\|PubMed:1538405, ECO:0000269\|PubMed:1722314}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Spherocytosis 4 (SPH4) [MIM:612653]: Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. {ECO:0000269\|PubMed:10580570, ECO:0000269\|PubMed:10745622, ECO:0000269\|PubMed:10942416, ECO:0000269\|PubMed:11380459, ECO:0000269\|PubMed:1378323, ECO:0000269\|PubMed:15813913, ECO:0000269\|PubMed:16227998, ECO:0000269\|PubMed:7530501, ECO:0000269\|PubMed:8547122, ECO:0000269\|PubMed:8640229, ECO:0000269\|PubMed:8943874, ECO:0000269\|PubMed:9012689, ECO:0000269\|PubMed:9207478, ECO:0000269\|PubMed:9233560, ECO:0000269\|PubMed:9973643}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Renal tubular acidosis, distal, autosomal dominant (AD-dRTA) [MIM:179800]: An autosomal dominant disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Renal tubular acidosis, distal, with hemolytic anemia (dRTA- HA) [MIM:611590]: A disease characterized by the association of hemolytic anemia with distal renal tubular acidosis, the reduced ability to acidify urine resulting in variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. {ECO:0000269\|PubMed:10926824, ECO:0000269\|PubMed:15211439, ECO:0000269\|PubMed:9854053}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Renal tubular acidosis, distal, with normal red cell morphology (dRTA-NRC) [MIM:611590]: A disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification. {ECO:0000269\|PubMed:15211439}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Cryohydrocytosis (CHC) [MIM:185020]: An autosomal dominant disorder of red cell membrane permeability characterized by cold- induced changes in cell volume, resulting in cold-sensitive stomatocytosis, and increased erythrocyte osmotic fragility and autohemolysis at 4 degrees Celsius. Patients present with mild to moderate hemolytic anemia, splenomegaly, fatigue, and pseudohyperkalemia due to a potassium leak from the erythrocytes. {ECO:0000269\|PubMed:16227998}. Note=The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.
Similarity:		Belongs to the anion exchanger (TC 2.A.31) family. {ECO:0000305}.