SLC4A1 Membrane Protein Introduction

Introduction of SLC4A1

Solute carrier family 4 member 1 (SLC4A1), also known as BND3 or AE1, is encoded by SLC4A1 gene and is a member of the anion exchanger (AE) family. It is expressed in the erythrocyte plasma membrane where it functions as a chloride/bicarbonate exchanger participating in the transport of carbon dioxide from tissues to lungs. The SLC4A1 protein consists of two structurally and functionally distinct domains. The N-terminal domain of the cytoplasm functions as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane related domain possesses 12-14 transmembrane segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. Besides, the cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II.

Function of SLC4A1 Membrane Protein

SLC4A1 is known as anion exchanger 1 (AE1) that transports negatively charged atoms (anions) across cell membranes. In particular, AE1 is responsible for mediating the exchange of negatively charged atoms of chlorine (chloride ions) with negatively charged bicarbonate molecules (bicarbonate ions) across plasma membranes. Hence AE1 also named as a chloride/bicarbonate exchanger (Cl^-/HCO3^- exchanger). The main function of AE1 is to maintain the correct acid levels (pH) in the body. It has been revealed that AE1 is present in specialized kidney cells, called alpha-intercalated cells. In alpha-intercalated cells, the exchange of bicarbonate through the AE1 protein allows acid to be released from the cell into the urine. Moreover, electroneutral chloride and bicarbonate exchange across the plasma membrane is crucial for CO₂ uptake and conversion into a proton and a bicarbonate ion in the red blood cell. And the bicarbonate is then eliminated in exchange for chloride from the cell by AE1. Mutations of SLC4A1 result in two types of disease, destabilization of red cell membrane leading to hereditary spherocytosis and defective kidney acid secretion leading to distal renal tubular acidosis. Additionally, some mutations in SLC4A1 may lead to novel blood group antigens.

Fig.1 Diego blood group (AE1; band 3; SLC4A1). (Cooling, 2015)

Application of SLC4A1 Membrane Protein in Literature

1. Park E., et al. Primary autosomal recessive distal renal tubular acidosis caused by a common homozygous slc4a1 mutation in two lao families. Journal of Korean Medical Science. 2018, 33(13):e95. PubMed ID: 29573245
   
   

   The mutational analyses report that all three patients with autosomal recessive (AR) dRTA carry the same homozygous SLC4A1 mutation, p.Gly701Asp.

2. Zhang Z., et al. Identification of two novel mutations in the SLC4A1 gene in two unrelated Chinese families with distal renal tubular acidosis. Archives of Medical Research. 2012, 43(4):298-304. PubMed ID: 22609520
   
   

   The results confirm that the C-terminal residues of the SLC4A1 protein play an important role in normal acidification processes and mutations in this region are inclined to result in autosomal dominant distal renal tubular acidosis.

3. Kager L., et al. Band 3 nullVIENNA, a novel homozygous SLC4A1 p.Ser477X variant causing severe hemolytic anemia, dyserythropoiesis and complete distal renal tubular acidosis. Pediatric Blood & Cancer. 2017, 64(3). PubMed ID: 27718309
   
   

   The article describes a novel nonsense mutation c.1430C>A (p.Ser477X) in exon 12 of SLC4A1 that is associated with severe hemolytic anemia, dyserythropoiesis and complete distal renal tubular acidosis.

4. Palazzo V., et al. The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis. Kidney International. 2017, 91(5):1243-1255. PubMed ID: 28233610
   
   

   The aim of this work is to analyze the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and to assess the clinical phenotype of distal renal tubular acidosis patients that are eventually typical of the different genetic forms of the disease.

5. Shiozaki A., et al. Expression and role of anion exchanger 1 in esophageal squamous cell carcinoma. Oncotarget. 2017, 8(11):17921-17935. PubMed ID: 28160546
   
   

   The results of the present study suggest that the diffuse expression of AE1 is related to a worse prognosis in patients with advanced esophageal squamous cell carcinoma and that it regulates tumor progression by affecting MAPK and Hedgehog signaling pathways.

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Reference

1. Cooling L. (2015). Blood groups in infection and host susceptibility. Clinical Microbiology Reviews. 28(3): 801-870.

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