SLC46A1 Membrane Protein Introduction

Introduction of SLC46A1

SLC46A1, also known as proton-coupled folate transporter (PCFT), is an integral membrane protein which belongs to the CTL (choline transporter-like) family. It is encoded by SLC46A1 gene and has 459 acid amino acid residues. Topological analyses predict PCFT protein possesses 12 transmembrane helices, 7 cytoplasmic domains with the N-and C-termini location, and 6 extracellular domains. SLC46A1 is highly expressed in kidney, liver, placenta, small intestine, spleen, retina, and retinal pigment epithelium.

Function of SLC46A1 Membrane Protein

SLC46A1 is a transmembrane proton-coupled folate transporter protein that plays a role in folate transport across cell membranes, optimally in acidic pH environments. It is highly expressed in the apical membrane or cytoplasm of intestinal cells and mediates the folate absorption from the intestinal lumen. It is also expressed in the choroid plexus where it moves folates into the cerebrospinal fluid. Loss of PCFT function may lead to the autosomal recessive hereditary folate malabsorption disease, resulting in a syndrome characterized by severe systemic and cerebral folate deficiency. Moreover, SLC46A1 SNPs also have been associated with the risk of neural tube defects and oral clefts induced by folate deficiency. In addition, PCFT protein also acts as a heme transporter in duodenal enterocytes which regulates heme uptake from the gut lumen into duodenal epithelial cells. Mutations in mice SLC46A1 gene increase the levels of homocysteine and display severe hematopoietic deficits.

Fig.1 PCFT topology. (Zhao, 2017)

Application of SLC46A1 Membrane Protein in Literature

1. Vandermeer J.E., et al. Evaluation of proton-coupled folate transporter (SLC46A1) polymorphisms as risk factors for neural tube defects and oral clefts. American Journal of Medical Genetics Part A. 2016, 170A(4):1007-16. PubMed ID: 26789141
   
   

   In this study, authors find nominally significant correlations between SLC46A1 SNPs and neural tube defects and oral clefts. But the results are still required to verify in other populations.

2. Aluri S., et al. Hereditary folate malabsorption due to a mutation in the external gate of the proton-coupled folate transporter SLC46A1. Blood Adv. 2018, 2(1):61-68. PubMed ID: 29344585
   
   

   The article demonstrates the N411K mutant in the external gate of the proton-coupled folate transporter SLC46A1 is associated with hereditary folate malabsorption.

3. Aluri S., et al. Residues in the eighth transmembrane domain of the proton-coupled folate transporter (SLC46A1) play an important role in defining the aqueous translocation pathway and in folate substrate binding. Biochim Biophys Acta. 2017, 1859(11):2193-2202. PubMed ID: 28802835
   
   

   The study indicates a very important role of the 8th transmembrane helix of SLC46A1 in defining the aqueous channel and the folate binding pocket.

4. Zhao R., et al. The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption. Molecular Aspects of Medicine. 2017, 53:57-72. PubMed ID: 27664775
   
   

   In this review, authors describe the functional and structural properties as well as regulation of SLC46A1 and contrast SLC46A1 properties with those of the reduced folate carrier (RFC).

5. Odin E., et al. Expression of folate pathway genes in stage iii colorectal cancer correlates with recurrence status following adjuvant bolus 5-FU-based chemotherapy. Molecular Medicine. 2015, 21(1):597-604. PubMed ID: 26193446
   
   

   The study implicates that the high expression of SLC46A1 and SLC19A1 are related to a decreased risk of recurrent colorectal cancer.

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Reference

1. Zhao R, et al. (2017). The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption. Molecular Aspects of Medicine. 53: 57-72.

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