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SLC28A3 Membrane Protein Introduction

Introduction of SLC28A3

SLC28A3 is encoded by CNT3 or SLC28A3 gene and is also known as Solute carrier family 28 member 3 (SLC28A3), Concentrative Na+-nucleoside cotransporter 3 (hCNT3). It belongs to the concentrative nucleoside transporters (CNTs) family, which mediate the salvage of nucleosides and the transport of therapeutic nucleoside analogs across plasma membranes by coupling the transport of ligands to the sodium gradient. The comparative structure model of the hCNT3 using the structure of vcCNT as a template reveals that hCNT3 possesses 13 helices.

Basic Information of SLC28A3
Protein Name Solute carrier family 28 member 3
Gene Name SLC28A3
Aliases Solute carrier family 28 member 3 (SLC28A3), Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)
Organism Homo sapiens (Human)
UniProt ID Q9HAS3
Transmembrane Times 13
Length (aa) 691
Sequence MELRSTAAPRAEGYSNVGFQNEENFLENENTSGNNSIRSRAVQSREHTNTKQDEEQVTVEQDSPRNREHMEDDDEEMQQKGCLERRYDTVCGFCRKHKTTLRHIIWGILLAGYLVMVISACVLNFHRALPLFVITVAAIFFVVWDHLMAKYEHRIDEMLSPGRRLLNSHWFWLKWVIWSSLVLAVIFWLAFDTAKLGQQQLVSFGGLIMYIVLLFLFSKYPTRVYWRPVLWGIGLQFLLGLLILRTDPGFIAFDWLGRQVQTFLEYTDAGASFVFGEKYKDHFFAFKVLPIVVFFSTVMSMLYYLGLMQWIIRKVGWIMLVTTGSSPIESVVASGNIFVGQTESPLLVRPYLPYITKSELHAIMTAGFSTIAGSVLGAYISFGVPSSHLLTASVMSAPASLAAAKLFWPETEKPKITLKNAMKMESGDSGNLLEAATQGASSSISLVANIAVNLIAFLALLSFMNSALSWFGNMFDYPQLSFELICSYIFMPFSFMMGVEWQDSFMVARLIGYKTFFNEFVAYEHLSKWIHLRKEGGPKFVNGVQQYISIRSEIIATYALCGFANIGSLGIVIGGLTSMAPSRKRDIASGAVRALIAGTVACFMTACIAGILSSTPVDINCHHVLENAFNSTFPGNTTKVIACCQSLLSSTVAKGPGEVIPGGNHSLYSLKGCCTLLNPSTFNCNGISNTF

Function of SLC28A3 Membrane Protein

Of the three human members of the SLC28 family, SLC28A3 is characterized by the broadest tissue distribution and substrate specificity. High levels of SLC28A3 have been found in the pancreas, bone marrow, and mammary gland; lower levels have been found in the intestine, lung, prostrate, testis, and liver. SLC28A3 is a symporter that couples the transport of one nucleoside to the symport of two Na+ ions or one proton. Its pharmacological importance stems from its ability to transport a wide variety of nucleoside-derived drugs, including first-line therapeutic agents for viral infections, such as valacyclovir, or solid tumors, such as gemcitabine. As such, it is an important mediator of drug response and resistance to anticancer nucleoside analogs. For example, elevated SLC28A3 expression levels in chronic lymphocytic leukemia (CLL) are associated with lower complete response rate to fludarabine therapy. In addition, in pancreatic cancer, some uncharacterized SLC28A3 polymorphisms, such as the nonsynonymous A25G mutation, have been associated with gemcitabine toxicity.

Comparative structure model of SLC28A3 Fig.1 Comparative structure model of SLC28A3 (Stecula, 2017).

Application of SLC28A3 Membrane Protein in Literature

  1. Stecula A., et al. Human Concentrative Nucleoside Transporter 3 (hCNT3, SLC28A3) Forms a Cyclic Homotrimer. Biochemistry. 2017, 56(27):3475-3483. PubMed ID: 28661652

    Authors in this article successfully express and purify the wild type human homologue, SLC28A3, demonstrating the homotrimer by size exclusion profiles and glutaraldehyde cross-linking. Meanwhile, comparative modeling of the trimerization domain and sequence coevolution analysis both indicate that oligomerization is critical to the stability and function of SLC28A3.

  2. Gorraitz E., et al. Effects of Na+ and H+ on steady-state and presteady-state currents of the human concentrative nucleoside transporter 3 (hCNT3). Pflügers Archiv - European Journal of Physiology. 2010, 460(3):617-632. PubMed ID: 20495821

    Authors in this article employ the two-electrode voltage clamp technique to compare the steady-state and presteady-state kinetics of SLC28A3 in the presence of Na+ and H+ to reveal that apparent affinity of SLC28A3 for uridine in H+ was insensitive to membrane voltage at negative potentials and decreased with depolarization.

  3. Errasti-Murugarren E., et al. (2007) Role of CNT3 in the transepithelial flux of nucleosides and nucleoside-derived drugs. The Journal of Physiology. 2007, 582(Pt 3):1249-1260. PubMed ID: 17412768

    The results of this article underline a critical role of SLC28A3 in the renal reabsorption of nucleosides and their derivatives as well as in their intracellular metabolism.

  4. Slugoski M.D., et al. A Conformationally Mobile Cysteine Residue (Cys-561) Modulates Na+ and H+ Activation of Human CNT3. The Journal of Biological Chemistry. 2008, 283(36):24922-24934. PubMed ID: 18621735

    The present investigation of this article validates a cysteine-less version of SLC28A3 as a template for substituted cysteine accessibility method studies of CNTs and reveals a pivotal functional role for Cys-561 in Na+- as well as H+-coupled modes of SLC28A3 nucleoside transport.

  5. Godoy V., et al. Functional crosstalk between the adenosine transporter CNT3 and purinergic receptors in the biliary epithelia. Journal of Hepatology. 2014, 61(6):1337-1343. PubMed ID: 25034758

    This article suggests the regulation exerted by A2A on SLC28A3 was dependent upon the cAMP/PKA/ERK/CREB axis, intracellular trafficking mechanisms and AMPK phosphorylation. Secretin increased the activity of the apically-located SLC28A3 and promoted additional basolateral SLC28A3-related activity.

SLC28A3 Preparation Options

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Reference

  1. Stecula A., et al. (2017) Human Concentrative Nucleoside Transporter 3 (hCNT3, SLC28A3) Forms a Cyclic Homotrimer. Biochemistry. 56(27):3475-3483.

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