ABCC4 Membrane Protein Introduction

Introduction of ABCC4

ABCC4, also known as canalicular multi-specific organic anion transporter (ABC Superfamily), BA464I2.1 (ATP-binding cassette, subfamily C (CFTR/MRP), member 4), MRP4, or MOATB, is an approximately 150 kDa transmembrane protein that participates in the export of proinflammatory factors. In humans, it is encoded by the ABCC4 gene which resides on the chromosome 13q32.1. ABCC3 consists of 1325 amino acids and belongs to the family of ATP-binding cassette transporters. This protein is ubiquitously expressed, particularly with high expressions in blood cells and hematopoietic stem cells. ABCC4 is a highly polymorphic gene, but there is limited information on functions of its variants showing available. These variants are related to various diseases, while no report has manifested a correlation between ABCC4 and immunological diseases.

Function of ABCC4 Membrane Protein

ABCC4 as a transmembrane protein implicated in the transport of substrates out of cells. It serves as an independent regulator of intracellular cyclic nucleotide levels as well as a mediator of cAMP-dependent signal transduction to the nucleus. Specifically, ABCC4 is required for the active transport of numerous bioactive substrates across the cell membrane. This molecular can pump varieties of substrates, involving eicosanoids, steroids, cyclic nucleotides, bile salts, and several drugs, out of the cell to control multiple signal pathways within cells, such as cancer, inflammation, platelet function, endothelial barrier function, vasodilation, vascular smooth muscle cell proliferation, and vascular smooth muscle cell proliferation. Recently, it is reported that ABCC4 is transcriptionally regulated by MYCN, a driver of neuroblastoma oncogenesis and a poor prognostic factor. High mRNA expression of ABCC4 has a strong capability to predict poor clinical outcome across numerous patient cohorts.

Fig.1 Structure of MRP4 (ABCC4) consisting of 2 clusters of 6 membrane-spanning segments and 2 regions containing nucleotide binding domains (NBDs). (Jedlitschky, 2012)

Application of ABCC4 Membrane Protein in Literature

1. Chantemargue B., et al. Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms. Pharmacol Res. 2018, 133: 318-327. PubMed ID: 29530601
   
   

   Authors constructed a model of the WT (wild type) MRP4 and p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds via molecular dynamics simulations. The molecular structure of WT MRP4 confirmed and improved the general knowledge about transmembrane helices and two nucleotide binding domains.

2. Vogt K., et al. Release of platelet-derived sphingosine-1-phosphate involves multidrug resistance protein 4 (MRP4/ABCC4) and is inhibited by statins. Thromb Haemost. 2018, 118(1): 132-142. PubMed ID: 29304533
   
   

   This paper determined the involvement of MRP4 in the S1P transport and a potential interference by statins. Transport studies in membrane vesicles of Sf9 cells recombinant human MRP4 demonstrated that MRP4 can mediate ATP-dependent transport of tritium- and fluorescein-labeled S1P.

3. Tanaka Y., et al. Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia. Pharmacogenomics J. 2018, 18(2): 275-280. PubMed ID: 28418010
   
   

   It was known that 6-Mercaptopurine (6-MP) was one of the main constituent of childhood acute lymphoblastic leukemia (ALL) treatment. The data in this study figured that ABCC4 and NUDT15 were main factors for 6-MP intolerability and interactions between these variants enhanced the intolerability to 6-MP.

4. Murray J, et al. Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo. Eur J Cancer. 2017, 83: 132-141. PubMed ID: 28735070
   
   

   The findings indicated a role for ABCC4 in the proliferation and chemoresistance of neuroblastoma cells and provided a rationale for a strategy where the inhibition of ABCC4 should attenuate the neuroblastoma growth and sensitize tumors to ABCC4 chemotherapeutic substrates.

5. Tanaka Y. Susceptibility to 6-mercaptopurine toxicity related with NUDT15 and ABCC4 variants in Japanese childhood acute lymphoblastic leukemia. Rinsho Ketsueki. 2017, 58(8): 950-956. PubMed ID: 28883280
   
   

   The review concluded that genotyping ABCC4 and NUDT15 promoted the prediction of 6-MP intolerability. The results of this study would facilitate the research in personalized medicines with Japanese patients who suffered from the childhood acute lymphoblastic leukemia (ALL).

ABCC4 Preparation Options

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Reference

1. Jedlitschky G, et al. (2012). Transporters in human platelets: physiologic function and impact for pharmacotherapy. Blood. 119(15), 3394-3402.

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