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Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking

BACKGROUND: Multidrug resistance-associated protein 4 (MRP4) is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC) transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host’s b...

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Autores principales: Dai, Fuhong, Yoo, Won Gi, Lee, Ji-Yun, Lu, Yanyan, Pak, Jhang Ho, Sohn, Woon-Mok, Hong, Sung-Jong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697364/
https://www.ncbi.nlm.nih.gov/pubmed/29157307
http://dx.doi.org/10.1186/s13071-017-2523-8
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author Dai, Fuhong
Yoo, Won Gi
Lee, Ji-Yun
Lu, Yanyan
Pak, Jhang Ho
Sohn, Woon-Mok
Hong, Sung-Jong
author_facet Dai, Fuhong
Yoo, Won Gi
Lee, Ji-Yun
Lu, Yanyan
Pak, Jhang Ho
Sohn, Woon-Mok
Hong, Sung-Jong
author_sort Dai, Fuhong
collection PubMed
description BACKGROUND: Multidrug resistance-associated protein 4 (MRP4) is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC) transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host’s bile duct, accumulation of bile juice can be toxic to the worm’s tissues and cells. Therefore, C. sinensis needs bile transporters to reduce accumulation of bile acids within its body. RESULTS: We cloned MRP4 (CsMRP4) from C. sinensis and obtained a cDNA encoding an open reading frame of 1469 amino acids. Phylogenetic analysis revealed that CsMRP4 belonged to the MRP/SUR/CFTR subfamily. A tertiary structure of CsMRP4 was generated by homology modeling based on multiple structures of MRP1 and P-glycoprotein. CsMRP4 had two membrane-spanning domains (MSD1 & 2) and two nucleotide-binding domains (NBD1 & 2) as common structural folds. Docking simulation with nine bile acids showed that CsMRP4 transports bile acids through the inner cavity. Moreover, it was found that CsMRP4 mRNA was more abundant in the metacercariae than in the adults. Mouse immune serum, generated against the CsMRP4-NBD1 (24.9 kDa) fragment, localized CsMRP4 mainly in mesenchymal tissues and oral and ventral suckers of the metacercariae and the adults. CONCLUSIONS: Our findings shed new light on MRPs and their homologs and provide a platform for further structural and functional investigations on the bile transporters and parasites’ survival. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13071-017-2523-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-56973642017-12-01 Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking Dai, Fuhong Yoo, Won Gi Lee, Ji-Yun Lu, Yanyan Pak, Jhang Ho Sohn, Woon-Mok Hong, Sung-Jong Parasit Vectors Research BACKGROUND: Multidrug resistance-associated protein 4 (MRP4) is a member of the C subfamily of the ABC family of ATP-binding cassette (ABC) transporters. MRP4 regulates ATP-dependent efflux of various organic anionic substrates and bile acids out of cells. Since Clonorchis sinensis lives in host’s bile duct, accumulation of bile juice can be toxic to the worm’s tissues and cells. Therefore, C. sinensis needs bile transporters to reduce accumulation of bile acids within its body. RESULTS: We cloned MRP4 (CsMRP4) from C. sinensis and obtained a cDNA encoding an open reading frame of 1469 amino acids. Phylogenetic analysis revealed that CsMRP4 belonged to the MRP/SUR/CFTR subfamily. A tertiary structure of CsMRP4 was generated by homology modeling based on multiple structures of MRP1 and P-glycoprotein. CsMRP4 had two membrane-spanning domains (MSD1 & 2) and two nucleotide-binding domains (NBD1 & 2) as common structural folds. Docking simulation with nine bile acids showed that CsMRP4 transports bile acids through the inner cavity. Moreover, it was found that CsMRP4 mRNA was more abundant in the metacercariae than in the adults. Mouse immune serum, generated against the CsMRP4-NBD1 (24.9 kDa) fragment, localized CsMRP4 mainly in mesenchymal tissues and oral and ventral suckers of the metacercariae and the adults. CONCLUSIONS: Our findings shed new light on MRPs and their homologs and provide a platform for further structural and functional investigations on the bile transporters and parasites’ survival. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13071-017-2523-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-11-21 /pmc/articles/PMC5697364/ /pubmed/29157307 http://dx.doi.org/10.1186/s13071-017-2523-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Dai, Fuhong
Yoo, Won Gi
Lee, Ji-Yun
Lu, Yanyan
Pak, Jhang Ho
Sohn, Woon-Mok
Hong, Sung-Jong
Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking
title Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking
title_full Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking
title_fullStr Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking
title_full_unstemmed Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking
title_short Multidrug resistance-associated protein 4 is a bile transporter of Clonorchis sinensis simulated by in silico docking
title_sort multidrug resistance-associated protein 4 is a bile transporter of clonorchis sinensis simulated by in silico docking
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697364/
https://www.ncbi.nlm.nih.gov/pubmed/29157307
http://dx.doi.org/10.1186/s13071-017-2523-8
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