Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)

Abstract Dynamic conformational changes play a major role in the function of proteins, including the ATP-Binding Cassette (ABC) transporters. Multidrug Resistance Protein 1 (MRP1) is an ABC exporter that protects cells from toxic molecules. Overexpression of MRP1 has been shown to confer Multidrug R...

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Autores principales:	Yuval Bin Kanner, Assaf Ganoth, Yossi Tsfadia
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9f35ae1891a940d4b2412cba4c56df47
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spelling	oai:doaj.org-article:9f35ae1891a940d4b2412cba4c56df472021-12-02T17:34:48ZExtracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)10.1038/s41598-021-91461-32045-2322https://doaj.org/article/9f35ae1891a940d4b2412cba4c56df472021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91461-3https://doaj.org/toc/2045-2322Abstract Dynamic conformational changes play a major role in the function of proteins, including the ATP-Binding Cassette (ABC) transporters. Multidrug Resistance Protein 1 (MRP1) is an ABC exporter that protects cells from toxic molecules. Overexpression of MRP1 has been shown to confer Multidrug Resistance (MDR), a phenomenon in which cancer cells are capable to defend themselves against a broad variety of drugs. In this study, we used varied computational techniques to explore the unique F583A mutation that is known to essentially lock the transporter in a low-affinity solute binding state. We demonstrate how macro-scale conformational changes affect MRP1’s stability and dynamics, and how these changes correspond to micro-scale structural perturbations in helices 10–11 and the nucleotide-binding domains (NBDs) of the protein in regions known to be crucial for its ATPase activity. We demonstrate how a single substitution of an outward-facing aromatic amino acid causes a long-range allosteric effect that propagates across the membrane, ranging from the extracellular ECL5 loop to the cytoplasmic NBD2 over a distance of nearly 75 Å, leaving the protein in a non-functional state, and provide the putative allosteric pathway. The identified allosteric structural pathway is not only in agreement with experimental data but enhances our mechanical understanding of MRP1, thereby facilitating the rational design of chemosensitizers toward the success of chemotherapy treatments.Yuval Bin KannerAssaf GanothYossi TsfadiaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuval Bin Kanner Assaf Ganoth Yossi Tsfadia Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)
description	Abstract Dynamic conformational changes play a major role in the function of proteins, including the ATP-Binding Cassette (ABC) transporters. Multidrug Resistance Protein 1 (MRP1) is an ABC exporter that protects cells from toxic molecules. Overexpression of MRP1 has been shown to confer Multidrug Resistance (MDR), a phenomenon in which cancer cells are capable to defend themselves against a broad variety of drugs. In this study, we used varied computational techniques to explore the unique F583A mutation that is known to essentially lock the transporter in a low-affinity solute binding state. We demonstrate how macro-scale conformational changes affect MRP1’s stability and dynamics, and how these changes correspond to micro-scale structural perturbations in helices 10–11 and the nucleotide-binding domains (NBDs) of the protein in regions known to be crucial for its ATPase activity. We demonstrate how a single substitution of an outward-facing aromatic amino acid causes a long-range allosteric effect that propagates across the membrane, ranging from the extracellular ECL5 loop to the cytoplasmic NBD2 over a distance of nearly 75 Å, leaving the protein in a non-functional state, and provide the putative allosteric pathway. The identified allosteric structural pathway is not only in agreement with experimental data but enhances our mechanical understanding of MRP1, thereby facilitating the rational design of chemosensitizers toward the success of chemotherapy treatments.
format	article
author	Yuval Bin Kanner Assaf Ganoth Yossi Tsfadia
author_facet	Yuval Bin Kanner Assaf Ganoth Yossi Tsfadia
author_sort	Yuval Bin Kanner
title	Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)
title_short	Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)
title_full	Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)
title_fullStr	Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)
title_full_unstemmed	Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)
title_sort	extracellular mutation induces an allosteric effect across the membrane and hampers the activity of mrp1 (abcc1)
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9f35ae1891a940d4b2412cba4c56df47
work_keys_str_mv	AT yuvalbinkanner extracellularmutationinducesanallostericeffectacrossthemembraneandhamperstheactivityofmrp1abcc1 AT assafganoth extracellularmutationinducesanallostericeffectacrossthemembraneandhamperstheactivityofmrp1abcc1 AT yossitsfadia extracellularmutationinducesanallostericeffectacrossthemembraneandhamperstheactivityofmrp1abcc1
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Extracellular mutation induces an allosteric effect across the membrane and hampers the activity of MRP1 (ABCC1)

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