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4. MRP1) Transporter Contains Multiple Amino Acids Essential for Its Expression

Author

Conseil, Gwenaëlle and Cole, Susan P. C.

Subjects
organic anion transport, structure-guided mutagenesis, cytoplasmic loop, MRP1, ABC transporter, multidrug resistance protein, site-directed mutagenesis, protein expression
Abstract

ABCC1 (human multidrug resistance protein 1 (hMRP1)) is an ATP-binding cassette transporter which effluxes xeno- and endobiotic organic anions and confers multidrug resistance through active drug efflux. The 17 transmembrane α-helices of hMRP1 are distributed among three membrane spanning domains (MSD0, 1, 2) with MSD1,2 each followed by a nucleotide binding domain to form the 4-domain core structure. Eight conserved residues in the first cytoplasmic loop (CL4) of MSD1 in the descending α-helix (Gly392, Tyr404, Arg405), the perpendicular coupling helix (Asn412, Arg415, Lys416), and the ascending α-helix (Glu422, Phe434) were targeted for mutagenesis. Mutants with both alanine and same charge substitutions of the coupling helix residues were expressed in HEK cells at wild-type hMRP1 levels and their transport activity was only moderately compromised. In contrast, mutants of the flanking amino acids (G392I, Y404A, R405A/K, E422A/D, and F434Y) were very poorly expressed although Y404F, E422D, and F434A were readily expressed and transport competent. Modeling analyses indicated that Glu422 and Arg615 could form an ion pair that might stabilize transporter expression. However, this was not supported by exchange mutations E422R/R615E which failed to improve hMRP1 levels. Additional structures accompanied by rigorous biochemical validations are needed to better understand the bonding interactions crucial for stable hMRP1 expression.

Published
2021
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6. Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model

Author

Szeri, Flóra, Corradi, Valentina, Niaziorimi, Fatemeh, Donnelly, Sylvia, Conseil, Gwenaëlle, Cole, Susan P C, Tieleman, D Peter, van de Wetering, Koen, Szeri, Flóra, Corradi, Valentina, Niaziorimi, Fatemeh, Donnelly, Sylvia, Conseil, Gwenaëlle, Cole, Susan P C, Tieleman, D Peter, and van de Wetering, Koen

Abstract

Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization inhibitor. Although ABCC6 is firmly linked to cellular ATP release, the molecular details of ABCC6-mediated ATP release remain elusive. Most of the currently available data support the hypothesis that ABCC6 is an ATP-dependent ATP efflux pump, an un-precedented function for an ABC transporter. This hypothesis implies the presence of an ATP-binding site in the substrate-binding cavity of ABCC6. We performed an extensive mutagenesis study using a new homology model based on recently published structures of its close homolog, bovine Abcc1, to characterize the substrate-binding cavity of ABCC6. Leukotriene C4 (LTC4), is a high-affinity substrate of ABCC1. We mutagenized fourteen amino acid residues in the rat ortholog of ABCC6, rAbcc6, that corresponded to the residues in ABCC1 found in the LTC4 binding cavity. Our functional characterization revealed that most of the amino acids in rAbcc6 corresponding to those found in the LTC4 binding pocket in bovine Abcc1 are not critical for ATP efflux. We conclude that the putative ATP binding site in the substrate-binding cavity of ABCC6/rAbcc6 is distinct from the bovine Abcc1 LTC4-binding site.

Published
2021

20. The Epstein—Barr Virus-Hybridoma Technique

Author

Roder, John C., Cole, Susan P. C., Atlaw, Tsehay, Campling, Barbara G., McGarry, Ronald C., Kozbor, Danuta, Engleman, Edgar G., editor, Foung, Steven K. H., editor, Larrick, James W., editor, and Raubitschek, Andrew A., editor

Published
1985
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22. Transmembrane Helix 11 of multidrug resistance protein 1 (MRP1/ABCC1): identification of Polar Amino acids important for substrate specificity and binding of ATP at Nucleotide binding domain 1

Author

Zhang, Da Wei, Nunoya, Kenichi, Vasa, Monika, Hong Mei, Gu, Theis, Ashley, Cole, Susan P. C., and Deeley, Roger G.

Subjects
Binding proteins -- Analysis, Amino acids -- Chemical properties, Chemistry, Analytic, Biological sciences, Chemistry
Abstract

The role of polar residues within and near transmembrane (TM) 11 of multidrug resistance protein 1 (MRP1), in determining the substrate specificity and/or overall reactivity of the protein, is investigated. The requirement of an amino acid with side-chain hydrogen binding potential at position 590 in TM11 for efficient binding of ATP to nucleotide binding domain 1 (NBD1) is shown.

Published
2004

23. Characterization of the role of polar amino acid residues within predicted transmembrane helix 17 in determining the substrate specificity of multidrug resistance protein 3

Author

Zhang, Da-Wei, Gu, Hong-Mei, Vasa, Monika, Muredda, Mario, Cole, Susan P. C., and Deeley, Roger G.

Subjects
Hydrogen bonding -- Physiological aspects, Drug resistance -- Causes of, Membrane proteins -- Physiological aspects, Amino acids -- Physiological aspects, Biochemistry -- Research, Biological sciences, Chemistry
Abstract

Research has been conducted on human multidrug resistance protein 3. The authors have investigated the role of hydrogen-bonding potential of the residues in transmembrane 17 of this protein in substrate specificity and activity, and they report the results.

Published
2003

28. A Review of the Structure, Preparation, and Application of NLCs, PNPs, and PLNs.

Author

Qianwen Li, Tiange Cai, Yinghong Huang, Xi Xia, Cole, Susan P. C., and Yu Cai

Subjects
DRUG stability, POLYMERS, NANOPARTICLES
Abstract

Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the characteristics of the SLN, improve drug stability and loading capacity, and prevent drug leakage. Polymer nanoparticles (PNPs) are an important component of drug delivery. These nanoparticles can effectively direct drug delivery to specific targets and improve drug stability and controlled drug release. Lipid-polymer nanoparticles (PLNs), a new type of carrier that combines liposomes and polymers, have been employed in recent years. These nanoparticles possess the complementary advantages of PNPs and liposomes. A PLN is composed of a core-shell structure; the polymer core provides a stable structure, and the phospholipid shell offers good biocompatibility. As such, the two components increase the drug encapsulation efficiency rate, facilitate surface modification, and prevent leakage of water-soluble drugs. Hence, we have reviewed the current state of development for the NLCs', PNPs', and PLNs' structures, preparation, and applications over the past five years, to provide the basis for further study on a controlled release drug delivery system. [ABSTRACT FROM AUTHOR]

Published
2017
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29. Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport

Author

Jin, Daqing, primary, Ni, Terri T., additional, Sun, Jianjian, additional, Wan, Haiyan, additional, Amack, Jeffrey D., additional, Yu, Guangju, additional, Fleming, Jonathan, additional, Chiang, Chin, additional, Li, Wenyan, additional, Papierniak, Anna, additional, Cheepala, Satish, additional, Conseil, Gwenaëlle, additional, Cole, Susan P. C., additional, Zhou, Bin, additional, Drummond, Iain A., additional, Schuetz, John D., additional, Malicki, Jarema, additional, and Zhong, Tao P., additional

Published
2014
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31. Applications of nanoparticle drug delivery systems for the reversal of multidrug resistance in cancer (Review).

Author

YINGHONG HUANG, COLE, SUSAN P. C., TIANGE CAI, and YU CAI

Subjects
*MULTIDRUG resistance, *CANCER chemotherapy, *CANCER patients, *CANCER treatment, *LIPOSOMES, *MESOPOROUS silica, *SAFETY
Abstract

Multidrug resistance (MDR) to chemotherapy presents a major obstacle in the treatment of cancer patients, which directly affects the clinical success rate of cancer therapy. Current research aims to improve the efficiency of chemotherapy, whilst reducing toxicity to prolong the lives of cancer patients. As with good biocompatibility, high stability and drug release targeting properties, nanodrug delivery systems alter the mechanism by which drugs function to reverse MDR, via passive or active targeting, increasing drug accumulation in the tumor tissue or reducing drug elimination. Given the potential role of nanodrug delivery systems used in multidrug resistance, the present study summarizes the current knowledge on the properties of liposomes, lipid nanoparticles, polymeric micelles and mesoporous silica nanoparticles, together with their underlying mechanisms. The current review aims to provide a reliable basis and useful information for the development of new treatment strategies of multidrug resistance reversal using nanodrug delivery systems. [ABSTRACT FROM AUTHOR]

Published
2016
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32. Chalcogenopyrylium Compounds as Modulators of the ATP-Binding Cassette Transporters P-Glycoprotein (P-gp/ABCB1) and Multidrug Resistance Protein 1 (MRP1/ABCC1)

Author

Ebert, Sean P., primary, Wetzel, Bryan, additional, Myette, Robert L., additional, Conseil, Gwenaëlle, additional, Cole, Susan P. C., additional, Sawada, Geri A., additional, Loo, Tip W., additional, Bartlett, M. Claire, additional, Clarke, David M., additional, and Detty, Michael R., additional

Published
2012
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