Stabilization of Human Multidrug Resistance Protein 4 (MRP4/ABCC4) Using Novel Solubilization Agents

SLAS Discovery
David HardyAnass Jawhari

Abstract

Membrane proteins (MPs) are important drug discovery targets for a wide range of diseases. However, elucidating the structure and function of native MP is notoriously challenging as their original structure has to be maintained once removed from the lipid bilayer. Conventionally, detergents have been used to solubilize MP with varying degrees of success concerning MP stability. To try to address this, new, more stabilizing agents have been developed, such as calixarene-based detergents and styrene-maleic acid (SMA) copolymer. Calixarene-based detergents exhibit enhanced solubilizing and stabilizing properties compared with conventional detergents, whereas SMA is able to extract MPs with their surrounding lipids, forming a nanodisc structure. Here we report a comparative study using classical detergents, calixarene-based detergents, and SMA to assess the solubilization and stabilization of the human ABC transporter MRP4 (multidrug resistance protein 4/ABCC4). We show that both SMA and calixarene-based detergents have a higher solubility efficiency (at least 80%) than conventional detergents, and show striking overstabilization features of MRP4 (up to 70 °C) with at least 30 °C stability improvement in comparison with the best co...Continue Reading

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Citations

Nov 21, 2019·SLAS Discovery·Veli-Pekka Jaakola, Mariafrancesca Scalise
Feb 18, 2020·Methods : a Companion to Methods in Enzymology·Clarisse FaugierAnass Jawhari
Jun 11, 2021·Biochemical Society Transactions·Lucas UngerAlice J Rothnie

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Methods Mentioned

BETA
SMA
electron microscopy
dot blot
electrophoresis
Thermal
thermal shift
affinity
circular dichroism

Software Mentioned

Image Studio
GraphPad Prism
ImageJ

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