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Anionic Polymerization of an Amphiphilic Copolymer for Preparation of Block Copolymer Micelles Stabilized by π-π Stacking Interactions
Published on: October 10, 2016
Exploring the P-glycoprotein binding cavity with polyoxyethylene alkyl ethers.
Xiaochun Li-Blatter1, Anna Seelig
1Biozentrum, University of Basel, Basel, Switzerland.
Biophysical Journal
|November 30, 2010
Summary
P-glycoprotein (ABCB1) binding of allocrits to its cavity is purely electrostatic, not hydrophobic. This interaction, crucial for flipping, involves polar allocrit parts binding electrostatically while hydrophobic parts associate with the lipid membrane.
Area of Science:
- Biochemistry
- Molecular Biology
- Membrane Transport
Background:
- P-glycoprotein (ABCB1) is an efflux pump that transports substrates (allocrits) from the cytosol to the extracellular space.
- Allocrit binding to the P-glycoprotein cavity is understood to involve lipid-water partitioning and subsequent binding within the membrane.
- The role of hydrophobic interactions in allocrit binding to the P-glycoprotein cavity remained unclear.
Purpose of the Study:
- To investigate the contribution of hydrophobic interactions to allocrit binding within the P-glycoprotein cavity.
- To elucidate the specific roles of different allocrit structural features in P-glycoprotein-mediated transport.
Main Methods:
- Utilized isothermal titration calorimetry (ITC) to analyze lipid-water partitioning of model allocrits.
- Employed ATPase activity measurements to assess allocrit binding to the P-glycoprotein cavity.
- Synthesized and tested polyoxyethylene alkyl ethers (C(m)EO(n)) with varying methylene and ethoxyl residues as model allocrits.
Main Results:
- Lipid-water partitioning of C(m)EO(n) was found to be purely hydrophobic, increasing with methylene and decreasing with ethoxyl residues.
- Allocrit binding to the P-glycoprotein cavity required a minimum of two ethoxyl residues and increased with their number.
- Direct evidence indicates that allocrit binding to the cavity is electrostatic, with no apparent hydrophobic contribution.
Conclusions:
- The binding of allocrits to the P-glycoprotein cavity is primarily driven by electrostatic interactions involving the polar residues of the allocrit.
- The hydrophobic portions of allocrits remain associated with the surrounding lipid membrane during the binding process.
- The synergistic interplay between electrostatic and hydrophobic interactions is critical for the function of P-glycoprotein in allocrit flipping.
