Cholesterol fillin model mechanism for substrate

Authors: Yasuhisa Kimura Atsushi Kodan Michinori Matsuo Kazumitsu Ueda

Publish Date: 2007/10/23

Volume: 39, Issue: 5-6, Pages: 447-452

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Abstract

Many of the 48 or 49 human ABC proteins are involved in lipid homeostasis and in defence against hydrophobic substances in food and the environment Defects in their functions cause various diseases suggesting that they play very important roles in human health however the mechanism of how they handle enormous numbers of hydrophobic compounds with various structures and molecular weights or phospholipids and cholesterol major components of cellular membranes is not known We compared the functions of drugtransporting and lipidtransporting ABC proteins and found that 1 ABC proteins either lipid or drug transporters have a similar substrate binding site which recognizes PL and cholesterol or drugs and cholesterol 2 Cholesterol in membranes binds to various ABC proteins together with PL or drugs and plays an important role in substrate recognition especially by ABCB1/MDR1 where cholesterol fills the empty space in the substrate binding site when small drugs bind to it ABC proteins exert very flexible substrate recognition ie onetomany interaction rather than the conventional rigid onetoone interaction We propose calling the mechanism the “cholesterol fillin model”

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